Role of the nervous system in cancer metastasis (Review)

  • Authors:
    • Sha Li
    • Yanlai Sun
    • Dongwei Gao
  • View Affiliations

  • Published online on: January 31, 2013     https://doi.org/10.3892/ol.2013.1168
  • Pages: 1101-1111
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

The notion that tumors lack innervation was proposed several years ago. However, nerve fibers are irregulatedly found in some tumor tissues. Their terminals interaction with cancer cells are considered to be neuro-neoplastic synapses. Moreover, neural-related factors, which are important players in the development and activity of the nervous system, have been found in cancer cells. Thus, they establish a direct connection between the nervous system and tumor cells. They modulate the process of metastasis, including degradation of base membranes, cancer cell invasion, migration, extravasation and colonization. Peripheral nerve invasion provides another pathway for the spread of cancer cells when blood and lymphatic metastases are absent, which is based on the interactions between the microenvironments of nerve fibers and tumor cells. The nervous system also modulates angiogenesis, the tumor microenvironment, bone marrow, immune functions and inflammatory pathways to influence metastases. Denervation of the tumor has been reported to enhance cancer metastasis. Stress, social isolation and other emotional factors may increase distant metastasis through releasing hormones from the brain, the hypothalamic-pituitary-adrenal axis and autonomic nervous system. Disruption of circadian rhythms will also promote cancer metastasis through direct and indirect actions of the nervous system. Therefore, the nervous system plays an important role in cancer metastasis.

Contents

Introduction

Search strategies and selection criteria

Connection, communication and interaction between the neural system and cancer cells

Nerve invasion is another route for cancer cell dissemination

The nervous system modulates angiogenesis and microenvironments in tumors to affect metastasis

Nervous system interacts with immune function and inflammation to influence cancer metastasis

Interactions between bone marrow and nervous system: implication for cancer metastasis

Cancer as an independent organ is being recognized and should not be isolated from the nervous system

Clinical and biological implications for the role of the nervous system in cancer metastasis

Conclusions

Introduction

Since the 1970s, it has been generally accepted in the field of pathology that tumors lack innervation (1). However, the nervous system is a superordinate structure in the body and controls the functions and activities of virtually all other tissues and organs. Cancer tissues are not isolated structures within organisms, therefore they should also interact with the neural system. This speculation has been testified from clinical, epidemiological and experimental studies.

One the one hand, neural functions and tissues exert important functions on cancer initiation and development. Firstly, psychological and behavioral factors, such as chronic stress, depression and social isolation, are considered to contribute to the initiation and progression of certain types of cancer (26). Stress is inevitable in human life. The brain is the key organ of the response to stress (7). In the whole brain, activation of the hypothalamic-pituitary-adrenal axis (HPA) plays an important role in the response (2,7). Thus, acting on certain areas in the brain has been reported to influence the growth and development of cancer (810). Secondly, the peripheral nervous system is also involved in cancer. 6-Hydroxydopamine was shown to influence the growth rate of certain tumors (11) and induce neuronal changes on the sympathetic nervous system to augment the growth of neuroblastoma (12), suggesting that an intact functional sympathetic nervous system is necessary for certain tumors. Peripheral nerve fibers were found to innervate some tumors (1316). Neurons of dorsal root ganglia interact with cancer cells (1719). Denervation of a tumor also alters the behavior of tumor growth (2022). Peripheral nerve invasion (PNI) induced by cancer is an independent factor for poor prognosis in some cancer patients (2326).

On the other hand, cancer also has remote effects on neural tissues (2729). These facts indicate that there is a bidirectional correlation between the nervous system and cancer and challenge the traditional view that cancers lack innervation. Therefore, the role of the nervous system in cancer is gaining attention in cancer research (5, 2931). Recently, the study by Sloan et al(32) study further showed that stress increases distant metastases but has little effect on primary tumor growth, prompting our interest in investigating the role of the nervous system in cancer metastasis.

It is well known that metastasis is the major cause of mortality from solid carcinomas. Despite great advances in metastasis research, the prognosis remains extremely poor. The formation of metastasis is a complex and sequential process, involving four basic steps: i) departure from the primary tumor, ii) survival in the circulatory system, iii) breaching of endothelium and basement membrane of target organs, and iv) establishment of a colony of metastatic cells (33). In these steps, immune functions, inflammation, organic microenvironments and bone marrow are involved (3440), all of which are directly or indirectly regulated by the nervous system. Thus, cancer metastasis may also establish connections with the nervous system through these pathophysiological changes and functional organs. Therefore, the nervous system may play an essential role in cancer metastasis. To gain a more comprehensive understanding of the role of the nervous system in cancer metastasis, we reviewed English-language literature on this topic and analyzed how the nervous system exerts its functions in cancer metastasis.

Search strategies and selection criteria

The literature-based review was conducted by searching for keywords in Pubmed and Google Scholar using the search terms: ‘cancer’, ‘tumor’, ‘neoplasm’, ‘malignant’, ‘metastasis’, ‘spread pathway’, ‘stress’, ‘depression’, ‘cancer-related neural disease’, ‘immune’, ‘inflammation’, ‘neuroendocrine’, ‘hypothalamic-pituitary-adrenal axis’, ‘innervation’, ‘nervous system’, ‘neurotransmitters’, ‘neurotrophic factors’, ‘semaphorins’, ‘psychoneuroimmunology’, ‘sympathetic’, ‘vagal’ and ‘vagus’. Only papers published in English prior to March 2012 and focusing on the association between the nervous system and cancer metastasis were included.

Connection, communication and interaction between the neural system and cancer cells

The nervous system is formed of the central and peripheral nervous systems, which modulate the functions of the whole body through two main methods. The first is that they have a direct connection through a specific structure of classical or non-classical synapses. The other is that they interact with each other through humoral modulations. If the two methods are also found in cancer, the connection between the nervous system and cancer will be established.

Classical and non-classical synapse structures are the elements by which neurons innervate other tissues. Several lines of evidence also support the existence of these anatomical structures in tumor tissues. Nerve fibers have been found in certain tumor tissues, which may be due to i) the possibility of nerve fiber innervation vessels in cancer tissues, ii) the persistence of pre-existing nerves, or nerves becoming included within the cancer owing to the invasive character of its growth, iii) nerve endings growing into cancer tissue, or iv) an integral part of the cancerous growth (41). The first possibility was excluded in the study by Mitchell et al(42). Although the second possibility exists and often leads to cancer pain, this type of nerve fiber is surrounded by cancer tissues and hardly exerts any function on cancer cells. The latter two were also observed in previous studies. Nerve fibers in central tumor areas were observed by Seifert et al(13,14,43) using a transmission electron microscope. These nerve fibers in tumor tissues were irregularly distributed and had abnormal morphologies, which indicated that occurrences of these abnormal nerve fibers were accompanied with tumor tissues but not the pre-existing nerve fibers in corresponding normal tissues (44). Experimental studies showed that rectal cancer cells stimulated neurogenesis when they were cocultured with neuroepithelial cells (18). Thus, denervation by resection, capsaicin or vagotomy slows tumor growth (2022) and promotes cancer progression and metastasis (4547). These facts indicate that neuro-neoplastic synapses may exist between nerve fibers and tumor cells (48,49), and that neurogenesis, like angiogenesis, is also a trait of cancer cells (18,48,50,51). Thus, in primary and pre-metastatic organs, cancer cells actively establish connections with nerve fibers and receive signals from the nervous system.

Although the above studies indicated that tumor tissues were innervated, others do not support this theory (42,52,53). However, humoral modulation is the alternative means for the neural system to modulate other organs, which is also found in cancer. The axes of the systems of the HPA and autonomic nervous system (ANS) are typical pathways of humoral modulation through releasing hormones and neurotransmitters to bind corresponding receptors in other tissues to modulate functions of various tissues, including cancer. Thus, making lesions in these areas have significant effects on the behavior of cancer growth and metastasis. For example, Pollak et al(54) showed that hypophysectomy inhibited metastatic behavior in murine osteosarcoma. Function of the pineal gland and effect of spatial disorientation had an important influence on metastasis (55). These effects were mainly via humoral modulators, including neurotransmitters and neuropeptides, neurotrophic factors, semaphorins and other axon growth factors. These modulators of neural development and maintainence have been found to exert essential functions in cancer growth and development, and have been studied and reviewed by numerous authors (5695). Cancer cells also express these molecules and their receptors. For example, breast cancer cells can express β-endorphin (96), and transplantation of β-endorphin neurons into the hypothalamus inhibit the growth and metastasis of mammary carcinoma (97). Cancer cells also promote neurite formation through generating neutrophic factors and axon growth molecules (98). Thus, they will establish a connection with the nervous system through humoral modulation.

Thus, the existence of neuro-neoplastic synapses and receptors of neural markers in cancer cells provides a substantial basis for communication between neurons and cancer cells. Recent studies have shown that the nervous system influences the process of cancer metastasis through nerve endings and humoral modulations (32,40,4447,58,67,7579,85,97,98). For cancer cells to form metastases in ectopic sites, they must depart from the primary tumor and conquer the barriers of primary tissue inhibition. Proteolytic enzymes can help tumor cells escape from primary cancer; i.e. by degrading the surrounding normal tissues. In this process, the overexpression of matrix metalloproteinases (MMPs) in tumor cells is one of the most sustained events (99,100); this may be induced by stress, neural-related factors and neurotransmitters. For example, Wu et al(101) reported that stress due to social isolation enhanced invasion and metastasis of colon cancer cells through increasing proteolytic proteases. Yang et al(102) also found that stress modulates levels of MMPs through activation of the HPA and sympathetic-adrenal medullary (SAM) axes. Heregulin-β1 and nerve growth factor, as essential factors in the normal development of the nervous system, mediate the activation of MMP-9 and MMP-2 to promote invasion of breast cancer cells (103) and pancreatic cancer cells (104,105). Neurotrophins also promote invasion by enhancing the production of basement membrane-degradative enzymes (106). Norepinephrine (NE) and γ-aminobutyric acid as classical neurotransmitters upregulate the expression of MMPs in nasopharyngeal cancer cells (107) and cancer cells of the prostate (108). Anoikis, a form of apoptosis, results from loss of cell-matrix interactions and acts as a physiological barrier to metastasis (109). Tropomyosin receptor kinase B (TrkB), a receptor of brain-derived neurotrophic factor (BDNF), induces cancer metastasis by suppression of anoikis (110112). Migration of cancer cells is a prerequisite for metastasis. Axon-guidance molecules, such as slits, semaphorins and netrins, can navigate or inhibit migration of cancer cells (77,85,113117). The neurotransmitter/receptor system is also involved in cancer cell migration (118). NE, a classical neurotransmitter, has a stimulatory effect on the migration of colon carcinoma cells (119) and breast cancer cells (120). A similar role was also reported for dopamine and neuropeptides, including met-enkephalin, substance P and bombesin (120). γ-aminobutyric acid as an inhibitory neurotransmitter in the brain inhibits the migratory activity of colon carcinoma cells (121). Although these substances are also expressed in other organs (122) and tumor cells, inhibition of the activity of corresponding neurons can reverse their effects on cancer cells. For example, β-blockers acting on the ANS inhibit the migration of cancer cells induced by NE (119). Chemokines exerting important effects on neurogenesis and brain development (123,124) are also important modulators of cancer metastasis (125127). In the process of cancer cell migration through the blood system, 99.9% of cancer cells are killed, which is called metastatic inefficiency (128). Mechanical forces including shear stress contribute to this inefficiency (129,130) while the shear force is mainly due to vasomotor changes. Nerve endings and receptors of neuropeptides are distributed in vascular walls (131). Based on the anatomical structures, the nervous system modulates the vascular functions, leading to changes in vascular dilation and constriction that can produce mechanical forces. Vascular permeability is important for cancer cell extravasation and colonization. Neuropeptides increase vascular permeability (132,133) to promote cancer cell extravasation and colonization. Thus, the process of cancer cell departure from the primary tumor, invasion, migration, cancer cell inefficiency, extravasation and colonization are associated with the nervous system.

