Angiogenesis in primary colorectal cancer and matched metastatic tissues: Biological and clinical implications for anti‑angiogenic therapies

Yin,Lei; Li,Jianning; Ma,Dejian; Li,Donghua; Sun,Yanlai

doi:10.3892/ol.2020.11450

Angiogenesis in primary colorectal cancer and matched metastatic tissues: Biological and clinical implications for anti‑angiogenic therapies

Authors:
- Lei Yin
- Jianning Li
- Dejian Ma
- Donghua Li
- Yanlai Sun
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Affiliations: Department of Gastrointestinal Surgery, Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, Huzhou, Zhejiang 313000, P.R. China, The Central Sterile Supply Department, Affiliated Hospital of Shandong Academy of Medical Sciences, Jinan, Shandong 250031, P.R. China, School of Medicine and Life Sciences, University of Jinan‑Shandong Academy of Medical Sciences, Jinan, Shandong 250062, P.R. China, Department of Radiotherapy, Yuncheng People's Hospital, Yuncheng, Shandong 274700, P.R. China, Department of Gastrointestinal Cancer Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250117, P.R. China
Published online on: March 6, 2020 https://doi.org/10.3892/ol.2020.11450
Pages: 3558-3566
Copyright: © Yin et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Metastasis remains a notable issue in patients with newly diagnosed colorectal carcinomas (CRC). Although anti‑angiogenic therapies target metastatic diseases, hypoxia‑inducible factor‑1 α (HIF‑1α) and vascular endothelial growth factor (VEGF) status are routinely evaluated in primary tumors as metastatic sites are infrequently biopsied. The present study aimed to investigate the expression and significance of HIF‑1α, VEGF and microvascular density (MVD) in primary tumors and corresponding metastatic CRC tissues. HIF‑1α, VEGF and CD34 status were analyzed via immunohistochemistry analysis in 46 patients who underwent surgical resection of primary CRC (35 colon and 11 rectum) and matched metastases (lymph node and liver metastases) in Shandong Cancer Hospital. The association between selected biomarker status and clinicopathological characteristics was analyzed, and expression levels in primary tumors and corresponding metastases were compared. A total of 46 paired colorectal primary tumor and synchronous metastases samples were acquired for analysis using a standardized HIF‑1α, VEGF and CD34 immunohistochemical procedure. The results demonstrated that the positive rates of HIF‑1α and VEGF in primary CRC were 70 and 73.9%, respectively. HIF‑1α (60.9%) and VEGF (58.7%) expression decreased in the lymph metastatic samples compared with primary CRC. Conversely, the level of MVD in primary tumors was significantly higher compared with metastatic tumors. No significant differences were demonstrated between HIF‑1α and VEGF expression and the different clinicopathological features in primary CRC and corresponding metastases. Primary carcinomas and matched metastatic tissues demonstrated a moderate level of consistent immunoreactivity for HIF‑1α and VEGF. HIF‑1α, VEGF and CD34 were expressed in both primary tumors and corresponding metastases of CRC, suggesting that they may be involved in the development of metastasis. HIF‑1α and VEGF expression in primary sites was consistent with that observed in metastases; however, it varied from that exhibited in MVD. The current analysis will improve the current understanding of the metastasis models and provide further evidence for evaluating the response to HIF‑1α and VEGF inhibitors.

