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Date of Award
Renal Cell Carcinoma (RCC) is the eighth most common cancer in the United States. Once this disease reaches metastatic stages, it has an estimated 12% 5-year survival rate. According to the American Cancer Society, 7/10 of RCC patients are diagnosed with the clear cell subtype and 3/10 of RCC patients develop bone metastases. Metastatic RCC (mRCC) tumors commonly exhibit a highly lytic phenotype and are associated with significant patient morbidity due to skeletal-related-events (SREs), which can include bone pain, fracture, hypercalcemia, etc. Previous studies from our lab, examining two commonly studied RCC cell lines (Caki-1 and 786-O), showed striking stimulatory effects of Caki-1, but not 786-O cells on osteoclast differentiation and maturation. Based on these findings, we set out to identify potential drivers of this highly lytic phenotype in mRCC and proposed that the osteolytic behavior of Caki-1 RCC cells is driven by a specific gene signature. Our initial studies examined the transcriptome of Caki-1 and 786-O cells via RNAseq analyses and identified three candidate genes linked to bone remodeling pathways: Endoglin (ENG), Osteopontin (SPP1) and Serglycin (SRGN). We focused predominantly on SRGN, a hematopoietic proteoglycan, as a potential inducer of bone destruction in mRCC. The results of our studies showed that SRGN is highly expressed in Caki-1 tumors in vitro and in vivo. Our data also revealed that the glycosylated form of SRGN is heavily secreted by Caki-1 cells compared to 786-O cells. To mechanistically study the role of SRGN in osteoclastogenesis and tumor behavior, we utilized siRNA-mediated approaches to knockdown SRGN and blocking antibodies to inhibit the interaction with its receptor CD44. Our results showed that SRGN downregulation modulates the secretion of ENG and SPP1 by Caki-1 cells. We also demonstrated that SRGN knockdown, blocking its receptor CD44, or blocking SPP1 all reduce Caki-1-mediated osteoclastogenesis. To summarize, we have shown that SRGN serves as a potential player in RCC-driven osteoclastogenesis. Further investigations of SRGN and its interaction with CD44 are needed to understand the molecular mechanisms involved in SRGN-mediated bone destruction. This thesis can serve as a foundation for future studies focused on identifying therapeutic targets for RCC-driven bone disease.
Ford, Charlea, "Investigating Drivers Of Tumor-Induced Bone Osteolysis In Metastatic Renal Cell Carcinoma" (2022). Wayne State University Theses. 859.