Targeting CXC motif chemokine receptor 4 inhibits the proliferation, migration and angiogenesis of lung cancer cells

He,Wei; Yang,Tong; Gong,Xin‑Hua; Qin,Ru‑Zhai; Zhang,Xiao‑Dong; Liu,Wen‑Dan

doi:10.3892/ol.2018.9076

Targeting CXC motif chemokine receptor 4 inhibits the proliferation, migration and angiogenesis of lung cancer cells

Authors:
- Wei He
- Tong Yang
- Xin‑Hua Gong
- Ru‑Zhai Qin
- Xiao‑Dong Zhang
- Wen‑Dan Liu
View Affiliations

Affiliations: Department of Medical Oncology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 511447, P.R. China, Department of Pathology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 511447, P.R. China, Department of General Medicine, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 511447, P.R. China
Published online on: July 4, 2018 https://doi.org/10.3892/ol.2018.9076
Pages: 3976-3982

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

An increasing volume of data indicates that disrupting the interaction between CXC motif chemokine receptor 4 (CXCR4) and its specific ligand, CXC motif chemokine 12 (CXCL12), may reduce tumor growth and metastasis. However, the translation from bench to bedside must be performed with extreme caution, as the CXCR4/CXCL12 axis is crucial for the normal development and maintenance of tissues and organs. In the present study, Cell Counting Kit‑8 and Transwell migration assays were used to detect in vitro proliferation and chemotaxis of CXCR4‑expressing A549 cells, a cell strain originating from human non‑small‑cell lung cancer (NSCLC), with or without the presence of AMD3100, a small‑molecule inhibitor specific to CXCR4 signaling. In a xenograft model established by injecting nude mice with A549 cells, tumor growth, CXCR4 expression and microvessel density (MVD) in the tumor mass were determined through tumor size measurements and immunohistochemical staining following intraperitoneal administration of AMD3100 or vehicle. The results demonstrated that CXCR4 blockade inhibited the proliferation of A549 cells and their migration towards CXCL12 in vitro. Tumor growth, CXCR4 expression and MVD were markedly reduced in nude mice treated with AMD3100 compared with mice treated with the vehicle. In conclusion, the present data demonstrated that CXCR4 targeting impaired NSCLC cell growth, angiogenesis and metastatic spread, indicating that it may represent a novel treatment strategy for NSCLC.