Therefore, the connections between the neural system and cancer through synapse, non-synapse or humoral modulation make it possible to establish reciprocal interactions and communications between cancers and neurons.

Nerve invasion is another route for cancer cell dissemination

Tumor dissemination from primary cancer is the first step in the formation of metastatic tumors at distant sites. Three major routes are considered to be involved in the spread of tumor cells: lymphatic vessels, blood vessels and serosal surfaces (130). The route of cancer cells along nerve fibers has been a forgotten pathway (134). Recently, PNI has been found in certain types of malignancies and identified to be another pathway for cancer cell dissemination, particularly in the absence of lymphatic or hematogenous metastasis (26). Although PNI has not been considered as a routine test in pathological reports, it has been identified as a key pathological feature in tumors and is used to predict clinical outcomes in many cancers (18,2326,135143).

It remains unknown what drives cancer cells to migrate along nerve fibers. In addition, since PNI has been accepted as an emerging route for cancer cell dissemination, PNI requires further definition. For the past 40 years, the predominant theory regarding the pathogenesis of PNI is that distributed tumor cells have the privilege of a low-resistance plane in the neural sheaths, which serves as a conduit for their migration. However, recent studies have shown that reciprocal signaling interactions between tumor cells and nerves may contribute to PNI. To explore these interactions, it is necessary to clarify the process of neurite formation. It has been shown that neurotrophic factors (NGF) and axonal guidance molecules are vital for axonal growth (144149). These molecules and their corresponding receptors are also found in tumor cells (61,64,84,86,115), which provide the possibility for cancer cells to bind to the neurite (150). In addition, stromal cells, extracellular matrix and their releasing factors are also involved in the process of axonal formation (151), and are also important for tumor cell migration. Thus, these tumor cells spreading along neural fibers may acquire the ability to respond to proinvasive signals within the peripheral nerve milieu and become neurotrophic. It is known that nerve fibers are composed of three layers, the epineurium, perineurium and endoneurium, from the outside to the inside. According to the definition of Liebig et al, when tumor cells are found within any of the three layers of the nerve sheath or tumor foci outside of the nerve with involvement of 33% of the nerve's circumference, PNI may be diagnosed (26). This definition provides a new concept in the study of cancer cell dissemination.

The nervous system modulates angiogenesis and microenvironments in tumors and affects metastasis

Angiogenesis is vital for the development of metastasis (152154). Vascular endothelial growth factor (VEGF) plays an important role in the process of angiogenesis. Several reports have demonstrated that psychological factors influence tumor angiogenesis in certain types of cancer through regulating of VEGF level. Chronic stress is common in cancer patients and often causes depression and bad moods. It has been reported that chronic stress mediates the vascularization of intraperitoneal metastasis and enhances tumor angiogenesis in the xenograft models of ovarian cancer via increasing VEGF expression (155,156). SNS can be activated in stressed animals (155) and may release neurotransmitters. These neurotransmitters, such as NE, dopamine and bradykinin, have been reported to induce or suppress VEGF expression (132,158161). Thus, the possible mechanism for chronic stress to enhance tumor angiogenesis may be that neurotransmitters released by activated SNS regulate VEGF expression to promote angiogenesis, which is also applicable to social isolation. It was reported that a perceived lack of social isolation was associated with elevated intratumoral NE in ovarian carcinoma patients. The elevated NE levels were correlated with high grade and advanced stage tumor (162) and indicated metastasis, which may be due to that NE induce VEGF expression and thus lead to stimulate angiogenesis (158). Other neural-related factors also have important effects on tumor angiogenesis. Axon growth molecules such as neuropilins and semaphorins can promote or inhibit angiogenesis (63,86,163166). A neuropeptide, calcitonin gene-related peptide (CGRP), can facilitate tumor-associated angiogenesis (167). Although it is expressed by other tissues, this experiment testifies that it is derived from neuronal systems. Neuropeptide Y also promotes angiogenesis through regulation of VEGF (168). Circadian rhythm is a basic regulator of normal physiology. Its disruption can also accelerate tumor growth through a Wnt signaling pathway (169), a critical pathway to regulate angiogenesis (170,171). Thus, the neural system is capable of modulating the process of angiogenesis. Moreover, neurogenesis also exists as a trait of certain types of cancer. Cancer cells also express these neural-related factors and their receptors. In fact, there are common molecules between angiogenesis and neurogenesis (172174), indicating that they may occur in concert in tumors and collectively exert functions on cancer metastasis (175).

The microenvironment regulates not only the growth of primary cancer but also the formation of metastasis, which is formed mainly of stromal cells and signal molecules. On the one hand, these cells and molecules have a direct or indirect correlation with the nervous system (73). Within the tumor microenvironment, stromal cells express β-adrenergic receptors that may be activated by neurotransmitters from local sympathetic nerve fibers and circulating blood. Macrophages in tumor microenvironments are important players in cancer metastasis, and are the key targets of β-adrenergic regulation in several cancer contexts (73). Certain molecules produced and released by neural tissues are the important origins of signals in the tumor microenvironment (176). However, stromal and tumor cells produce neural-related factors to stimulate neurite formation, receive nervous signals and act on the nervous system. Thus, cancer cells are able to take advantage of the factors produced by the nerve fibers to generate a positive microenvironment for cell survival and proliferation in the primary site and secondary organ. Therefore, the microenvironments and neural system establish a feedback loop. They also collectively contribute to the growth of primary cancer and the secondary tumor.

Nervous system interacts with immune function and inflammation to influence cancer metastasis

The immune system has been identified to play a vital role in cancer metastasis (35,177,178). The association between the immune system and the nervous system has been widely studied and reviewed by many neurobiologists and immunologists (179,180). Several pathways are involved in the interaction between them. Among them, the neuroendocrine and neuronal pathways are the most significant, and are involved in the control of the humoral and cellular immune responses including the immunosuppressive effect, immunosurveillance and immunoenhancement. However, the immune system also influences the central nervous system. The bidirectional neural-immune interactions mainly occur through the neural and immune signal molecules including hormones, neurotransmitters, neuropeptides, cytokines or their receptors, all of which have been demonstrated to contribute to the process of metastasis (181183). Thus, the neural system modulates cancer metastasis through the immune system. For example, mood disorders, such as stress and depression, inhibit the immune system by decreasing cytotoxic T-cell and natural killer (NK) cells involved in innate immunity that can surveil for cancer metastasis (2). Therefore, stress enhances tumor metastasis via suppression of the immune system (184,185). It also has been identified that mood and relevant immunological status, along with important biological prognostic variables may contribute to the notable outcome variance in early-stage breast cancer (186). Circadian rhythm modulates the immune system by conveying timing information. Circadian disruption may lead to vulnerabilitys to infection and other diseases, including cancer (187,188). Therefore, the nervous system and its psychological or behavioral factors modulate metastasis through immune molecules, cells and effects (189).

The immune effect can induce an inflammatory response. However, unlike the association between the nervous system and immune system, the role of the nervous system in inflammation has only recently been described. It was also found that as well as controlling heart rate and other vital functions in real time, the nervous system reflexively regulates the inflammatory response (190,191). The vagus nerve, the arc of the reflex and neural-related factors such as netrin-1 and neuropeptides, are all involved in the control of inflammation (131,192200). Thus, the nervous system modulation of cancer development via inflammatory responses has been recognized. Inflammation has been thought to be a driving force for cancer metastasis (36). The inflammatory cells and pathways are the players in cancer metastasis. These players are reported to be influenced by the nervous system. Macrophages are key players not only for inflammation but also metastasis, and are regulated by neuromediators (196,198). Stress has been demonstrated to increase the level of IL-6 (201), which is a proinflammatory factor and plays an important role in cancer metastasis. NE and β-adrenergic receptors that can be induced by stress also regulate IL-6 (202,203). The transcription factor NF-κB is a significant inflammatory factor that has been identified to play a role in cancer development and metastasis (183,204). The neuronal guidance molecule netrin-1 is a direct transcriptional target of NF-κB and demonstrates upregulation under inflammatory conditions (205). Therefore, the nervous system modulates cancer metastasis through immunity and inflammation.

Interactions between bone marrow and nervous system: implication for cancer metastasis

A recent discovery revealed the mechanism of bone marrow recruiting disseminated tumor cells (206). Moreover, it also plays an important role in sustaining tumor angiogenesis (207), microenvironment (208,209) and formation of the preniche for cancer cells arriving in pre-metastatic organs (210,211). Bone marrow recruits disseminated tumor cells by a recently discovered mechanism (206). It has been found that bone marrow can be innervated by the nervous system, including the ANS and noradrenergic sympathetic nerve fibers (212216). Preprotachykinin-I (PPT-I) peptides, a family of neuropeptides released by the ANS, are hematopoietic modulators and are highly expressed in cancer cells, which may explain the early integration of cancer cells in the bone marrow (217,218). Progenitor cells of bone marrow may contribute to tumor vascularization (207,219,220). The neurotransmitter dopamine regulates the process of mobilization of endothelial progenitor cells from bone marrow to tumor (221). Stromal cells of the bone marrow are an important source of tumor microenvironments (222), including formation of the pre-metastatic niche in metastatic organs. For example, tumor macrophages, which are derived from bone marrow, contribute to metastasis (223225). During migration, they are navigated by the nervous system (226228). Bone marrow stem cells play an important role in the repair of tissue injury, and are also thought to contribute to neurogenesis in cancer (50). They migrate from bone marrow to a terminal, then lodge and mature in the terminal under the control of the nervous system (228,229). Therefore, the role of bone marrow in cancer metastasis is modulated by the nervous system.

Cancer as an independent organ is being recognized and should not be isolated from the nervous system

As cancer is formed of cancer cells and their surrouding tissues, and there are interactions between tumor cells and their micro- and macroenvironment, cancer is now being considered as a new organ or an independent structure in the body (230). Egeblad et al(231) considered tumors to be independent from other organs in the whole organism. This cancer organ is comprised of tumor cells, extracellular matrix, stromal cells and vessels. Although these components are abnormal, they can be organized into a new organ in a pathophysiological manner, which further exchanges and interacts with other organs. Thus, metastasis is viewed to be a result of the interactions between the tumor and the rest of the body. Mareel et al(232) viewed cancer as an ecosystem inside a living organism. The ecosystem comprises the primary tumor, lymph node and distant metastasis, bone marrow, blood and lymph circulation. The five elements constitute a vicious circle and interact with each other, finally leading to an influence on the whole system. Egeblad et al and Mareel et al had different views on cancer but shared the understanding that cancer is an independent system from other organ systems of the body. In this system, the components exchange information and communicate with other systems. However, these two views do not refer to the nerve system. It is well known that the constitutive elements of organs as well as microecosystems are all under the control of nervous system. In the process of metastasis, these elements exchange information with the nervous system. More importantly, the role of the neural system cannot be replaced by other systems. As a central system, it processes and stores information released by cancer cells. In clinical phenomena of cancer metastasis, metastatic tumors still resemble their primary cancers even after decades of dormancy. Comparisons between primary tumors and matched metastasis reveals similarities both at cancer cell and stromal levels, which may be modulated by the neural system.

