Effects of CCL5 on the biological behavior of breast cancer and the mechanisms of its interaction with tumor‑associated macrophages

An,Gaili; Wu,Fang; Huang,Shangke; Feng,Lu; Bai,Jun; Gu,Shanzhi; Zhao,Xinhan

doi:10.3892/or.2019.7344

Effects of CCL5 on the biological behavior of breast cancer and the mechanisms of its interaction with tumor‑associated macrophages

Authors:
- Gaili An
- Fang Wu
- Shangke Huang
- Lu Feng
- Jun Bai
- Shanzhi Gu
- Xinhan Zhao
View Affiliations

Affiliations: Department of Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China, Department of Medical Neonatology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China, Department of Clinical Oncology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China, Department of College of Forensic Medicine, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, P.R. China
Published online on: October 1, 2019 https://doi.org/10.3892/or.2019.7344
Pages: 2499-2511
Copyright: © An et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The recurrence and metastasis of breast cancer limit the effectiveness of clinical treatments, making them important issues for clinicians to address. Tumor‑associated macrophages (TAMs) contribute to regulating the immune system. C‑C motif chemokine ligand 5 (CCL5) is an inflammatory chemokine that promotes chemotaxis on cells involved in the immune/inflammatory response. Breast cancer cells that secrete CCL5 act on THP‑1 cells, influencing the invasion and metastasis of tumors. However, knowledge remains limited regarding the mechanism underlying the effects of CCL5 on breast cancer cells and TAMs, as well as the mechanisms promoting the migration and invasion of breast cancer. The present study demonstrated that the positive expression of CCL5 was associated with lymph node status and tumor‑node‑metastasis stage. Treatment with ≥20 ng/ml CCL5 significantly promoted the migration and invasion of MCF‑7 and MDA‑MB‑231 cells. CCL5‑small interfering RNA intervention significantly decreased the migration and invasion of the two cell types. In vitro, THP‑1 cells were successfully induced to become TAMs, which were then recruited via the chemotactic effects of CCL5. This process was achieved through the co‑stimulation of phorbol‑12‑myristate‑13‑acetate, interleukin‑4 (IL‑4) and IL‑13. The nuclear factor‑κB (NF‑κB) signaling pathway was activated to regulate EMT, as well as the migration and invasion process of MCF‑7 cells, when co‑cultured with TAMs. We also reported that blocking the expression of CCL5 in vivo may significantly inhibit the growth of human breast cancer xenografts. Therefore, targeting CCL5 may be considered as a novel therapeutic strategy for suppressing the invasion and metastasis of breast cancer.

