The Ron Proto-oncogene Product Is a Phenotypic Marker of Renal Oncocytoma

Abstract

The proto-oncogene product Ron is the receptor for macrophage stimulating protein, a scatter factor that stimulates cell proliferation, prevents apoptosis, and induces an invasive cell phenotype. We investigated the expression of Ron, Ki-67 (proliferation index), p53, and bcl-2 (proapoptotic and antiapoptotic proteins, respectively) in 50 renal tumors (19 clear cell carcinomas, 18 oncocytomas, 7 papillary cell carcinomas, 5 chromophobe cell carcinomas, and 1 carcinoma with sarcomatoid areas). In addition, we studied Ron in normal kidney and in the renal carcinoma cell line Caki-1. Immunostaining and Western blot showed Ron in normal kidney and in all oncocytomas but never in renal cell carcinomas or in Caki-1. In addition, Western blot showed that Ron was expressed in phosphorylated, i.e., active, form. Bcl-2 was strongly expressed in oncocytomas, whereas Ki-67 and p53 were much less expressed in oncocytomas than in carcinomas. These results indicate in Ron a marker that differentiates oncocytoma from the other renal epithelial tumors. We therefore think that Ron may prove to be a new tool for a sound and precise diagnosis of oncocytoma, a benign tumor that cannot always be distinguished from carcinomas at histologic examination. The overexpression of bcl-2, but not p53 in oncocytoma, suggests that the MSP/Ron system sustains the growth of oncocytoma by opposing apoptosis.

The diagnostic and prognostic utility of claudin expression in renal cell neoplasms

“…[28][29][30][31][32][33][34][35][36][37][38] Renal cell carcinoma marker antibody, CD10, glutathione S-transferase-a and others have shown specificity for clear cell renal cell carcinoma, 28,29 a-Methylacyl CoA racemase is expressed in papillary renal cell carcinoma, 30 whereas parvalbumin, b-defensin 1 and most recently KIT are used as markers for chromophobe renal cell carcinoma and oncocytoma. [31][32][33] However a marker with sufficient specificity to differentiate between chromophobe renal cell carcinoma and oncocytomas has not yet been unequivocally established.…”

“…36 Inversely, RON proto-oncogene product and S100 protein were found preferentially expressed in oncocytoma warranting further investigation. 37,38 Preclinical studies have demonstrated a developmental expression of claudin isoforms in the renal tissue, 39 and have identified a distinct pattern of expression of isoforms 7 and 8 along the mouse distal nephron. 10 Gene expression profiling studies in humans have proposed in recent years that chromophobe renal cell carcinoma and oncocytoma are distinguishable by mRNA expression profiles and have indicated claudin 7 as one of the candidate markers for chromophobe renal cell carcinoma.…”

CD10 is expressed in a subset of chromophobe renal cell carcinomas

“…Data about the expression profiling of renal epithelial neoplasms have been growing in the recent literature 15,[19][20][21][22] and the search for immunohistochemical markers uniquely positive for the most common renal cell neoplasms is extensive. 5,13,15,[22][23][24][25] CD10 has been suggested as a marker useful in the differential diagnosis of renal tumors. [5][6][7][8] Droz et al 8 observed CD10 immunoreactivity in all 28 renal cell carcinomas tested and Chu and Arber 6 reported 41 out of 46 renal cell carcinomas (clear cell and papillary renal cell carcinomas) positive for CD10, but no chromophobe renal cell carcinomas were evaluated in these studies.…”

Ron Kinase Transphosphorylation Sustains MET Oncogene Addiction

“…Scattered observations suggest that RON is overexpressed and aberrantly activated in a number of human cancers, including intestinal (7), pancreatic (8), gastric (9), pulmonary (10), mammary (11), ovarian (12), hepatocellular (13), urinary (14), and renal carcinomas (15) where it plays a role in tumor progression, possibly being involved in the metastatic spread (16). Moreover, RON overexpression correlates with an unfavorable clinical outcome in bladder (14) and breast (17) cancers.…”