Autocrine CSF-1 and CSF-1 Receptor Coexpression Promotes Renal Cell Carcinoma Growth

Abstract

Renal cell carcinoma is increasing in incidence but the molecular mechanisms regulating its growth remain elusive. Co-expression of the monocytic growth factor CSF-1 and its receptor CSF-1R on renal tubular epithelial cells (TEC) will promote proliferation and anti-apoptosis during regeneration of renal tubules. Here we show that a CSF-1-dependent autocrine pathway is also responsible for the growth of renal cell carcinoma (RCC). CSF-1 and CSF-1R were co-expressed in RCC and TEC proximally adjacent to RCC. CSF-1 engagement of CSF-1R promoted RCC survival and proliferation and reduced apoptosis, in support of the likelihood that CSF-1R effector signals mediate RCC growth. In vivo CSF-1R blockade using a CSF-1R tyrosine kinase inhibitor decreased RCC proliferation and macrophage infiltration in a manner associated with a dramatic reduction in tumor mass. Further mechanistic investigations linked CSF-1 and EGF signaling in RCC. Taken together, our results suggest that budding RCC stimulates the proximal adjacent microenvironment in the kidney to release mediators of CSF-1, CSF-1R and EGF expression in RCC. Further, our findings imply that targeting CSF-1/CSF-1R signaling may be therapeutically effective in RCC.

Failed renoprotection by alternatively activated bone marrow macrophages is due to a proliferation-dependent phenotype switch in vivo

“…M-CSF has been shown to be vital for monocyte/macrophage development and differentiation and is found to be expressed in various organs. [43][44][45][46] In this study, increased M-CSF expression was demonstrated in kidney tubular-epithelial cells of AN kidney, as it has been shown in other models of kidney disease including lupus nephropathy, unilateral ureteral obstruction, and ischemia/reperfusion. [47][48][49] Increased M-CSF expression of tubular cells correlated with proliferation of transfused BM-M2 macrophages.…”

Glioblastoma-derived Macrophage Colony-stimulating Factor (MCSF) Induces Microglial Release of Insulin-like Growth Factor-binding Protein 1 (IGFBP1) to Promote Angiogenesis

“…In breast cancer and renal cell carcinoma, MCSF and its receptor MCSFR are co-expressed in tumor cells, allowing an autocrine action and thereby increasing malignancy and proliferation (36,50). Likewise, data indicate expression of both MCSF and its receptor MCSFR in glioma, suggesting autocrine and paracrine effects (43).…”

“…induces tumor cell proliferation in renal cell carcinoma in an autocrine way and might contribute to M2 polarization of macrophages in glioma (35,36). To explore the autocrine functions of MCSF in glioma, various properties like proliferation, chemosensitivity, anchorage-independent growth, migration, and invasion were monitored after the addition of recombinant MCSF (rMCSF), ectopic overexpression (Fig.…”

The Role of Inflammation in Kidney Cancer

“…Treatment of RCC and TEC cell lines with CSF-1 showed increased cell proliferation in a dose-dependent manner, and this response was inhibited with a blocking antibody. RCC cell lines stimulated with TNF-α/LPS showed an increased rate of apoptosis, and adding a blocking anti-CSF-1R Ab further increased the response (Menke et al 2012). CSF-1 may have an autocrine and paracrine role in RCC promoting tumor cell proliferation, and decreasing apoptosis.…”