View Figures

View References

1	Jemal A, Center MM, DeSantis C and Ward EM: Global patterns of cancer incidence and mortality rates and trends. Cancer Epidemiol Biomarkers Prev. 19:1893–1907. 2010. View Article : Google Scholar : PubMed/NCBI
2	Mantovani A, Allavena P, Sica A and Balkwill F: Cancer-related inflammation. Nature. 454:436–444. 2008. View Article : Google Scholar : PubMed/NCBI
3	Sica A, Allavena P and Mantovani A: Cancer related inflammation: The macrophage connection. Cancer Lett. 267:204–215. 2008. View Article : Google Scholar : PubMed/NCBI
4	Lin EY, Nguyen AV, Russell RG and Pollard JW: Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy. J Exp Med. 193:727–740. 2001. View Article : Google Scholar : PubMed/NCBI
5	Lin EY and Pollard JW: Macrophages: Modulators of breast cancer progression. Novartis Found Symp. 256:158–168. 2004.PubMed/NCBI
6	Yang J, Liao D, Chen C, Liu Y, Chuang TH, Xiang R, Markowitz D, Reisfeld RA and Luo Y: Tumor-associated macrophages regulate murine breast cancer stem cells through a novel paracrine EGFR/Stat3/Sox-2 signaling pathway. Stem Cells. 31:248–258. 2013. View Article : Google Scholar : PubMed/NCBI
7	Donlon TA, Krensky AM, Wallace MR, Collins FS, Lovett M and Clayberger C: Localization of a human T-cell-specific gene, RANTES (D17S136E), to chromosome 17q11.2-q12. Genomics. 6:548–553. 1990. View Article : Google Scholar : PubMed/NCBI
8	Mrowietz U, Schwenk U, Maune S, Bartels J, Küpper M, Fichtner I, Schröder JM and Schadendorf D: The chemokine RANTES is secreted by human melanoma cells and is associated with enhanced tumour formation in nude mice. Br J Cancer. 79:1025–1031. 1999. View Article : Google Scholar : PubMed/NCBI
9	Wertel I, Tarkowski R, Bednarek W and Kotarski J: Relationship between RANTES and dendritic cells in ovarian cancer patients. Front Biosci (Elite Ed). 3:227–232. 2011. View Article : Google Scholar : PubMed/NCBI
10	Vaday GG, Peehl DM, Kadam PA and Lawrence DM: Expression of CCL5 (RANTES) and CCR5 in prostate cancer. Prostate. 66:124–134. 2006. View Article : Google Scholar : PubMed/NCBI
11	Soria G and Ben-Baruch A: The inflammatory chemokines CCL2 and CCL5 in breast cancer. Cancer Lett. 267:271–285. 2008. View Article : Google Scholar : PubMed/NCBI
12	Milliken D, Scotton C, Raju S, Balkwill F and Wilson J: Analysis of chemokines and chemokine receptor expression in ovarian cancer ascites. Clin Cancer Res. 8:1108–1114. 2002.PubMed/NCBI
13	Tang X: Tumor-associated macrophages as potential diagnostic and prognostic biomarkers in breast cancer. Cancer Lett. 332:3–10. 2013. View Article : Google Scholar : PubMed/NCBI
14	Greene FL, Page DL, Fleming ID, et al: AJCC cancer staging manual6th. Springer-Verlag; New York, NY: 2002
15	Tjiu JW, Chen JS, Shun CT, Lin SJ, Liao YH, Chu CY, Tsai TF, Chiu HC, Dai YS, Inoue H, et al: Tumor-associated macrophage-induced invasion and angiogenesis of human basal cell carcinoma cells by cyclooxygenase-2 induction. J Invest Dermatol. 129:1016–1025. 2009. View Article : Google Scholar : PubMed/NCBI
16	Siveen KS and Kuttan G: Role of macrophages in tumour progression. Immunol Lett. 123:97–102. 2009. View Article : Google Scholar : PubMed/NCBI
17	Wu H, Xu JB, He YL, Peng JJ, Zhang XH, Chen CQ, Li W and Cai SR: Tumor-associated macrophages promote angiogenesis and lymphangiogenesis of gastric cancer. J Surg Oncol. 106:462–468. 2012. View Article : Google Scholar : PubMed/NCBI
18	Lewis JS, Landers RJ, Underwood JC, Harris AL and Lewis CE: Expression of vascular endothelial growth factor by macrophages is up-regulated in poorly vascularized areas of breast carcinomas. J Pathol. 192:150–158. 2000. View Article : Google Scholar : PubMed/NCBI
19	Nagakawa Y, Aoki T, Kasuya K, Tsuchida A and Koyanagi Y: Histologic features of venous invasion, expression of vascular endothelial growth factor and matrix metalloproteinase-2 and matrix metalloproteinase-9, and the relation with liver metastasis in pancreatic cancer. Pancreas. 24:169–178. 2002. View Article : Google Scholar : PubMed/NCBI
20	Soria G, Ofri-Shahak M, Haas I, Yaal-Hahoshen N, Leider-Trejo L, Leibovich-Rivkin T, Weitzenfeld P, Meshel T, Shabtai E, Gutman M and Ben-Baruch A: Inflammatory mediators in breast cancer: Coordinated expression of TNFα & IL-1β with CCL2 & CCL5 and effects on epithelial-to-mesenchymal transition. BMC Cancer. 11:1302011. View Article : Google Scholar : PubMed/NCBI
21	Hagemann T, Robinson SC, Schulz M, Trümper L, Balkwill FR and Binder C: Enhanced invasiveness of breast cancer cell lines upon co-cultivation with macrophages is due to TNF-alpha dependent up-regulation of matrix metalloproteases. Carcinogenesis. 25:1543–1549. 2004. View Article : Google Scholar : PubMed/NCBI
22	Lim J and Thiery JP: Epithelial-mesenchymal transitions: Insights from development. Development. 139:3471–3486. 2012. View Article : Google Scholar : PubMed/NCBI
23	Aldinucci D and Colombatti A: The inflammatory chemokine CCL5 and cancer progression. Mediators Inflamm. 2014:2923762014. View Article : Google Scholar : PubMed/NCBI
24	Cambien B, Richard-Fiardo P, Karimdjee BF, Martini V, Ferrua B, Pitard B, Schmid-Antomarchi H and Schmid-Alliana A: CCL5 neutralization restricts cancer growth and potentiates the targeting of PDGFRβ in colorectal carcinoma. PLoS One. 6:e288422011. View Article : Google Scholar : PubMed/NCBI
25	Huber MA, Kraut N and Beug H: Molecular requirements for epithelial-mesenchymal transition during tumor progression. Curr Opin Cell Biol. 17:548–558. 2005. View Article : Google Scholar : PubMed/NCBI
26	Huber MA, Azoitei N, Baumann B, Grünert S, Sommer A, Pehamberger H, Kraut N, Beug H and Wirth T: NF-kappaB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression. J Clin Invest. 114:569–581. 2004. View Article : Google Scholar : PubMed/NCBI
27	Huang CY, Fong YC, Lee CY, Chen MY, Tsai HC, Hsu HC and Tang CH: CCL5 increases lung cancer migration via PI3K, Akt and NF-kappaB pathways. Biochem Pharmacol. 77:794–803. 2009. View Article : Google Scholar : PubMed/NCBI
28	Grivennikov SI, Greten FR and Karin M: Immunity, inflammation, and cancer. Cell. 140:883–899. 2010. View Article : Google Scholar : PubMed/NCBI
29	Bond M, Fabunmi RP, Baker AH and Newby AC: Synergistic upregulation of metalloproteinase-9 by growth factors and inflammatory cytokines: An absolute requirement for transcription factor NF-kappa B. FEBS Lett. 435:29–34. 1998. View Article : Google Scholar : PubMed/NCBI
30	Chen JJ, Lin YC, Yao PL, Yuan A, Chen HY, Shun CT, Tsai MF, Chen CH and Yang PC: Tumor-associated macrophages: The double-edged sword in cancer progression. J Clin Oncol. 23:953–964. 2005. View Article : Google Scholar : PubMed/NCBI