Autocrine MCP-1/CCR2 signaling stimulates proliferation and migration of renal carcinoma cells

• Published in: Oncology letters 2016-09, Vol.12 (3), p.2201-2209
• Main Authors: Küper, Christoph, Beck, Franz-Xaver, Neuhofer, Wolfgang
• Format: Article
• Language: English
• Subjects: 786-O cells; Angiogenesis; autocrine signaling; Breast cancer; CaKi-1 cells; Cancer therapies; Carcinoma, Renal cell; Cell culture; Cell growth; Cell proliferation; Cellular signal transduction; chemokine (C-C motif) receptor type 2; Chemokines; Development and progression; Genetic aspects; Health aspects; Kidney cancer; Metastasis; monocyte chemoattractant protein-1; nuclear factor of activated T cells 5; Oncology; Properties; Prostate; Proteins; Recruitment; renal cell carcinoma; Transcription factors; Vascular endothelial growth factor
• ISSN: 1792-1074; 1792-1082
• DOI: 10.3892/ol.2016.4875

The chemokine monocyte chemoattractant protein-1 [MCP-1; also known as chemokine (C-C motif) ligand 2] is an important mediator of monocyte recruitment during inflammatory processes. Pathologically high expression levels of MCP-1 by tumor cells have been observed in a variety of cancer types. In the majority of cases, high MCP-1 expression is associated with a poor prognosis, as infiltration of the tumor with inflammatory monocytes promotes tumor progression and metastasis. MCP-1 is also expressed in renal cell carcinoma (RCC). In the present study, the function and the regulation of MCP-1 was investigated in two RCC cell lines, CaKi-1 and 786-O. In both cell lines, expression of MCP-1 was significantly enhanced compared with non-cancerous control cells. As expected, secretion of MCP-1 into the medium facilitated the recruitment of peripheral blood monocytes via the chemokine (C-C motif) receptor type 2 (CCR2). As expression of CCR2 was also detected in 786-O and CaKi-1 cells, the effect of autocrine MCP-1/CCR2 signaling was evaluated in these cells. In proliferation assays, administration of an MCP-1 neutralizing antibody or of a CCR2 antagonist to CaKi-1 and 786-O cells significantly decreased cell growth; supplementation of the growth medium with recombinant human MCP-1 had no additional effect on proliferation. The migration ability of RCC cells was impaired by MCP-1 neutralization or pharmacological CCR2 inhibition, while it was stimulated by the addition of recombinant human MCP-1, compared with untreated control cells. Finally, substantial differences in the regulation of MCP-1 expression were observed between RCC cell lines. In CaKi-1 cells, expression of MCP-1 appears to be largely mediated by the transcription factor nuclear factor of activated T cells 5, while in 786-O cells, deletion of the tumor suppressor gene Von-Hippel-Lindau appeared to be responsible for MCP-1 upregulation, as suggested by previous studies. Taken together, the results of the current study indicate that expression of MCP-1 in RCC cells promotes tumor progression and metastasis not only by paracrine, but also by autocrine, MCP-1/CCR2 signaling events, enhancing cell proliferation and migration ability. Therefore, the present findings suggest the MCP-1/CCR2 axis is a potential target for future therapeutic strategies in the treatment of metastatic RCC.