Clinical and biological implications for the role of nervous system in cancer metastasis

From the above findings, we can conclude that the neural system has an important influence on cancer metastasis. Stress, depression and social isolation as psychological factors have been reported to promote distant metastasis, which is due to them suppressing immune functions (185), promoting angiogenesis, activating macrophages and releasing proinflammatory factors, such as IL-6 (201) and TNF-α (101) and acting on the HPA and ANS (3,233) to release neurotransmitters (234). Circadian rhythm also influences distant metastasis through modulation of angiogenesis (235), the HPA and the immune system (187,236,237). The brain modulates cancer development including cancer metastasis through the vagus nerve (45). It has significant biological and clinical relevance.

Firstly, stress is a common phenomenon and prompts cancer metastasis, indicating that suppressing stress and modulating mood will be helpful for cancer patients (234,238). Thus, psychologically effective interventions on individuals with a variety of cancers can be resistant to cancer progression and improve clinical outcome for advanced cancer patients (239). Secondly, under circumstances without lymph node and blood metastasis, PNI offers another pathway for the spread of cancer cells. Determining the mechanism of PNI may provide additional options for the prevention and treatment of metastasis by inhibiting the pathway. Thirdly, neoangiogenesis and neurogenesis may exert their effects in concert on cancer metastasis. Inhibition of neoangiogenesis alone has little and even reverse effects on treating metastasis (240). For example, VEGF inhibitors have been reported to have no value in metastatic breast cancer (241) and even enhance metastasis in animal studies (240,242). Establishing the common molecules between the two types of genesis in cancer tissues and identify them as new targets is likely to aid in treating cancer metastasis. Fourthly, modulating the activities of the nervous system has an important influence on cancer metastasis. The brain is able to show functional or pathological changes when other organs in the whole organism are affected by cancer. The monitoring of these changes in the brain may be a new diagnostic approach to detect tumorigenesis and cancer recurrence. The vagus nerve is central in the response to extrinsic and intrinsic stressors and receiving the signals of the brain and other visceral organs, including cancer. Thus, inhibition of the activity of the vagus nerve is another strategy to prevent cancer metastasis (243245). For example, β-blockers are being considered to be a novel adjuvant to existing therapeutic strategies in clinical oncology (73). Finally, as important modulators in the nervous system and cancer, neurotrophic factors, neuropilins, axonal guidance molecules, neurotransmitters and their receptors are being considered to exploit new drugs to be used to treat metastasis (78,82,111,165,234,246250).

The study of metastasis is multifaceted (251). Numerous investigators have devoted themselves to metastasis from their own profession. Although their studies have made great advances, a number of questions remain to be addressed. The connection between the neural system and cancer that we propose in this review is not based on analogy of the association between the nervous system and the immune system but on current studies. The aim of this review was to aid individuals to gain a deeper understanding of cancer metastasis to a certain extent. Although it may not produce major breakthroughs in cancer metastsis, the role of the nervous system in cancer metastasis should not be neglected.

Conclusions

In conclusion, the possible existing synapses in tumor cells and neural-related factors, such as neurotrophic factors and neurotransmitters, make it possible to establish direct connections between the nervous system and cancer. PNI offers another pathway for cancer cell distribution. On an anatomical basis, the nervous system is involved in the processes of metastasis, including tumor cell growth, proliferation, angiogenesis, apoptosis, departure from primary cancer, migration, extravasation and colonization, metastatic inefficiency, and modulators of cancer metastasis such as immunity, inflammation and bone marrow. Therefore, the nervous system plays an important role in cancer metastasis. Understanding its mechanism has important implications for exploring the biology of metastasis and the management of cancer metastasis.

References

1 

Willis RA: The Spread of Tumors in the Human Body. 3rd edition. Butterworths; London: 1973

2 

Reiche EM, Nunes SO and Morimoto HK: Stress, depression, the immune system, and cancer. Lancet Oncol. 5:617–625. 2004. View Article : Google Scholar : PubMed/NCBI

3 

Lutgendorf SK and Sood AK: Biobehavioral factors and cancer progression: physiological pathways and mechanisms. Psychosom Med. 73:724–730. 2011. View Article : Google Scholar : PubMed/NCBI

4 

Thaker PH and Sood AK: Neuroendocrine influences on cancer biology. Semin Cancer Biol. 18:164–170. 2008. View Article : Google Scholar : PubMed/NCBI

5 

Armaiz-Pena GN, Lutgendorf SK, Cole SW and Sood AK: Neuroendocrine modulation of cancer progression. Brain Behav Immun. 23:10–15. 2009. View Article : Google Scholar

6 

Williams JB, Pang D, Delgado B, Kocherginsky M, Tretiakova M, Krausz T, Pan D, He J, McClintock MK and Conzen SD: A model of gene-environment interaction reveals altered mammary gland gene expression and increased tumor growth following social isolation. Cancer Prev Res (Phila). 2:850–861. 2009. View Article : Google Scholar

7 

McEwen BS: Physiology and neurobiology of stress and adaptation: central role of the brain. Physiol Rev. 87:873–904. 2007. View Article : Google Scholar : PubMed/NCBI

8 

Toh YC: Inhibitory effect of hypothalamic lesions on liver tumor induction by N-2-fluorenylacetamide in male rats. Cancer Res. 38:42–51. 1978.PubMed/NCBI

9 

Karasek M and Pawlikowski M: Pineal gland, melatonin and cancer. NEL Review. Neuro Endocrinol Lett. 20:139–144. 1999.PubMed/NCBI

10 

Bruni JE and Montemurro DG: Effect of hypothalamic lesions on the genesis of spontaneous mammary gland tumors in the mouse. Cancer Res. 31:854–863. 1971.PubMed/NCBI

11 

Chelmicka-Szorc E and Arnason BG: Effect of 6-hydroxydopamine on tumor growth. Cancer Res. 36:2382–2384. 1976.PubMed/NCBI

12 

Chelmicka-Schorr E and Arnason BG: Modulatory effect of the sympathetic nervous system on neuroblastoma tumor growth. Cancer Res. 38:1374–1375. 1978.PubMed/NCBI

13 

Seifert P and Spitznas M: Tumours may be innervated. Virchows Arch. 438:228–231. 2001. View Article : Google Scholar : PubMed/NCBI

14 

Seifert P, Benedic M and Effert P: Nerve fibers in tumors of the human urinary bladder. Virchows Arch. 440:291–297. 2002. View Article : Google Scholar : PubMed/NCBI

15 

Lu SH, Zhou Y, Que HP and Liu SJ: Peptidergic innervation of human esophageal and cardiac carcinoma. World J Gastroenterol. 9:399–403. 2003.PubMed/NCBI

16 

Liang YJ, Zhou P, Wongba W, Guardiola J, Walker J and Yu J: Pulmonary innervation, inflammation and carcinogenesis. Sheng Li Xue Bao. 62:191–195. 2010.PubMed/NCBI

17 

Li JH, Ma QY, Shen SG and Hu HT: Stimulation of dorsal root ganglion neurons activity by pancreatic cancer cell lines. Cell Biol Int. 32:1530–1535. 2008. View Article : Google Scholar : PubMed/NCBI

18 

Albo D, Akay CL, Marshall CL, Wilks JA, Verstovsek G, Liu H, Agarwal N, Berger DH and Ayala GE: Neurogenesis in colorectal cancer is a marker of aggressive tumor behavior and poor outcomes. Cancer. 117:4834–4845. 2011. View Article : Google Scholar : PubMed/NCBI

19 

Ayala GE, Wheeler TM, Shine HD, Schmelz M, Frolov A, Chakraborty S and Rowley D: In vitro dorsal root ganglia and human prostate cell line interaction: redefining perineural invasion in prostate cancer. Prostate. 49:213–223. 2001. View Article : Google Scholar : PubMed/NCBI

20 

Batkin S, Piette LH and Wildman E: Effect of muscle denervation on growth of transplanted tumor in mice. Proc Natl Acad Sci USA. 67:1521–1527. 1970. View Article : Google Scholar : PubMed/NCBI

21 

Papageorgiou A, Trontzos C, Kallistratos H, Kokkas B, Grigoriadis N and Grammaticos P: Slowing growth and histology changes in Lewis lung carcinoma implanted in a partly denervated muscle. Cancer Invest. 21:869–872. 2003. View Article : Google Scholar : PubMed/NCBI

22 

Romeo HE, Colombo LL, Esquifino AI, Rosenstein RE, Chuluyan HE and Cardinali DP: Slower growth of tumours in sympathetically denervated murine skin. J Auton Nerv Syst. 32:159–164. 1991. View Article : Google Scholar : PubMed/NCBI

23 

Peng J, Sheng W, Huang D, Venook AP, Xu Y, Guan Z and Cai S: Perineural invasion in pT3N0 rectal cancer: the incidence and its prognostic effect. Cancer. 117:1415–1421. 2011. View Article : Google Scholar : PubMed/NCBI

24 

Feng FY, Qian Y, Stenmark MH, Halverson S, Blas K, Vance S, Sandler HM and Hamstra DA: Perineural invasion predicts increased recurrence, metastasis, and death from prostate cancer following treatment with dose-escalated radiation therapy. Int J Radiat Oncol Biol Phys. 81:e361–e367. 2011. View Article : Google Scholar

25 

Poeschl EM, Pollheimer MJ, Kornprat P, Lindtner RA, Schlemmer A, Rehak P, Vieth M and Langner C: Perineural invasion: correlation with aggressive phenotype and independent prognostic variable in both colon and rectum cancer. J Clin Oncol. 28:e358–e360. e361–e362. 2010. View Article : Google Scholar : PubMed/NCBI

26 

Liebig C, Ayala G, Wilks JA, Berger DH and Albo D: Perineural invasion in cancer: a review of the literature. Cancer. 115:3379–3391. 2009. View Article : Google Scholar : PubMed/NCBI

27 

Khasraw M and Posner JB: Neurological complications of systemic cancer. Lancet Neurol. 9:1214–1227. 2010. View Article : Google Scholar

28 

Toothaker TB and Rubin M: Paraneoplastic neurological syndromes: a review. Neurologist. 15:21–33. 2009. View Article : Google Scholar : PubMed/NCBI

29 

Mravec B, Gidron Y and Hulin I: Neurobiology of cancer: Interactions between nervous, endocrine and immune systems as a base for monitoring and modulating the tumorigenesis by the brain. Semin Cancer Biol. 18:150–163. 2008. View Article : Google Scholar : PubMed/NCBI

30 

Entschladen F, Palm D, Niggemann B and Zaenker KS: The cancer's nervous tooth: Considering the neuronal crosstalk within tumors. Semin Cancer Biol. 18:171–175. 2008.

31 

Ondicova K and Mravec B: Role of nervous system in cancer aetiopathogenesis. Lancet Oncol. 11:596–601. 2010. View Article : Google Scholar : PubMed/NCBI

32 

Sloan EK, Priceman SJ, Cox BF, Yu S, Pimentel MA, Tangkanangnukul V, Arevalo JM, Morizono K, Karanikolas BD, Wu L, Sood AK and Cole SW: The sympathetic nervous system induces a metastatic switch in primary breast cancer. Cancer Res. 70:7042–7052. 2010. View Article : Google Scholar : PubMed/NCBI

33 

Gupta GP and Massague J: Cancer metastasis: building a framework. Cell. 127:679–695. 2006. View Article : Google Scholar : PubMed/NCBI

34 

de Visser KE, Eichten A and Coussens LM: Paradoxical roles of the immune system during cancer development. Nat Rev Cancer. 6:24–37. 2006.

