TGF-B signaling in Neuroblastoma and Renal Cell Carcinoma

Abstract: The tubular cells of the adult kidney are normally mitotically quiescent, in stark contrast to the massive regenerative capacity of the injured renal epithelium. In Paper I we characterized a new cell population of progenitor cells using ALDH as a selection marker. These cells are situated in the proximal tubular epithelium and are called proximal tubular progenitor cells (PTPCs). Gene expression analysis of the PTPCs together with functional and immunohistochemical studies revealed that these cells might be responsible for the regeneration of damaged tubular epithelium. Clear cell RCC (ccRCC) is the most common type of RCC and is characterized by loss of function of the tumor suppressor gene von Hippel-Lindau (VHL). In Paper II and III we investigated the role of Notch and TGF-β signaling in ccRCC. Here we reported a cross talk between the two pathways and demonstrated a correlation between elevated TGF-β activity and worse prognosis in ccRCC patients. This correlation, in corroboration with functional migration and proliferation data, suggested that ccRCC cells have escaped the cytostatic effects of TGF-β signaling and that TGF-β instead increases the metastatic potential of ccRCCs. Sarcomatoid areas can occasionally be found in all types of renal malignancies and patients displaying sarcomatoid features have a very poor prognosis. In Paper IV we analyzed six ccRCC cases with sarcomatoid areas and show that sarcomatoid RCC demonstrate an enhanced expression of epithelial-to-mesenchymal transition (EMT)-related markers as compared to the ccRCC counterparts and that TGF-β might be the driving force behind this process. Neuroblastoma (NB) is a tumor arising the sympathetic nervous system in children and high-risk NBs are characterized by increased MYC-N/MYC activity. In Paper V we examined the protein response upon activation of the micro-RNA cluster miR-17-92 in NB using quantitative mass spectrometry. We showed that activation of the miR-17-92 cluster affected multiple oncogenic pathways including key effectors of the TGF-β signaling cascade. We report a connection between elevated expression of miR-17-92, low TGF-β signaling, and decreased patient survival.