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1	Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA and Jemal A: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 68:394–424. 2018. View Article : Google Scholar : PubMed/NCBI
2	Song X, Zhao Z, Barber B, Gregory C, Schutt D and Gao S: Characterizing medical care by disease phase in metastatic colorectal cancer. Am J Manag Care. 17 (Suppl 5):SP20–SP25. 2011.PubMed/NCBI
3	Devesa H, Pereira L, Gonçalves A, Brito T, Almeida T, Torres R and Midoes A: Axillary lymph node metastasis of colon cancer-case report and literature review. Case Rep Clin Med. 12:669–673. 2014. View Article : Google Scholar
4	Kirstein MM, Lange A, Prenzler A, Manns MP, Kubicka S and Vogel A: Targeted therapies in metastatic colorectal cancer: A systematic review and assessment of currently available data. Oncologist. 19:1156–1168. 2014. View Article : Google Scholar : PubMed/NCBI
5	Kim DH, Sung B, Kang YJ, Hwang SY, Kim MJ, Yoon JH, Im E and Kim ND: Sulforaphane inhibits hypoxia-induced HIF-1α and VEGF expression and migration of human colon cancer cells. Int J Oncol. 47:2226–2232. 2015. View Article : Google Scholar : PubMed/NCBI
6	Ajith TA: Current insights and future perspectives of hypoxia-inducible factor targeted therapy in cancer. J Basic Clin Physiol Pharmacol. 30:11–18. 2018. View Article : Google Scholar : PubMed/NCBI
7	Semenza GL: HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. J Clin Invest. 123:3664–3671. 2013. View Article : Google Scholar : PubMed/NCBI
8	Nieves BJ, D'Amore PA and Bryan BA: The function of vascular endothelial growth factor. Biofactors. 35:332–337. 2009. View Article : Google Scholar : PubMed/NCBI
9	Iwasaki K, Yabushita H, Ueno T and Wakatsuki A: Role of hypoxia-inducible factor-1α, carbonic anhydrase-IX, glucose transporter-1 and vascular endothelial growth factor associated with lymph node metastasis and recurrence in patients with locally advanced cervical cancer. Oncol Lett. 10:1970–1978. 2015. View Article : Google Scholar : PubMed/NCBI
10	Brahimi-Horn MC, Chiche J and Pouyssegur J: Hypoxia and cancer. J Mol Med (Berl). 85:1301–1307. 2007. View Article : Google Scholar : PubMed/NCBI
11	Cohen SA, Yu M, Baker K, Redman M, Wu C, Heinzerling TJ, Wirtz RM, Charalambous E, Pentheroudakis G, Kotoula V, et al: The CpG island methylator phenotype is concordant between primary colorectal carcinoma and matched distant metastases. Clin Epigenetics. 9:462017. View Article : Google Scholar : PubMed/NCBI
12	Luo KJ, Hu Y, Wen J and Fu JH: CyclinD1, p53, E-cadherin, and VEGF discordant expression in paired regional metastatic lymph nodes of esophageal squamous cell carcinoma: A tissue array analysis. J Surg Oncol. 104:236–243. 2011. View Article : Google Scholar : PubMed/NCBI
13	Knosel T, Schluns K, Dietel M and Petersen I: Chromosomal alterations in lung metastases of colorectal carcinomas: Associations with tissue specific tumor dissemination. Clin Exp Metastasis. 22:533–538. 2005. View Article : Google Scholar : PubMed/NCBI
14	Wu Y, Jin M, Xu H, Shimin Z, He S, Wang L and Zhang Y: Clinicopathologic significance of HIF-1α, CXCR4, and VEGF expression in colon cancer. Clin Dev Immunol. 2010(pii): 5375312010.PubMed/NCBI
15	Qiu Y and Zhou H: Expression of HIF-1alpha and VEGF in human laryngeal carcinoma and its relationship with angiogenes. Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 28:389–393. 2014.(In Chinese). PubMed/NCBI
16	Matsuo Y, Ding Q, Desaki R, Maemura K, Mataki Y, Shinchi H, Natsugoe S and Takao S: Hypoxia inducible factor-1 alpha plays a pivotal role in hepatic metastasis of pancreatic cancer: An immunohistochemical study. J Hepatobiliary Pancreat Sci. 21:105–112. 2014. View Article : Google Scholar : PubMed/NCBI
17	Schlingemann RO, Rietveld FJ, de Waal RM, Bradley NJ, Skene AI, Davies AJ, Greaves MF, Denekamp J and Ruiter DJ: Leukocyte antigen CD34 is expressed by a subset of cultured endothelial cells and on endothelial abluminal microprocesses in the tumor stroma. Lab Invest. 62:690–696. 1990.PubMed/NCBI