35 

DeNardo DG, Johansson M and Coussens LM: Immune cells as mediators of solid tumor metastasis. Cancer Metastasis Rev. 27:11–18. 2008. View Article : Google Scholar : PubMed/NCBI

36 

Wu Y and Zhou BP: Inflammation: a driving force speeds cancer metastasis. Cell Cycle. 8:3267–3273. 2009. View Article : Google Scholar : PubMed/NCBI

37 

Solinas G, Marchesi F, Garlanda C, Mantovani A and Allavena P: Inflammation-mediated promotion of invasion and metastasis. Cancer Metastasis Rev. 29:243–248. 2010. View Article : Google Scholar : PubMed/NCBI

38 

Nguyen DX, Bos PD and Massague J: Metastasis: from dissemination to organ-specific colonization. Nat Rev Cancer. 9:274–284. 2009. View Article : Google Scholar : PubMed/NCBI

39 

Sung SY, Hsieh CL, Wu D, Chung LW and Johnstone PA: Tumor microenvironment promotes cancer progression, metastasis, and therapeutic resistance. Curr Probl Cancer. 31:36–100. 2007. View Article : Google Scholar : PubMed/NCBI

40 

Calorini L and Bianchini F: Environmental control of invasiveness and metastatic dissemination of tumor cells: the role of tumor cell-host cell interactions. Cell Commun Signal. 8:242010.PubMed/NCBI

41 

Shapiro DM and Warren S: Cancer innervation. Cancer Res. 9:707–711. 1949.

42 

Mitchell BS, Schumacher U, Stauber VV and Kaiserling E: Are breast tumours innervated? Immunohistological investigations using antibodies against the neuronal marker protein gene product 95 (PGP 95) in benign and malignant breast lesions. Eur J Cancer. 30A:1100–1103. 1994. View Article : Google Scholar

43 

Seifert P and Spitznas M: Axons in human choroidal melanoma suggest the participation of nerves in the control of these tumors. Am J Ophthalmol. 133:711–713. 2002. View Article : Google Scholar : PubMed/NCBI

44 

Feng F, Yang J, Tong L, Yuan S, Tian Y, Hong L, Wang W and Zhang H: Substance P immunoreactive nerve fibres are related to gastric cancer differentiation status and could promote proliferation and migration of gastric cancer cells. Cell Biol Int. 35:623–629. 2011. View Article : Google Scholar

45 

Gidron Y, Perry H and Glennie M: Does the vagus nerve inform the brain about preclinical tumours and modulate them? Lancet Oncol. 6:245–248. 2005. View Article : Google Scholar : PubMed/NCBI

46 

Erin N, Boyer PJ, Bonneau RH, Clawson GA and Welch DR: Capsaicin-mediated denervation of sensory neurons promotes mammary tumor metastasis to lung and heart. Anticancer Res. 24:1003–1009. 2004.PubMed/NCBI

47 

Erin N, Akdas BG, Harms JF and Clawson GA: Vagotomy enhances experimental metastases of 4THMpc breast cancer cells and alters substance P level. Regul Pept. 151:35–42. 2008. View Article : Google Scholar : PubMed/NCBI

48 

Palm D and Entschladen F: Neoneurogenesis and the neuroneoplastic synapse. Prog Exp Tumor Res. 39:91–98. 2007. View Article : Google Scholar : PubMed/NCBI

49 

Zanker KS: The neuro-neoplastic synapse: does it exist? Prog Exp Tumor Res. 39:154–161. 2007.PubMed/NCBI

50 

Varner JA: Stem cells and neurogenesis in tumors. Prog Exp Tumor Res. 39:122–129. 2007. View Article : Google Scholar : PubMed/NCBI

51 

Ayala GE, Dai H, Powell M, Li R, Ding Y, Wheeler TM, Shine D, Kadmon D, Thompson T, Miles BJ, Ittmann MM and Rowley D: Cancer-related axonogenesis and neurogenesis in prostate cancer. Clin Cancer Res. 14:7593–7603. 2008. View Article : Google Scholar : PubMed/NCBI

52 

Mitchell BS, Schumacher U and Kaiserling E: Are tumours innervated? Immunohistological investigations using antibodies against the neuronal marker protein gene product 95 (PGP 95) in benign, malignant and experimental tumours. Tumour Biol. 15:269–274. 1994. View Article : Google Scholar

53 

Terada T and Matsunaga Y: S-100-positive nerve fibers in hepatocellular carcinoma and intrahepatic cholangiocarcinoma: an immunohistochemical study. Pathol Int. 51:89–93. 2001. View Article : Google Scholar : PubMed/NCBI

54 

Pollak M, Sem AW, Richard M, Tetenes E and Bell R: Inhibition of metastatic behavior of murine osteosarcoma by hypophysectomy. J Natl Cancer Inst. 84:966–971. 1992. View Article : Google Scholar : PubMed/NCBI

55 

Giraldi T, Perissin L, Zorzet S, Rapozzi V and Rodani MG: Metastasis and neuroendocrine system in stressed mice. Int J Neurosci. 74:265–278. 1994. View Article : Google Scholar : PubMed/NCBI

56 

Marchetti B, Spinola PG, Pelletier G and Labrie F: A potential role for catecholamines in the development and progression of carcinogen-induced mammary tumors: hormonal control of beta-adrenergic receptors and correlation with tumor growth. J Steroid Biochem Mol Biol. 38:307–320. 1991. View Article : Google Scholar : PubMed/NCBI

57 

Fava G, Marucci L, Glaser S, Francis H, De Morrow S, Benedetti A, Alvaro D, Venter J, Meininger C, Patel T, Taffetani S, Marzioni M, Summers R, Reichenbach R and Alpini G: Gamma-Aminobutyric acid inhibits cholangiocarcinoma growth by cyclic AMP-dependent regulation of the protein kinase A/extracellular signal-regulated kinase 1/2 pathway. Cancer Res. 65:11437–11446. 2005. View Article : Google Scholar

58 

Al-Wadei HA, Plummer HK III and Schuller HM: Nicotine stimulates pancreatic cancer xenografts by systemic increase in stress neurotransmitters and suppression of the inhibitory neurotransmitter gamma-aminobutyric acid. Carcinogenesis. 30:506–511. 2009. View Article : Google Scholar

59 

Yamanaka Y, Mammoto T, Kirita T, Mukai M, Mashimo T, Sugimura M, Kishi Y and Nakamura H: Epinephrine inhibits invasion of oral squamous carcinoma cells by modulating intra-cellular cAMP. Cancer Lett. 176:143–148. 2002. View Article : Google Scholar : PubMed/NCBI

60 

Wang T, Huang W and Chen F: Baclofen, a GABAB receptor agonist, inhibits human hepatocellular carcinoma cell growth in vitro and in vivo. Life Sci. 82:536–541. 2008. View Article : Google Scholar : PubMed/NCBI

61 

Ellis LM: The role of neuropilins in cancer. Mol Cancer Ther. 5:1099–1107. 2006. View Article : Google Scholar

62 

Rizzolio S and Tamagnone L: Multifaceted role of neuropilins in cancer. Curr Med Chem. 18:3563–3575. 2011. View Article : Google Scholar : PubMed/NCBI

63 

Kreuter M, Bielenberg D, Hida Y, Hida K and Klagsbrun M: Role of neuropilins and semaphorins in angiogenesis and cancer. Ann Hematol. 81(Suppl 2): S742002.PubMed/NCBI

64 

Chedotal A, Kerjan G and Moreau-Fauvarque C: The brain within the tumor: new roles for axon guidance molecules in cancers. Cell Death Differ. 12:1044–1056. 2005. View Article : Google Scholar : PubMed/NCBI

65 

Nakagawara A: Trk receptor tyrosine kinases: a bridge between cancer and neural development. Cancer Lett. 169:107–114. 2001. View Article : Google Scholar : PubMed/NCBI

66 

Wong HP, Ho JW, Koo MW, Yu L, Wu WK, Lam EK, Tai EK, Ko JK, Shin VY, Chu KM and Cho CH: Effects of adrenaline in human colon adenocarcinoma HT-29 cells. Life Sci. 88:1108–1112. 2011. View Article : Google Scholar : PubMed/NCBI

67 

Marin YE and Chen S: Involvement of metabotropic glutamate receptor 1, a G protein coupled receptor, in melanoma development. J Mol Med (Berl). 82:735–749. 2004. View Article : Google Scholar : PubMed/NCBI

68 

Castro-Rivera E, Ran S, Brekken RA and Minna JD: Semaphorin 3B inhibits the phosphatidylinositol 3-kinase/Akt pathway through neuropilin-1 in lung and breast cancer cells. Cancer Res. 68:8295–8303. 2008. View Article : Google Scholar : PubMed/NCBI

69 

Kigel B, Varshavsky A, Kessler O and Neufeld G: Successful inhibition of tumor development by specific class-3 semaphorins is associated with expression of appropriate semaphorin receptors by tumor cells. PLoS One. 3:e32872008. View Article : Google Scholar : PubMed/NCBI

70 

Pisick E, Jagadeesh S and Salgia R: Receptor tyrosine kinases and inhibitors in lung cancer. Scientific World Journal. 4:589–604. 2004. View Article : Google Scholar : PubMed/NCBI

71 

Muller JM: Potential inhibition of the neuro-neoplastic interactions: the clue of a GPCR-targeted therapy. Prog Exp Tumor Res. 39:130–153. 2007. View Article : Google Scholar : PubMed/NCBI

72 

Fitzgerald PJ: Is norepinephrine an etiological factor in some types of cancer? Int J Cancer. 124:257–263. 2009. View Article : Google Scholar : PubMed/NCBI

73 

Cole SW and Sood AK: Molecular pathways: beta-adrenergic signaling pathways in cancer. Clin Cancer Res. 18:1201–1206. 2011. View Article : Google Scholar

74 

Al-Wadei HA, Plummer HK III, Ullah MF, Unger B, Brody JR and Schuller HM: Social stress promotes and γ-aminobutyric acid inhibits tumor growth in mouse models of non-small cell lung cancer. Cancer Prev Res (Phila). 5:189–196. 2012.

75 

Casazza A, Kigel B, Maione F, Capparuccia L, Kessler O, Giraudo E, Mazzone M, Neufeld G and Tamagnone L: Tumour growth inhibition and anti-metastatic activity of a mutated furin-resistant Semaphorin 3E isoform. EMBO Mol Med. 4:234–250. 2012. View Article : Google Scholar : PubMed/NCBI

76 

Erin N, Zhao W, Bylander J, Chase G and Clawson G: Capsaicin-induced inactivation of sensory neurons promotes a more aggressive gene expression phenotype in breast cancer cells. Breast Cancer Res Treat. 99:351–364. 2006. View Article : Google Scholar : PubMed/NCBI

77 

Nasarre P, Potiron V, Drabkin H and Roche J: Guidance molecules in lung cancer. Cell Adh Migr. 4:130–145. 2010. View Article : Google Scholar

78 

Weick A and Augustin HG: Double attack on tumors by targeting with guidance molecules. Arterioscler Thromb Vasc Biol. 31:721–722. 2011. View Article : Google Scholar : PubMed/NCBI

79 

Bernet A and Fitamant J: Netrin-1 and its receptors in tumour growth promotion. Expert Opin Ther Targets. 12:995–1007. 2008. View Article : Google Scholar : PubMed/NCBI

80 

Schuller HM and Al-Wadei HA: Neurotransmitter receptors as central regulators of pancreatic cancer. Future Oncol. 6:221–228. 2010. View Article : Google Scholar : PubMed/NCBI

81 

Novotny A, Ryberg K, Heiman UJ, Nilsson L, Khorram-Manesh A, Nordgren S, Delbro DS and Nylund G: Is acetylcholine a signaling molecule for human colon cancer progression? Scand J Gastroenterol. 46:446–455. 2011. View Article : Google Scholar : PubMed/NCBI

82 

Al-Wadei HA, Al-Wadei MH and Schuller HM: Cooperative regulation of non-small cell lung carcinoma by nicotinic and beta-adrenergic receptors: a novel target for intervention. PLoS One. 7:e299152012. View Article : Google Scholar : PubMed/NCBI

83 

Al-Wadei HA, Ullah MF and Al-Wadei M: GABA (γ-aminobutyric acid), a non-protein amino acid counters the β-adrenergic cascade-activated oncogenic signaling in pancreatic cancer: a review of experimental evidence. Mol Nutr Food Res. 55:1745–1758. 2011.

