Abstract
Deficiency of tumor suppressor FLCN leads to the activation of the mTOR signaling pathway in human BHD-associated renal cell carcinomas (RCC). We have previously developed a renal distal tubule-collecting duct-Henle's loop-specific Flcn knockout (KO) mouse model (Flcnflox/flox/Ksp-Cre). This mouse model can only survive for three weeks after birth due to the development of polycystic kidney and uremia. Whether these cystic solid hyperplasia changes seen in those KO mice are tumorigenic or malignant is unknown. In this study, we demonstrated that genetic disruption of Flcn in mouse kidney distal tubule cells could lead to tumorigenic transformation of these cells to develop allograft tumors with an aggressive histologic phenotype. Consistent with previous reports, we showed that the mTOR pathway plays an important role in the growth of these Flcn-deficient allograft and human UOK 257-1 xenograft tumors. We further demonstrated that the mTOR inhibitor, sirolimus, suppresses the tumor's growth, suggesting that mTOR inhibitors might be effective in control of FLCN-deficient RCC, especially in BHD renal tumorigenesis.
Highlights
The mammalian target of rapamycin is a protein kinase that integrates a variety of signaling pathways that regulate cellular growth, proliferation and metabolism [1]
Immunohistochemical analysis with a panel of kidney-specific markers (AQP1, PAX2, and CK7) demonstrated that these tumors were renal cell carcinomas. (Figure 2E–2H) The histological features are consistent with sarcomatoid renal cell carcinoma (SRCC) (Figure 2F–2H)
While SRCC may evolve from any type of renal cell carcinoma, many reports have noted that chromophobe cell carcinoma is the most common histologic variant associated with SRCC transformation www.impactjournals.com/oncotarget www.impactjournals.com/oncotarget www.impactjournals.com/oncotarget
Summary
The mammalian target of rapamycin (mTOR) is a protein kinase that integrates a variety of signaling pathways that regulate cellular growth, proliferation and metabolism [1]. Known as rapamycin, is one of the inhibitors of mTOR [4]. Sirolimus provides its therapeutic effects by inhibiting both protein kinase complex mTORC1 and mTORC2. Sirolimus inhibits the growth of many tumor cell lines in vitro and exhibits antitumor activity in murine tumor models [4]. Guba et al demonstrated in a mouse model that sirolimus inhibited tumor progression through antiangiogenic activity related to impaired production of VEGF and limiting proliferative response of endothelial cells to stimulation by VEGF [5]. Sirolimus has been shown to inhibit the progression of dermal Kaposi’s sarcoma [7]
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