18	Hlatky L, Hahnfeldt P and Folkman J: Clinical application of antiangiogenic therapy: microvessel density, what it does and doesn't tell us. J Natl Cancer Inst. 94:883–893. 2002. View Article : Google Scholar : PubMed/NCBI
19	Shimomura M, Hinoi T, Kuroda S, Adachi T, Kawaguchi Y, Sasada T, Takakura Y, Egi H, Okajima M, Tashiro H, et al: Overexpression of hypoxia inducible factor-1 alpha is an independent risk factor for recurrence after curative resection of colorectal liver metastases. Ann Surg Oncol. 20 (Suppl 3):S527–S536. 2013. View Article : Google Scholar : PubMed/NCBI
20	Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, et al: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 350:2335–2342. 2004. View Article : Google Scholar : PubMed/NCBI
21	Jensen NF, Smith DH, Nygard SB, Romer MU, Nielsen KV and Brunner N: Predictive biomarkers with potential of converting conventional chemotherapy to targeted therapy in patients with metastatic colorectal cancer. Scand J Gastroenterol. 47:340–355. 2012. View Article : Google Scholar : PubMed/NCBI
22	Ulivi P, Marisi G and Passardi A: Relationship between hypoxia and response to antiangiogenic therapy in metastatic colorectal cancer. Oncotarget. 7:46678–46691. 2016. View Article : Google Scholar : PubMed/NCBI
23	Cao D, Hou M, Guan YS, Jiang M, Yang Y and Gou HF: Expression of HIF-1alpha and VEGF in colorectal cancer: Association with clinical outcomes and prognostic implications. BMC cancer. 9:4322009. View Article : Google Scholar : PubMed/NCBI
24	Simiantonaki N, Taxeidis M, Jayasinghe C, Kurzik-Dumke U and Kirkpatrick CJ: Hypoxia-inducible factor 1 alpha expression increases during colorectal carcinogenesis and tumor progression. BMC Cancer. 8:3202008. View Article : Google Scholar : PubMed/NCBI
25	Berk V, Deniz K, Bozkurt O, Ozaslan E, Karaca H, Inanc M, Duran AO and Ozkan M: Predictive significance of VEGF and HIF-1α expression in patients with metastatic colorectal cancer receiving chemotherapy combinations with bevacizumab. Asian Pac J Cancer Prev. 16:6149–6154. 2015. View Article : Google Scholar : PubMed/NCBI
26	Kurokawa T, Miyamoto M, Kato K, Cho Y, Kawarada Y, Hida Y, Shinohara T, Itoh T, Okushiba S, Kondo S and Katoh H: Overexpression of hypoxia-inducible-factor 1alpha (HIF-1alpha) in oesophageal squamous cell carcinoma correlates with lymph node metastasis and pathologic stage. Br J Cancer. 89:1042–1047. 2003. View Article : Google Scholar : PubMed/NCBI
27	Maxwell PH, Dachs GU, Gleadle JM, Nicholls LG, Harris AL, Stratford IJ, Hankinson O, Pugh CW and Ratcliffe PJ: Hypoxia-inducible factor-1 modulates gene expression in solid tumors and influences both angiogenesis and tumor growth. Proc Natl Acad Sci USA. 94:8104–8109. 1997. View Article : Google Scholar : PubMed/NCBI
28	Ioannou M, Paraskeva E, Baxevanidou K, Simos G, Papamichali R, Papacharalambous C, Samara M and Koukoulis G: HIF-1α in colorectal carcinoma: Review of the literature. J BUON. 20:680–689. 2015.PubMed/NCBI
29	Bar J, Herbst RS and Onn A: Targeted drug delivery strategies to treat lung metastasis. Expert Opin Drug Deliv. 6:1003–1016. 2009. View Article : Google Scholar : PubMed/NCBI
30	Shim H, Lau SK, Devi S, Yoon Y, Cho HT and Liang Z: Lower expression of CXCR4 in lymph node metastases than in primary breast cancers: Potential regulation by ligand-dependent degradation and HIF-1alpha. Biochem Biophys Res Commun. 346:252–258. 2006. View Article : Google Scholar : PubMed/NCBI
31	Fraga CA, de Oliveira MV, de Oliveira ES, Barros LO, Santos FB, Gomez RS, De-Paula AM and Guimarães AL: A high HIF-1α expression genotype is associated with poor prognosis of upper aerodigestive tract carcinoma patients. Oral Oncol. 48:130–135. 2012. View Article : Google Scholar : PubMed/NCBI
32	Jilaveanu LB, Puligandla M, Weiss SA, Wang XV, Zito C, Flaherty KT, Boeke M, Neumeister V, Camp RL, Adeniran A, Pins M, et al: Tumor microvessel density as a prognostic marker in high-risk renal cell carcinoma patients treated on ECOG-ACRIN E2805. Clin Cancer Res. 24:217–223. 2018. View Article : Google Scholar : PubMed/NCBI