84 

Neufeld G, Shraga-Heled N, Lange T, Guttmann-Raviv N, Herzog Y and Kessler O: Semaphorins in cancer. Front Biosci. 10:751–760. 2005. View Article : Google Scholar : PubMed/NCBI

85 

Rizzolio S and Tamagnone L: Semaphorin signals on the road to cancer invasion and metastasis. Cell Adh Migr. 1:62–68. 2007. View Article : Google Scholar : PubMed/NCBI

86 

Chen C, Li M, Chai H, Yang H, Fisher WE and Yao Q: Roles of neuropilins in neuronal development, angiogenesis, and cancers. World J Surg. 29:271–275. 2005. View Article : Google Scholar : PubMed/NCBI

87 

Baba T, Kariya M, Higuchi T, Mandai M, Matsumura N, Kondoh E, Miyanishi M, Fukuhara K, Takakura K and Fujii S: Neuropilin-1 promotes unlimited growth of ovarian cancer by evading contact inhibition. Gynecol Oncol. 105:703–711. 2007. View Article : Google Scholar : PubMed/NCBI

88 

Warrington RJ and Lewis KE: Natural antibodies against nerve growth factor inhibit in vitro prostate cancer cell metastasis. Cancer Immunol Immunother. 60:187–195. 2011. View Article : Google Scholar : PubMed/NCBI

89 

Arakawa H: Netrin-1 and its receptors in tumorigenesis. Nat Rev Cancer. 4:978–987. 2004. View Article : Google Scholar : PubMed/NCBI

90 

Kalariti N, Pissimissis N and Koutsilieris M: The glutamatergic system outside the CNS and in cancer biology. Expert Opin Investig Drugs. 14:1487–1496. 2005. View Article : Google Scholar : PubMed/NCBI

91 

Watanabe M, Maemura K, Oki K, Shiraishi N, Shibayama Y and Katsu K: Gamma-aminobutyric acid (GABA) and cell proliferation: focus on cancer cells. Histol Histopathol. 21:1135–1141. 2006.PubMed/NCBI

92 

Chang HJ, Yoo BC, Lim SB, Jeong SY, Kim WH and Park JG: Metabotropic glutamate receptor 4 expression in colorectal carcinoma and its prognostic significance. Clin Cancer Res. 11:3288–3295. 2005. View Article : Google Scholar : PubMed/NCBI

93 

Park SY, Lee SA, Han IH, Yoo BC, Lee SH, Park JY, Cha IH, Kim J and Choi SW: Clinical significance of metabotropic glutamate receptor 5 expression in oral squamous cell carcinoma. Oncol Rep. 17:81–87. 2007.PubMed/NCBI

94 

Palma C: Tachykinins and their receptors in human malignancies. Curr Drug Targets. 7:1043–1052. 2006. View Article : Google Scholar : PubMed/NCBI

95 

Ruscica M, Dozio E, Motta M and Magni P: Relevance of the neuropeptide Y system in the biology of cancer progression. Curr Top Med Chem. 7:1682–1691. 2007. View Article : Google Scholar : PubMed/NCBI

96 

Chatikhine VA, Delpech B, Duval C, Chauzy C, D'Aniou J and Chevrier A: Expression of beta-endorphin in human breast cancer and adenofibromas. Ann NY Acad Sci. 680:473–475. 1993. View Article : Google Scholar : PubMed/NCBI

97 

Sarkar DK, Zhang C, Murugan S, Dokur M, Boyadjieva NI, Ortiguela M, Reuhl KR and Mojtehedzadeh S: Transplantation of beta-endorphin neurons into the hypothalamus promotes immune function and restricts the growth and metastasis of mammary carcinoma. Cancer Res. 71:6282–6291. 2011. View Article : Google Scholar : PubMed/NCBI

98 

Mancino M, Ametller E, Gascon P and Almendro V: The neuronal influence on tumor progression. Biochim Biophys Acta. 1816:105–118. 2011.PubMed/NCBI

99 

MacDougall JR and Matrisian LM: Contributions of tumor and stromal matrix metalloproteinases to tumor progression, invasion and metastasis. Cancer Metastasis Rev. 14:351–362. 1995. View Article : Google Scholar : PubMed/NCBI

100 

Deryugina EI and Quigley JP: Matrix metalloproteinases and tumor metastasis. Cancer Metastasis Rev. 25:9–34. 2006. View Article : Google Scholar

101 

Wu W, Yamaura T, Murakami K, Ogasawara M, Hayashi K, Murata J and Saiki I: Involvement of TNF-alpha in enhancement of invasion and metastasis of colon 26-L5 carcinoma cells in mice by social isolation stress. Oncol Res. 11:461–469. 1999.PubMed/NCBI

102 

Yang EV, Bane CM, MacCallum RC, Kiecolt-Glaser JK, Malarkey WB and Glaser R: Stress-related modulation of matrix metalloproteinase expression. J Neuroimmunol. 133:144–150. 2002. View Article : Google Scholar : PubMed/NCBI

103 

Yao J, Xiong S, Klos K, Nguyen N, Grijalva R, Li P and Yu D: Multiple signaling pathways involved in activation of matrix metalloproteinase-9 (MMP-9) by heregulin-beta1 in human breast cancer cells. Oncogene. 20:8066–8074. 2001. View Article : Google Scholar : PubMed/NCBI

104 

Okada Y, Eibl G, Guha S, Duffy JP, Reber HA and Hines OJ: Nerve growth factor stimulates MMP-2 expression and activity and increases invasion by human pancreatic cancer cells. Clin Exp Metastasis. 21:285–292. 2004. View Article : Google Scholar : PubMed/NCBI

105 

Okada Y, Eibl G, Duffy JP, Reber HA and Hines OJ: Glial cell-derived neurotrophic factor upregulates the expression and activation of matrix metalloproteinase-9 in human pancreatic cancer. Surgery. 134:293–299. 2003. View Article : Google Scholar : PubMed/NCBI

106 

Menter DG, Herrmann JL and Nicolson GL: The role of trophic factors and autocrine/paracrine growth factors in brain metastasis. Clin and Exp Metastasis. 13:67–88. 1995. View Article : Google Scholar : PubMed/NCBI

107 

Yang EV, Sood AK, Chen M, Li Y, Eubank TD, Marsh CB, Jewell S, Flavahan NA, Morrison C, Yeh PE, Lemeshow S and Glaser R: Norepinephrine up-regulates the expression of vascular endothelial growth factor, matrix metalloproteinase (MMP)-2, and MMP-9 in nasopharyngeal carcinoma tumor cells. Cancer Res. 66:10357–10364. 2006. View Article : Google Scholar

108 

Azuma H, Inamoto T, Sakamoto T, Kiyama S, Ubai T, Shinohara Y, Maemura K, Tsuji M, Segawa N, Masuda H, Takahara K, Katsuoka Y and Watanabe M: Gamma-aminobutyric acid as a promoting factor of cancer metastasis; induction of matrix metalloproteinase production is potentially its underlying mechanism. Cancer Res. 63:8090–8096. 2003.

109 

Simpson CD, Anyiwe K and Schimmer AD: Anoikis resistance and tumor metastasis. Cancer Lett. 272:177–185. 2008. View Article : Google Scholar : PubMed/NCBI

110 

Douma S, Van Laar T, Zevenhoven J, Meuwissen R, Van Garderen E and Peeper DS: Suppression of anoikis and induction of metastasis by the neurotrophic receptor TrkB. Nature. 430:1034–1039. 2004. View Article : Google Scholar : PubMed/NCBI

111 

Geiger TR and Peeper DS: The neurotrophic receptor TrkB in anoikis resistance and metastasis: a perspective. Cancer Res. 65:7033–7036. 2005. View Article : Google Scholar : PubMed/NCBI

112 

Geiger TR and Peeper DS: Critical role for TrkB kinase function in anoikis suppression, tumorigenesis, and metastasis. Cancer Res. 67:6221–6229. 2007. View Article : Google Scholar : PubMed/NCBI

113 

Strizzi L, Bianco C, Raafat A, Abdallah W, Chang C, Raafat D, Hirota M, Hamada S, Sun Y, Normanno N, Callahan R, Hinck L and Salomon D: Netrin-1 regulates invasion and migration of mouse mammary epithelial cells overexpressing Cripto-1 in vitro and in vivo. J Cell Sci. 118:4633–4643. 2005. View Article : Google Scholar : PubMed/NCBI

114 

Christensen C, Ambartsumian N, Gilestro G, Thomsen B, Comoglio P, Tamagnone L, Guldberg P and Lukanidin E: Proteolytic processing converts the repelling signal Sema3E into an inducer of invasive growth and lung metastasis. Cancer Res. 65:6167–6177. 2005. View Article : Google Scholar : PubMed/NCBI

115 

Kruger RP, Aurandt J and Guan KL: Semaphorins command cells to move. Nat Rev Mol Cell Biol. 6:789–800. 2005. View Article : Google Scholar : PubMed/NCBI

116 

Kim HK, Zhang H, Li H, Wu TT, Swisher S, He D, Wu L, Xu J, Elmets CA, Athar M, Xu XC and Xu H: Slit2 inhibits growth and metastasis of fibrosarcoma and squamous cell carcinoma. Neoplasia. 10:1411–1420. 2008.PubMed/NCBI

117 

Casazza A, Finisguerra V, Capparuccia L, Camperi A, Swiercz JM, Rizzolio S, Rolny C, Christensen C, Bertotti A, Sarotto I, Risio M, Trusolino L, Weitz J, Schneider M, Mazzone M, Comoglio PM and Tamagnone L: Sema3E-Plexin D1 signaling drives human cancer cell invasiveness and meta-static spreading in mice. J Clin Invest. 120:2684–2698. 2010. View Article : Google Scholar : PubMed/NCBI

118 

Entschladen F, Lang K, Drell TL, Joseph J and Zaenker KS: Neurotransmitters are regulators for the migration of tumor cells and leukocytes. Cancer Immunol Immunother. 51:467–482. 2002. View Article : Google Scholar : PubMed/NCBI

119 

Masur K, Niggemann B, Zanker KS and Entschladen F: Norepinephrine-induced migration of SW 480 colon carcinoma cells is inhibited by beta-blockers. Cancer Res. 61:2866–2869. 2001.PubMed/NCBI