View Figures

View References

1	Siegel R, Naishadham D and Jemal A: Cancer statistics, 2012. CA Cancer J Clin. 62:10–29. 2012. View Article : Google Scholar : PubMed/NCBI
2	Siegel R, DeSantis C, Virgo K, Stein K, Mariotto A, Smith T, Cooper D, Gansler T, Lerro C, Fedewa S, et al: Cancer treatment and survivorship statistics, 2012. CA Cancer J Clin. 62:220–241. 2012. View Article : Google Scholar : PubMed/NCBI
3	Roy I, Evans DB and Dwinell MB: Chemokines and chemokine receptors: Update on utility and challenges for the clinician. Surgery. 155:961–973. 2014. View Article : Google Scholar : PubMed/NCBI
4	Chatterjee S, Azad Behnam B and Nimmagadda S: The intricate role of CXCR4 in cancer. Adv Cancer Res. 124:31–82. 2014. View Article : Google Scholar : PubMed/NCBI
5	Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, McClanahan T, Murphy E, Yuan W and Wagner SN: Involvement of chemokine receptors in breast cancer metastasis. Nature. 410:50–56. 2001. View Article : Google Scholar : PubMed/NCBI
6	Sarvaiya PJ, Guo D, Ulasov I, Gabikian P and Lesniak MS: Chemokines in tumor progression and metastasis. Oncotarget. 4:2171–2185. 2013. View Article : Google Scholar : PubMed/NCBI
7	Wu Y, Zhang C, Xu W, Zhang J, Zheng Y, Lu Z, Liu D and Jiang K: CXC motif chemokine receptor 4 gene polymorphism and cancer risk. Medicine (Baltimore). 95:e53172016. View Article : Google Scholar : PubMed/NCBI
8	Zhao H, Guo L, Zhao H, Zhao J, Weng H and Zhao B: CXCR4 over-expression and survival in cancer: A system review and meta-analysis. Oncotarget. 6:5022–5040. 2015.PubMed/NCBI
9	Zhou XM, He L, Hou G, Jiang B, Wang YH and Zhao L: Clinicopathological significance of CXCR4 in non-small cell lung cancer. Drug Des Devel Ther. 9:1349–1358. 2015. View Article : Google Scholar : PubMed/NCBI
10	Wang L, Wang Z, Liu X and Liu F: High-level C-X-C chemokine receptor type 4 expression correlates with brain-specific metastasis following complete resection of non-small cell lung cancer. Oncol Lett. 7:1871–1876. 2014. View Article : Google Scholar : PubMed/NCBI
11	Wald O, Shapira OM and Izhar U: CXCR4/CXCL12 axis in non small cell lung cancer (NSCLC) pathologic roles and therapeutic potential. Theranostics. 3:26–33. 2013. View Article : Google Scholar : PubMed/NCBI
12	Liu T, Li X, You S, Bhuyan SS and Dong L: Effectiveness of AMD3100 in treatment of leukemia and solid tumors: From original discovery to use in current clinical practice. Exp Hematol Oncol. 5:192016. View Article : Google Scholar : PubMed/NCBI
13	Brennecke P, Arlt MJ, Campanile C, Husmann K, Gvozdenovic A, Apuzzo T, Thelen M, Born W and Fuchs B: CXCR4 antibody treatment suppresses metastatic spread to the lung of intratibial human osteosarcoma xenografts in mice. Clin Exp Metastasis. 31:339–349. 2014. View Article : Google Scholar : PubMed/NCBI
14	Ullman-Cullere MH and Foltz CJ: Body conditioning scoring: A rapid and accurate method for assessing health status in mice. Lab Anim Sci. 49:319–323. 1999.PubMed/NCBI
15	Sun X, Charbonneau C, Wei L, Yang W, Chen Q and Terek RM: CXCR4-targeted therapy inhibits VEGF expression and chondrosarcoma angiogenesis and metastasis. Mol Cancer Ther. 12:1163–1170. 2013. View Article : Google Scholar : PubMed/NCBI
16	Marechal R, Demetter P, Nagy N, Berton A, Decaestecker C, Polus M, Closset J, Devière J, Salmon I and Van Laethem JL: High expression of CXCR4 may predict poor survival in resected pancreatic adenocarcinoma. Br J cancer 5. 100:1444–1451. 2009. View Article : Google Scholar
17	Sood AK, Fletcher MS, Gruman LM, Coffin JE, Jabbari S, Khalkhali-Ellis Z, Arbour N, Seftor EA and Hendrix MJ: The paradoxical expression of maspin in ovarian carcinoma. Clin Cancer Res. 8:2924–2932. 2002.PubMed/NCBI
18	Weidner N, Semple JP, Welch WR and Folkman J: Tumor angiogenesis and metastasis-correlation in invasive breast carcinoma. N Engl J Med. 324:1–8. 1991. View Article : Google Scholar : PubMed/NCBI
19	Liu Y, Wu BQ, Geng H, Xu ML and Zhong HH: Association of chemokine and chemokine receptor expression with the invasion and metastasis of lung carcinoma. Oncol Lett. 10:1315–1322. 2015. View Article : Google Scholar : PubMed/NCBI
20	Gil M, Seshadri M, Komorowski MP, Abrams SI and Kozbor D: Targeting CXCL12/CXCR4 signaling with oncolytic virotherapy disrupts tumor vasculature and inhibits breast cancer metastases. Proc Natl Acad Sci USA. 110:E1291–E1300. 2013. View Article : Google Scholar : PubMed/NCBI
21	Choi WT, Yang Y, Xu Y and An J: Targeting chemokine receptor CXCR4 for treatment of HIV-1 infection, tumor progression, and metastasis. Curr Top Med Chem. 14:1574–1589. 2014. View Article : Google Scholar : PubMed/NCBI