33	Peeters CF, Westphal JR, de Waal RM, Ruiter DJ, Wobbes T and Ruers TJ: Vascular density in colorectal liver metastases increases after removal of the primary tumor in human cancer patients. Int J Cancer. 112:554–559. 2004. View Article : Google Scholar : PubMed/NCBI
34	Guo M, Mu Y, Yu D, Li J, Chen F, Wei B, Bi S, Yu J and Liang F: Comparison of the expression of TGF-β1, E-cadherin, N-cadherin, TP53, RB1CC1 and HIF-1α in oral squamous cell carcinoma and lymph node metastases of humans and mice. Oncol Lett. 15:1639–1645. 2018.PubMed/NCBI
35	Jeong HS, Jones D, Liao S, Wattson DA, Cui CH, Duda DG, Willett CG, Jain RK and Padera TP: Investigation of the lack of angiogenesis in the formation of lymph node metastases. J Natl Cancer Inst. 107(pii): djv1552015.PubMed/NCBI
36	Roberts N, Kloos B, Cassella M, Podgrabinska S, Persaud K, Wu Y, Pytowski B and Skobe M: Inhibition of VEGFR-3 activation with the antagonistic antibody more potently suppresses lymph node and distant metastases than inactivation of VEGFR-2. Cancer Res. 66:2650–2657. 2006. View Article : Google Scholar : PubMed/NCBI
37	Willett CG, Duda DG, Ancukiewicz M, Shah M, Czito BG, Bentley R, Poleski M, Fujita H, Lauwers GY, Carroll M, et al: A safety and survival analysis of neoadjuvant bevacizumab with standard chemoradiation in a phase I/II study compared with standard chemoradiation in locally advanced rectal cancer. Oncologist. 15:845–851. 2010. View Article : Google Scholar : PubMed/NCBI
38	Stessels F, Van den Eynden G, Van der Auwera I, Salgado R, V n den Heuvel E, Harris AL, Jackson DG, Colpaert CG, van Marck EA, Dirix LY and Vermeulen PB: Breast adenocarcinoma liver metastases, in contrast to colorectal cancer liver metastases, display a non-angiogenic growth pattern that preserves the stroma and lacks hypoxia. Br J Cancer. 90:1429–1436. 2004. View Article : Google Scholar : PubMed/NCBI
39	van der Wal GE, Gouw AS, Kamps JA, Moorlag HE, Bulthuis ML, Molema G and de Jong KP: Angiogenesis in synchronous and metachronous colorectal liver metastases: The liver as a permissive soil. Ann Surg. 255:86–94. 2012. View Article : Google Scholar : PubMed/NCBI
40	Rajaganeshan R, Prasad R, Guillou PJ, Scott N, Poston G and Jayne DG: Expression patterns of hypoxic markers at the invasive margin of colorectal cancers and liver metastases. Eur J Surg Oncol. 35:1286–1294. 2009. View Article : Google Scholar : PubMed/NCBI
41	Raluca BA, Cimpean AM, Cioca A, Cretu O, Mederle O, Ciolofan A, Gaje P and Raica M: Endothelial cell proliferation and vascular endothelial growth factor expression in primary colorectal cancer and corresponding liver metastases. Asian Pac J Cancer Prev. 6:4549–4553. 2015. View Article : Google Scholar
42	Sandhu J, Lavingia V and Fakih M: Systemic treatment for metastatic colorectal cancer in the era of precision medicine. J Surg Oncol. 119:564–582. 2019. View Article : Google Scholar : PubMed/NCBI
43	Kim YW, Ko YT, Kim NK, Chung HC, Min BS, Lee KY, Park JP and Kim H: A comparative study of protein expression in primary colorectal cancer and synchronous hepatic metastases: The significance of matrix metalloproteinase-1 expression as a predictor of liver metastasis. Scand J Gastroenterol. 45:217–225. 2010. View Article : Google Scholar : PubMed/NCBI
44	Nakamoto RH, Uetake H, Iida S, Kolev YV, Soumaoro LT, Takagi Y, Yasuno M and Sugihara K: Correlations between cyclooxygenase-2 expression and angiogenic factors in primary tumors and liver metastases in colorectal cancer. Jpn J Clin Oncol. 37:679–685. 2007. View Article : Google Scholar : PubMed/NCBI
45	Kobayashi H, Sugihara K, Uetake H, Higuchi T, Yasuno M, Enomoto M, Kuramochi H, Lenz HJ, Danenberg KD and Danenberg PV: Messenger RNA expression of vascular endothelial growth factor and its receptors in primary colorectal cancer and corresponding liver metastasis. Ann Surg Oncol. 15:1232–1238. 2008. View Article : Google Scholar : PubMed/NCBI
46	Klein CA: Parallel progression of primary tumors and metastases. Nat Rev Cancer. 9:302–312. 2009. View Article : Google Scholar : PubMed/NCBI