120 

Drell TT, Joseph J, Lang K, Niggemann B, Zaenker KS and Entschladen F: Effects of neurotransmitters on the chemokinesis and chemotaxis of MDA-MB-468 human breast carcinoma cells. Breast Cancer Res Treat. 80:63–70. 2003. View Article : Google Scholar : PubMed/NCBI

121 

Joseph J, Niggemann B, Zaenker KS and Entschladen F: The neurotransmitter gamma-aminobutyric acid is an inhibitory regulator for the migration of SW 480 colon carcinoma cells. Cancer Res. 62:6467–6469. 2002.PubMed/NCBI

122 

Watanabe M, Maemura K, Kanbara K, Tamayama T and Hayasaki H: GABA and GABA receptors in the central nervous system and other organs. Int Rev Cytol. 213:1–47. 2002. View Article : Google Scholar : PubMed/NCBI

123 

Miller RJ, Rostene W, Apartis E, Banisadr G, Biber K, Milligan ED, White FA and Zhang J: Chemokine action in the nervous system. J Neurosci. 28:11792–11795. 2008. View Article : Google Scholar : PubMed/NCBI

124 

Zhang N and Oppenheim JJ: Crosstalk between chemokines and neuronal receptors bridges immune and nervous systems. J Leukoc Biol. 78:1210–1214. 2005. View Article : Google Scholar : PubMed/NCBI

125 

Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, McClanahan T, Murphy E, Yuan W, Wagner SN, Barrera JL, Mohar A, Verastegui E and Zlotnik A: Involvement of chemokine receptors in breast cancer metastasis. Nature. 410:50–56. 2001. View Article : Google Scholar : PubMed/NCBI

126 

Balkwill F: Cancer and the chemokine network. Nat Rev Cancer. 4:540–550. 2004. View Article : Google Scholar

127 

Singh S, Sadanandam A and Singh RK: Chemokines in tumor angiogenesis and metastasis. Cancer Metastasis Rev. 26:453–467. 2007. View Article : Google Scholar : PubMed/NCBI

128 

Weiss L: Cancer cell traffic from the lungs to the liver: an example of metastatic inefficiency. Int J Cancer. 25:385–392. 1980. View Article : Google Scholar : PubMed/NCBI

129 

Weiss L: Deformation-driven, lethal damage to cancer cells. Its contribution to metastatic inefficiency. Cell Biophys. 18:73–79. 1991. View Article : Google Scholar : PubMed/NCBI

130 

Bacac M and Stamenkovic I: Metastatic cancer cell. Annu Rev Pathol. 3:221–247. 2008. View Article : Google Scholar

131 

Brain SD: Sensory neuropeptides: their role in inflammation and wound healing. Immunopharmacology. 37:133–152. 1997. View Article : Google Scholar : PubMed/NCBI

132 

Ishihara K, Kamata M, Hayashi I, Yamashina S and Majima M: Roles of bradykinin in vascular permeability and angiogenesis in solid tumor. Int Immunopharmacol. 2:499–509. 2002. View Article : Google Scholar : PubMed/NCBI

133 

O'Connor TM, O'Connell J, O'Brien DI, Goode T, Bredin CP and Shanahan F: The role of substance P in inflammatory disease. J Cell Physiol. 201:167–180. 2004.

134 

Marchesi F, Piemonti L, Mantovani A and Allavena P: Molecular mechanisms of perineural invasion, a forgotten pathway of dissemination and metastasis. Cytokine Growth Factor Rev. 21:77–82. 2010. View Article : Google Scholar : PubMed/NCBI

135 

Jhawer M, Coit D, Brennan M, Qin LX, Gonen M, Klimstra D, Tang L, Kelsen DP and Shah MA: Perineural invasion after preoperative chemotherapy predicts poor survival in patients with locally advanced gastric cancer: gene expression analysis with pathologic validation. Am J Clin Oncol. 32:356–362. 2009. View Article : Google Scholar

136 

Bilici A, Seker M, Ustaalioglu BB, Kefeli U, Yildirim E, Yavuzer D, Aydin FM, Salepci T, Oncel M and Gumus M: Prognostic significance of perineural invasion in patients with gastric cancer who underwent curative resection. Ann Surg Oncol. 17:2037–2044. 2010. View Article : Google Scholar : PubMed/NCBI

137 

Ceyhan GO, Liebl F, Maak M, Schuster T, Becker K, Langer R, Demir IE, Hartel M, Friess H and Rosenberg R: The severity of neural invasion is a crucial prognostic factor in rectal cancer independent of neoadjuvant radiochemotherapy. Ann Surg. 252:797–804. 2010. View Article : Google Scholar : PubMed/NCBI

138 

Binmadi NO and Basile JR: Perineural invasion in oral squamous cell carcinoma: a discussion of significance and review of the literature. Oral Oncol. 47:1005–1010. 2011. View Article : Google Scholar : PubMed/NCBI

139 

Tai SK, Li WY, Chu PY, Chang SY, Tsai TL, Wang YF and Huang JL: Risks and clinical implications of perineural invasion in T1-2 oral tongue squamous cell carcinoma. Head Neck. 34:994–1001. 2011.PubMed/NCBI

140 

Miller ME, Palla B, Chen Q, Elashoff DA, Abemayor E, St John JM and Lai CK: A novel classification system for perineural invasion in noncutaneous head and neck squamous cell carcinoma: histologic subcategories and patient outcomes. Am J Otolaryngol. 33:212–215. 2012. View Article : Google Scholar

141 

Hibi T, Mori T, Fukuma M, Yamazaki K, Hashiguchi A, Yamada T, Tanabe M, Aiura K, Kawakami T, Ogiwara A, Kosuge T, Kitajima M, Kitagawa Y and Sakamoto M: Synuclein-gamma is closely involved in perineural invasion and distant metastasis in mouse models and is a novel prognostic factor in pancreatic cancer. Clin Cancer Res. 15:2864–2871. 2009. View Article : Google Scholar : PubMed/NCBI

142 

Karak SG, Quatrano N, Buckley J and Ricci AJ: Prevalence and significance of perineural invasion in invasive breast carcinoma. Conn Med. 74:17–21. 2010.PubMed/NCBI

143 

Meinel A, Fischer U, Bilek K, Hentschel B and Horn LC: Morphological parameters associated with perineural invasion (PNI) in carcinoma of the cervix uteri. Int J Surg Pathol. 19:159–163. 2011. View Article : Google Scholar : PubMed/NCBI

144 

Bixby JL and Harris WA: Molecular mechanisms of axon growth and guidance. Annu Rev Cell Biol. 7:117–159. 1991. View Article : Google Scholar : PubMed/NCBI

145 

Goldberg JL: How does an axon grow? Genes Dev. 17:941–958. 2003. View Article : Google Scholar : PubMed/NCBI

146 

Pasterkamp RJ, Peschon JJ, Spriggs MK and Kolodkin AL: Semaphorin 7A promotes axon outgrowth through integrins and MAPKs. Nature. 424:398–405. 2003. View Article : Google Scholar : PubMed/NCBI

147 

Chilton JK: Molecular mechanisms of axon guidance. Dev Biol. 292:13–24. 2006. View Article : Google Scholar : PubMed/NCBI

148 

Winckler B: BDNF instructs the kinase LKB1 to grow an axon. Cell. 129:459–460. 2007. View Article : Google Scholar : PubMed/NCBI

149 

Artigiani S, Comoglio PM and Tamagnone L: Plexins, semaphorins, and scatter factor receptors: a common root for cell guidance signals? Iubmb Life. 48:477–482. 1999. View Article : Google Scholar : PubMed/NCBI

150 

Iwahashi N, Nagasaka T, Tezel G, Iwashita T, Asai N, Murakumo Y, Kiuchi K, Sakata K, Nimura Y and Takahashi M: Expression of glial cell line-derived neurotrophic factor correlates with perineural invasion of bile duct carcinoma. Cancer. 94:167–174. 2002. View Article : Google Scholar : PubMed/NCBI

151 

Tomaselli KJ, Reichardt LF and Bixby JL: Distinct molecular interactions mediate neuronal process outgrowth on nonneuronal cell surfaces and extracellular matrices. J Cell Biol. 103:2659–2672. 1986. View Article : Google Scholar : PubMed/NCBI

152 

Folkman J: Role of angiogenesis in tumor growth and metastasis. Semin Oncol. 29:15–18. 2002. View Article : Google Scholar : PubMed/NCBI

153 

Hillen F and Griffioen AW: Tumour vascularization: sprouting angiogenesis and beyond. Cancer Metastasis Rev. 26:489–502. 2007. View Article : Google Scholar : PubMed/NCBI

154 

Weis SM and Cheresh DA: Tumor angiogenesis: molecular pathways and therapeutic targets. Nat Med. 17:1359–1370. 2011. View Article : Google Scholar : PubMed/NCBI

155 

Lutgendorf SK, Cole S, Costanzo E, Bradley S, Coffin J, Jabbari S, Rainwater K, Ritchie JM, Yang M and Sood AK: Stress-related mediators stimulate vascular endothelial growth factor secretion by two ovarian cancer cell lines. Clin Cancer Res. 9:4514–4521. 2003.PubMed/NCBI

156 

Thaker PH, Han LY, Kamat AA, Arevalo JM, Takahashi R, Lu C, Jennings NB, Armaiz-Pena G, Bankson JA, Ravoori M, Merritt WM, Lin YG, Mangala LS, Kim TJ, Coleman RL, Landen CN, Li Y, Felix E, Sanguino AM, Newman RA, Lloyd M, Gershenson DM, Kundra V, Lopez-Berestein G, Lutgendorf SK, Cole SW and Sood AK: Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma. Nat Med. 12:939–944. 2006. View Article : Google Scholar : PubMed/NCBI

157 

Tilan J and Kitlinska J: Sympathetic neurotransmitters and tumor angiogenesis - link between stress and cancer progression. J Oncol. 5397062010.PubMed/NCBI

158 

Park SY, Kang JH, Jeong KJ, Lee J, Han JW, Choi WS, Kim YK, Kang J, Park CG and Lee HY: Norepinephrine induces VEGF expression and angiogenesis by a hypoxia-inducible factor-1α protein-dependent mechanism. Int J Cancer. 128:2306–2316. 2011.PubMed/NCBI

159 

Chakroborty D, Sarkar C, Basu B, Dasgupta PS and Basu S: Catecholamines regulate tumor angiogenesis. Cancer Res. 69:3727–3730. 2009. View Article : Google Scholar : PubMed/NCBI

160 

Chakroborty D, Sarkar C, Mitra RB, Banerjee S, Dasgupta PS and Basu S: Depleted dopamine in gastric cancer tissues: dopamine treatment retards growth of gastric cancer by inhibiting angiogenesis. Clin Cancer Res. 10:4349–4356. 2004. View Article : Google Scholar : PubMed/NCBI

161 

Basu S, Nagy JA, Pal S, Vasile E, Eckelhoefer IA, Bliss VS, Manseau EJ, Dasgupta PS, Dvorak HF and Mukhopadhyay D: The neurotransmitter dopamine inhibits angiogenesis induced by vascular permeability factor/vascular endothelial growth factor. Nat Med. 7:569–574. 2001. View Article : Google Scholar

162 

Lutgendorf SK, DeGeest K, Dahmoush L, Farley D, Penedo F, Bender D, Goodheart M, Buekers TE, Mendez L, Krueger G, Clevenger L, Lubaroff DM, Sood AK and Cole SW: Social isolation is associated with elevated tumor norepinephrine in ovarian carcinoma patients. Brain Behav Immun. 25:250–255. 2011. View Article : Google Scholar : PubMed/NCBI