22	Liang S, Peng X, Li X, Yang P, Xie L, Li Y, Du C and Zhang G: Silencing of CXCR4 sensitizes triple-negative breast cancer cells to cisplatin. Oncotarget. 6:1020–1030. 2015. View Article : Google Scholar : PubMed/NCBI
23	DiPersio JF, Stadtmauer EA, Nademanee A, Micallef IN, Stiff PJ, Kaufman JL, Maziarz RT, Hosing C, Früehauf S, Horwitz M, et al: Plerixafor and G-CSF versus placebo and G-CSF to mobilize hematopoietic stem cells for autologous stem cell transplantation in patients with multiple myeloma. Blood. 113:5720–5726. 2009.PubMed/NCBI
24	Nikkhoo B, Jalili A, Fakhari S, Sheikhesmaili F, Fathi F, Rooshani D, Feizi Hoseinpour MA and Nikzaban M: Nuclear pattern of CXCR4 expression is associated with a better overall survival in patients with gastric cancer. J Oncol. 2014:8080122014. View Article : Google Scholar : PubMed/NCBI
25	Spano JP, Andre F, Morat L, Sabatier L, Besse B, Combadiere C, Deterre P, Martin A, Azorin J, Valeyre D, et al: Chemokine receptor CXCR4 and early-stage non-small cell lung cancer: Pattern of expression and correlation with outcome. Ann Oncol. 15:613–617. 2004. View Article : Google Scholar : PubMed/NCBI
26	Popple A, Durrant LG, Spendlove I, Rolland P, Scott IV, Deen S and Ramage JM: The chemokine, CXCL12, is an independent predictor of poor survival in ovarian cancer. Br J Cancer. 106:1306–1313. 2012. View Article : Google Scholar : PubMed/NCBI
27	Minamiya Y, Saito H, Takahashi N, Ito M, Imai K, Ono T, Motoyama S and Ogawa J: Expression of the chemokine receptor CXCR4 correlates with a favorable prognosis in patients with adenocarcinoma of the lung. Lung Cancer. 68:466–471. 2010. View Article : Google Scholar : PubMed/NCBI
28	Yadav SS, Prasad SB, Das M, Kumari S, Pandey LK, Singh S, Pradhan S and Narayan G: Epigenetic silencing of CXCR4 promotes loss of cell adhesion in cervical cancer. Biomed Res Int. 2014:5814032014. View Article : Google Scholar : PubMed/NCBI
29	Mirisola V, Zuccarino A, Bachmeier BE, Sormani MP, Falter J, Nerlich A and Pfeffer U: CXCL12/SDF1 expression by breast cancers is an independent prognostic marker of disease-free and overall survival. Eur J Cancer. 45:2579–2587. 2009. View Article : Google Scholar : PubMed/NCBI
30	Roy I, Zimmerman NP, Mackinnon AC, Tsai S, Evans DB and Dwinell MB: CXCL12 chemokine expression suppresses human pancreatic cancer growth and metastasis. PLoS One. 9:e904002014. View Article : Google Scholar : PubMed/NCBI
31	Wendt MK, Johanesen PA, Kang-Decker N, Binion DG, Shah V and Dwinell MB: Silencing of epithelial CXCL12 expression by DNA hypermethylation promotes colonic carcinoma metastasis. Oncogene. 25:4986–4997. 2006. View Article : Google Scholar : PubMed/NCBI
32	Williams SA, Harata-Lee Y, Comerford I, Anderson RL, Smyth MJ and McColl SR: Multiple functions of CXCL12 in a syngeneic model of breast cancer. Mol Cancer. 9:2502010. View Article : Google Scholar : PubMed/NCBI
33	Gong X, Yang T, Liu W, Liao K and He W: Expression and clinical significance of chemokine receptor CXCR4 in non-small cell lung cancer. J Trop Med. 16:829–831. 2016.(In Chinese).
34	Popper HH: Progression and metastasis of lung cancer. Cancer Metastasis Rev. 35:75–91. 2016. View Article : Google Scholar : PubMed/NCBI
35	Righi E, Kashiwagi S, Yuan J, Santosuosso M, Leblanc P, Ingraham R, Forbes B, Edelblute B, Collette B, Xing D, et al: CXCL12/CXCR4 blockade induces multimodal antitumor effects that prolong survival in an immunocompetent mouse model of ovarian cancer. Cancer Res. 71:5522–5534. 2011. View Article : Google Scholar : PubMed/NCBI
36	Choi YH, Burdick MD, Strieter BA, Mehrad B and Strieter RM: CXCR4, but not CXCR7, discriminates metastatic behavior in non-small cell lung cancer cells. Mol Cancer Res. 12:38–47. 2014. View Article : Google Scholar : PubMed/NCBI
37	Rivas-Fuentes S, Salgado-Aguayo A, Belloso Pertuz S, Rosete Gorocica P, Alvarado-Vasquez N and Aquino-Jarquin G: Role of chemokines in non-small cell lung cancer: Angiogenesis and inflammation. J Cancer. 6:938–952. 2015. View Article : Google Scholar : PubMed/NCBI
38	Iakovlev VV, Gabril M, Dubinski W, Scorilas A, Youssef YM, Faragalla H, Kovacs K, Rotondo F, Metias S, Arsanious A, et al: Microvascular density as an independent predictor of clinical outcome in renal cell carcinoma: An automated image analysis study. Lab Invest. 92:46–56. 2012. View Article : Google Scholar : PubMed/NCBI
39	Weidner N, Carroll PR, Flax J, Blumenfeld W and Folkman J: Tumor angiogenesis correlates with metastasis in invasive prostate carcinoma. Am J Pathol. 143:401–409. 1993.PubMed/NCBI