163 

Basile JR, Castilho RM, Williams VP and Gutkind JS: Semaphorin 4D provides a link between axon guidance processes and tumor-induced angiogenesis. Proc Natl Acad Sci USA. 103:9017–9022. 2006. View Article : Google Scholar : PubMed/NCBI

164 

Kigel B, Rabinowicz N, Varshavsky A, Kessler O and Neufeld G: Plexin-A4 promotes tumor progression and tumor angiogenesis by enhancement of VEGF and bFGF signaling. Blood. 118:4285–4296. 2011. View Article : Google Scholar : PubMed/NCBI

165 

Casazza A, Fu X, Johansson I, Capparuccia L, Andersson F, Giustacchini A, Squadrito ML, Venneri MA, Mazzone M, Larsson E, Carmeliet P, De Palma M, Naldini L, Tamagnone L and Rolny C: Systemic and targeted delivery of semaphorin 3A inhibits tumor angiogenesis and progression in mouse tumor models. Arterioscler Thromb Vasc Biol. 31:741–749. 2011. View Article : Google Scholar : PubMed/NCBI

166 

Sakurai A, Doci C and Gutkind JS: Semaphorin signaling in angiogenesis, lymphangiogenesis and cancer. Cell Res. 22:23–32. 2012. View Article : Google Scholar : PubMed/NCBI

167 

Toda M, Suzuki T, Hosono K, Hayashi I, Hashiba S, Onuma Y, Amano H, Kurihara Y, Kurihara H, Okamoto H, Hoka S and Majima M: Neuronal system-dependent facilitation of tumor angiogenesis and tumor growth by calcitonin gene-related peptide. Proc Natl Acad Sci USA. 105:13550–13555. 2008. View Article : Google Scholar : PubMed/NCBI

168 

Lee EW, Michalkiewicz M, Kitlinska J, Kalezic I, Switalska H, Yoo P, Sangkharat A, Ji H, Li L, Michalkiewicz T, Ljubisavljevic M, Johansson H, Grant DS and Zukowska Z: Neuropeptide Y induces ischemic angiogenesis and restores function of ischemic skeletal muscles. J Clin Invest. 111:1853–1862. 2003. View Article : Google Scholar : PubMed/NCBI

169 

Filipski E and Levi F: Circadian disruption in experimental cancer processes. Integr Cancer Ther. 8:298–302. 2009. View Article : Google Scholar : PubMed/NCBI

170 

Goodwin AM and D'Amore PA: Wnt signaling in the vasculature. Angiogenesis. 5:1–9. 2002. View Article : Google Scholar : PubMed/NCBI

171 

Masckauchan TN and Kitajewski J: Wnt/Frizzled signaling in the vasculature: new angiogenic factors in sight. Physiology (Bethesda). 21:181–188. 2006. View Article : Google Scholar : PubMed/NCBI

172 

Adams RH and Eichmann A: Axon guidance molecules in vascular patterning. Cold Spring Harb Perspect Biol. 2:a18752010. View Article : Google Scholar

173 

Melani M and Weinstein BM: Common factors regulating patterning of the nervous and vascular systems. Annu Rev Cell Dev Biol. 26:639–665. 2010. View Article : Google Scholar : PubMed/NCBI

174 

Carmeliet P and Tessier-Lavigne M: Common mechanisms of nerve and blood vessel wiring. Nature. 436:193–200. 2005. View Article : Google Scholar : PubMed/NCBI

175 

Entschladen F, Palm D, Drell TT, Lang K and Zaenker KS: Connecting a tumor to the environment. Curr Pharm Des. 13:3440–3444. 2007. View Article : Google Scholar : PubMed/NCBI

176 

Capparuccia L and Tamagnone L: Semaphorin signaling in cancer cells and in cells of the tumor microenvironment - two sides of a coin. J Cell Sci. 122:1723–1736. 2009. View Article : Google Scholar : PubMed/NCBI

177 

Schirrmacher V, Fogel M, Russmann E, Bosslet K, Altevogt P and Beck L: Antigenic variation in cancer metastasis: immune escape versus immune control. Cancer Metastasis Rev. 1:241–274. 1982. View Article : Google Scholar : PubMed/NCBI

178 

Tan W, Zhang W, Strasner A, Grivennikov S, Cheng JQ, Hoffman RM and Karin M: Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL-RANK signalling. Nature. 470:548–553. 2011. View Article : Google Scholar : PubMed/NCBI

179 

Rabin BS, Cohen S, Ganguli R, Lysle DT and Cunnick JE: Bidirectional interaction between the central nervous system and the immune system. Crit Rev Immunol. 9:279–312. 1989.PubMed/NCBI

180 

Steinman L: Connections between the immune system and the nervous system. Proc Natl Acad Sci USA. 90:7912–7914. 1993. View Article : Google Scholar : PubMed/NCBI

181 

Grivennikov SI, Greten FR and Karin M: Immunity, inflammation, and cancer. Cell. 140:883–899. 2010. View Article : Google Scholar

182 

Lin WW and Karin M: A cytokine-mediated link between innate immunity, inflammation, and cancer. J Clin Invest. 117:1175–1183. 2007. View Article : Google Scholar : PubMed/NCBI

183 

Karin M and Greten FR: NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol. 5:749–759. 2005. View Article : Google Scholar : PubMed/NCBI

184 

Ben-Eliyahu S, Yirmiya R, Liebeskind JC, Taylor AN and Gale RP: Stress increases metastatic spread of a mammary tumor in rats: evidence for mediation by the immune system. Brain Behav Immun. 5:193–205. 1991. View Article : Google Scholar : PubMed/NCBI

185 

Ben-Eliyahu S, Page GG, Yirmiya R and Shakhar G: Evidence that stress and surgical interventions promote tumor development by suppressing natural killer cell activity. Int J Cancer. 80:880–888. 1999. View Article : Google Scholar : PubMed/NCBI

186 

Levy SM, Herberman RB, Lippman M, D'Angelo T and Lee J: Immunological and psychosocial predictors of disease recurrence in patients with early-stage breast cancer. Behav Med. 17:67–75. 1991. View Article : Google Scholar : PubMed/NCBI

187 

Logan RW and Sarkar DK: Circadian nature of immune function. Mol Cell Endocrinol. 349:82–90. 2012. View Article : Google Scholar

188 

Rana S and Mahmood S: Circadian rhythm and its role in malignancy. J Circadian Rhythms. 8:32010. View Article : Google Scholar : PubMed/NCBI

189 

Kiecolt-Glaser JK and Glaser R: Psychoneuroimmunology and cancer: fact or fiction? Eur J Cancer. 35:1603–1607. 1999. View Article : Google Scholar : PubMed/NCBI

190 

Tracey KJ: The inflammatory reflex. Nature. 420:853–859. 2002. View Article : Google Scholar

191 

Libert C: Inflammation: A nervous connection. Nature. 421:328–329. 2003. View Article : Google Scholar : PubMed/NCBI

192 

Rosas-Ballina M and Tracey KJ: Cholinergic control of inflammation. J Intern Med. 265:663–679. 2009. View Article : Google Scholar

193 

Rosenberger P, Schwab JM, Mirakaj V, Masekowsky E, Mager A, Morote-Garcia JC, Unertl K and Eltzschig HK: Hypoxia-inducible factor-dependent induction of netrin-1 dampens inflammation caused by hypoxia. Nat Immunol. 10:195–202. 2009. View Article : Google Scholar : PubMed/NCBI

194 

Tracey KJ: Reflex control of immunity. Nat Rev Immunol. 9:418–428. 2009. View Article : Google Scholar : PubMed/NCBI

195 

Van Der Zanden EP, Boeckxstaens GE and de Jonge WJ: The vagus nerve as a modulator of intestinal inflammation. Neurogastroenterol Motil. 21:6–17. 2009.PubMed/NCBI

196 

Ley S, Weigert A and Brune B: Neuromediators in inflammation - a macrophage/nerve connection. Immunobiology. 215:674–684. 2010. View Article : Google Scholar : PubMed/NCBI

197 

Meregnani J, Clarencon D, Vivier M, Peinnequin A, Mouret C, Sinniger V, Picq C, Job A, Canini F, Jacquier-Sarlin M and Bonaz B: Anti-inflammatory effect of vagus nerve stimulation in a rat model of inflammatory bowel disease. Auton Neurosci. 160:82–89. 2011. View Article : Google Scholar : PubMed/NCBI

198 

Pohanka M, Snopkova S, Havlickova K, Bostik P, Sinkorova Z, Fusek J, Kuca K and Pikula J: Macrophage-assisted inflammation and pharmacological regulation of the cholinergic anti-inflammatory pathway. Curr Med Chem. 18:539–551. 2011. View Article : Google Scholar : PubMed/NCBI

199 

Cerejeira J, Nogueira V, Luis P, Vaz-Serra A and Mukaetova-Ladinska EB: The cholinergic system and inflammation: common pathways in delirium pathophysiology. J Am Geriatr Soc. 60:669–675. 2012. View Article : Google Scholar : PubMed/NCBI

200 

Peterson CY, Krzyzaniak M, Coimbra R and Chang DC: Vagus nerve and postinjury inflammatory response. Arch Surg. 147:76–80. 2012. View Article : Google Scholar : PubMed/NCBI

201 

Kiecolt-Glaser JK, Preacher KJ, MacCallum RC, Atkinson C, Malarkey WB and Glaser R: Chronic stress and age-related increases in the proinflammatory cytokine IL-6. Proc Natl Acad Sci USA. 100:9090–9095. 2003. View Article : Google Scholar : PubMed/NCBI

202 

Madden KS, Szpunar MJ and Brown EB: beta-Adrenergic receptors (beta-AR) regulate VEGF and IL-6 production by divergent pathways in high beta-AR-expressing breast cancer cell lines. Breast Cancer Res Treat. 130:747–758. 2011. View Article : Google Scholar : PubMed/NCBI

203 

Yang EV, Kim SJ, Donovan EL, Chen M, Gross AC, Webster MJ, Barsky SH and Glaser R: Norepinephrine upregulates VEGF, IL-8, and IL-6 expression in human melanoma tumor cell lines: implications for stress-related enhancement of tumor progression. Brain Behav Immun. 23:267–275. 2009. View Article : Google Scholar : PubMed/NCBI

204 

Stathopoulos GT, Sherrill TP, Han W, Sadikot RT, Yull FE, Blackwell TS and Fingleton B: Host nuclear factor-kappaB activation potentiates lung cancer metastasis. Mol Cancer Res. 6:364–371. 2008. View Article : Google Scholar : PubMed/NCBI

205 

Paradisi A and Mehlen P: Netrin-1, a missing link between chronic inflammation and tumor progression. Cell Cycle. 9:1253–1262. 2010. View Article : Google Scholar : PubMed/NCBI

206 

Pantel K and Brakenhoff RH: Dissecting the metastatic cascade. Nat Rev Cancer. 4:448–456. 2004. View Article : Google Scholar : PubMed/NCBI

207 

Rafii S, Lyden D, Benezra R, Hattori K and Heissig B: Vascular and haematopoietic stem cells: novel targets for anti-angiogenesis therapy? Nat Rev Cancer. 2:826–835. 2002. View Article : Google Scholar : PubMed/NCBI

208 

Direkze NC, Hodivala-Dilke K, Jeffery R, Hunt T, Poulsom R, Oukrif D, Alison MR and Wright NA: Bone marrow contribution to tumor-associated myofibroblasts and fibroblasts. Cancer Res. 64:8492–8495. 2004. View Article : Google Scholar : PubMed/NCBI

209 

Ishii G, Sangai T, Oda T, Aoyagi Y, Hasebe T, Kanomata N, Endoh Y, Okumura C, Okuhara Y, Magae J, Emura M, Ochiya T and Ochiai A: Bone-marrow-derived myofibroblasts contribute to the cancer-induced stromal reaction. Biochem Biophys Res Commun. 309:232–240. 2003. View Article : Google Scholar : PubMed/NCBI

210 

Psaila B and Lyden D: The metastatic niche: adapting the foreign soil. Nat Rev Cancer. 9:285–293. 2009. View Article : Google Scholar : PubMed/NCBI

211 

Kaplan RN, Riba RD, Zacharoulis S, Bramley AH, Vincent L, Costa C, MacDonald DD, Jin DK, Shido K, Kerns SA, Zhu Z, Hicklin D, Wu Y, Port JL, Altorki N, Port ER, Ruggero D, Shmelkov SV, Jensen KK, Rafii S and Lyden D: VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature. 438:820–827. 2005. View Article : Google Scholar

212 

Miyan JA, Broome CS and Whetton AD: Neural regulation of bone marrow. Blood. 92:2971–2973. 1998.PubMed/NCBI

213 

Canaani J, Kollet O and Lapidot T: Neural regulation of bone, marrow, and the microenvironment. Front Biosci. 3:1021–1031. 2011. View Article : Google Scholar : PubMed/NCBI

214 

Benestad HB, Strom-Gundersen I, Iversen PO, Haug E and Nja A: No neuronal regulation of murine bone marrow function. Blood. 91:1280–1287. 1998.PubMed/NCBI

215 

Artico M, Bosco S, Cavallotti C, Agostinelli E, Giuliani-Piccari G, Sciorio S, Cocco L and Vitale M: Noradrenergic and cholinergic innervation of the bone marrow. Int J Mol Med. 10:77–80. 2002.PubMed/NCBI

216 

Imai S, Tokunaga Y, Maeda T, Kikkawa M and Hukuda S: Calcitonin gene-related peptide, substance P, and tyrosine hydroxylase-immunoreactive innervation of rat bone marrows: an immunohistochemical and ultrastructural investigation on possible efferent and afferent mechanisms. J Orthop Res. 15:133–140. 1997. View Article : Google Scholar

217 

Singh D, Joshi DD, Hameed M, Qian J, Gascon P, Maloof PB, Mosenthal A and Rameshwar P: Increased expression of preprotachykinin-I and neurokinin receptors in human breast cancer cells: implications for bone marrow metastasis. Proc Natl Acad Sci USA. 97:388–393. 2000. View Article : Google Scholar : PubMed/NCBI

218 

Castro TA, Cohen MC and Rameshwar P: The expression of neurokinin-1 and preprotachykinin-1 in breast cancer cells depends on the relative degree of invasive and metastatic potential. Clin Exp Metastasis. 22:621–628. 2005. View Article : Google Scholar : PubMed/NCBI

219 

Lyden D, Hattori K, Dias S, Costa C, Blaikie P, Butros L, Chadburn A, Heissig B, Marks W, Witte L, Wu Y, Hicklin D, Zhu Z, Hackett NR, Crystal RG, Moore MA, Hajjar KA, Manova K, Benezra R and Rafii S: Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat Med. 7:1194–1201. 2001. View Article : Google Scholar : PubMed/NCBI

220 

Rajantie I, Ilmonen M, Alminaite A, Ozerdem U, Alitalo K and Salven P: Adult bone marrow-derived cells recruited during angiogenesis comprise precursors for periendothelial vascular mural cells. Blood. 104:2084–2086. 2004. View Article : Google Scholar

221 

Chakroborty D, Chowdhury UR, Sarkar C, Baral R, Dasgupta PS and Basu S: Dopamine regulates endothelial progenitor cell mobilization from mouse bone marrow in tumor vascularization. J Clin Invest. 118:1380–1389. 2008. View Article : Google Scholar : PubMed/NCBI

222 

Zhang W: Mesenchymal stem cells in cancer: friends or foes. Cancer Biol Ther. 7:252–254. 2008. View Article : Google Scholar : PubMed/NCBI

223 

Pollard JW: Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer. 4:71–78. 2004. View Article : Google Scholar : PubMed/NCBI

224 

Condeelis J and Pollard JW: Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell. 124:263–266. 2006. View Article : Google Scholar : PubMed/NCBI

225 

Qian BZ and Pollard JW: Macrophage diversity enhances tumor progression and metastasis. Cell. 141:39–51. 2010. View Article : Google Scholar : PubMed/NCBI

226 

Maestroni GJ: Catecholaminergic regulation of hematopoiesis in mice. Blood. 92:2971–2973. 1998.PubMed/NCBI

227 

Maestroni GJ: Dendritic cell migration controlled by alpha 1b-adrenergic receptors. J Immunol. 165:6743–6747. 2000. View Article : Google Scholar : PubMed/NCBI

228 

Katayama Y, Battista M, Kao WM, Hidalgo A, Peired AJ, Thomas SA and Frenette PS: Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow. Cell. 124:407–421. 2006. View Article : Google Scholar : PubMed/NCBI

229 

Mendez-Ferrer S, Lucas D, Battista M and Frenette PS: Haematopoietic stem cell release is regulated by circadian oscillations. Nature. 452:442–447. 2008. View Article : Google Scholar : PubMed/NCBI

230 

Bissell MJ and Radisky D: Putting tumours in context. Nat Rev Cancer. 1:46–54. 2001. View Article : Google Scholar : PubMed/NCBI

231 

Egeblad M, Nakasone ES and Werb Z: Tumors as organs: complex tissues that interface with the entire organism. Dev Cell. 18:884–901. 2010. View Article : Google Scholar : PubMed/NCBI

232 

Mareel M, Oliveira MJ and Madani I: Cancer invasion and metastasis: interacting ecosystems. Virchows Arch. 454:599–622. 2009. View Article : Google Scholar : PubMed/NCBI

233 

Ben-Eliyahu S, Shakhar G, Page GG, Stefanski V and Shakhar K: Suppression of NK cell activity and of resistance to metastasis by stress: a role for adrenal catecholamines and beta-adrenoceptors. Neuroimmunomodulat. 8:154–164. 2000. View Article : Google Scholar : PubMed/NCBI

234 

Schuller HM, Al-Wadei HA, Ullah MF and Plummer HK III: Regulation of pancreatic cancer by neuropsychological stress responses: a novel target for intervention. Carcinogenesis. 33:191–196. 2012. View Article : Google Scholar : PubMed/NCBI

235 

Yasuniwa Y, Izumi H, Wang KY, Shimajiri S, Sasaguri Y, Kawai K, Kasai H, Shimada T, Miyake K, Kashiwagi E, Hirano G, Kidani A, Akiyama M, Han B, Wu Y, Ieiri I, Higuchi S and Kohno K: Circadian disruption accelerates tumor growth and angio/stromagenesis through a Wnt signaling pathway. PLoS One. 5:e153302010. View Article : Google Scholar : PubMed/NCBI

236 

Arjona A and Sarkar DK: Are circadian rhythms the code of hypothalamic-immune communication? Insights from natural killer cells. Neurochem Res. 33:708–718. 2010. View Article : Google Scholar : PubMed/NCBI

237 

Filipski E, King VM, Li X, Granda TG, Mormont MC, Liu X, Claustrat B, Hastings MH and Levi F: Host circadian clock as a control point in tumor progression. J Natl Cancer Inst. 94:690–697. 2002. View Article : Google Scholar : PubMed/NCBI

238 

Andersen BL, Kiecolt-Glaser JK and Glaser R: A biobehavioral model of cancer stress and disease course. Am Psychol. 49:389–404. 1994. View Article : Google Scholar : PubMed/NCBI

239 

Spiegel D: Mind matters in cancer survival. Psychooncology. 21:588–593. 2012. View Article : Google Scholar : PubMed/NCBI

240 

Ebos JM, Lee CR, Cruz-Munoz W, Bjarnason GA, Christensen JG and Kerbel RS: Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell. 15:232–239. 2009. View Article : Google Scholar : PubMed/NCBI

241 

Rugo HS: Inhibiting angiogenesis in breast cancer: the beginning of the end or the end of the beginning? J Clin Oncol. 30:898–901. 2012. View Article : Google Scholar : PubMed/NCBI

242 

Pàez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H and Viñals F: Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell. 15:220–231. 2009.PubMed/NCBI

243 

Powe DG and Entschladen F: Targeted therapies: Using beta-blockers to inhibit breast cancer progression. Nat Rev Clin Oncol. 8:511–512. 2011. View Article : Google Scholar : PubMed/NCBI

244 

Barron TI, Connolly RM, Sharp L, Bennett K and Visvanathan K: Beta blockers and breast cancer mortality: a population-based study. J Clin Oncol. 29:2635–2644. 2011. View Article : Google Scholar : PubMed/NCBI

245 

Syromiatnikov AV and Alistratov AV: Changes in the efferent impulsation in the vagus nerves during the metastasis of Lewis lung carcinoma in mice. Eksp Onkol. 11:47–50. 1989.PubMed/NCBI

246 

Li ZJ and Cho CH: Neurotransmitters, more than meets the eye--neurotransmitters and their perspectives in cancer development and therapy. Eur J Pharmacol. 667:17–22. 2011. View Article : Google Scholar : PubMed/NCBI

247 

Schuller HM, Al-Wadei HA and Majidi M: GABA B receptor is a novel drug target for pancreatic cancer. Cancer. 112:767–778. 2008. View Article : Google Scholar : PubMed/NCBI

248 

Yang ZF, Ho DW, Lam CT, Luk JM, Lum CT, Yu WC, Poon RT and Fan ST: Identification of brain-derived neurotrophic factor as a novel functional protein in hepatocellular carcinoma. Cancer Res. 65:219–225. 2005.PubMed/NCBI

249 

Harburg GC and Hinck L: Navigating breast cancer: axon guidance molecules as breast cancer tumor suppressors and oncogenes. J Mammary Gland Biol Neoplasia. 16:257–270. 2011. View Article : Google Scholar : PubMed/NCBI

250 

Mehlen P, Delloye-Bourgeois C and Chedotal A: Novel roles for Slits and netrins: axon guidance cues as anticancer targets? Nat Rev Cancer. 11:188–197. 2011. View Article : Google Scholar : PubMed/NCBI

251 

Welch DR, Cooper CR, Hurst DR, Lynch CC, Martin MD, Vaidya KS, VanSaun MN and Mastro AM: Metastasis Research Society-American Association For Cancer Research Joint Conference on Metastasis. Cancer Res. 68:9578–9582. 2008. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

April 2013
Volume 5 Issue 4

Print ISSN: 1792-1074
Online ISSN:1792-1082

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Li S, Sun Y and Gao D: Role of the nervous system in cancer metastasis (Review). Oncol Lett 5: 1101-1111, 2013.
APA
Li, S., Sun, Y., & Gao, D. (2013). Role of the nervous system in cancer metastasis (Review). Oncology Letters, 5, 1101-1111. https://doi.org/10.3892/ol.2013.1168
MLA
Li, S., Sun, Y., Gao, D."Role of the nervous system in cancer metastasis (Review)". Oncology Letters 5.4 (2013): 1101-1111.
Chicago
Li, S., Sun, Y., Gao, D."Role of the nervous system in cancer metastasis (Review)". Oncology Letters 5, no. 4 (2013): 1101-1111. https://doi.org/10.3892/ol.2013.1168