Studies on renal progenitor cells and kidney cancer
Abstract: Kidney cancer and renal injuries affect millions of people in the world resulting in high patient morbidity and mortality, as well as one of the most extensive medical costs for society. Upon renal injury the kidney has an endogenous ability to repair damaged tubules and restore kidney function, provided that the patient receives adequate supportive care in time. The molecular basis for this regeneration process is still not fully elucidated and the cellular origin for regeneration is extensively debated. Kidney cancer is characterized by vague clinical symptoms and pronounced resistance to common cancer therapies, like chemotherapy and radiation. Consequently, nearly 25% of patients present with spread disease already at diagnosis. For these patients a dismal prognosis awaits, with a 5-year survival rate of less than 10%. Thus, there is a desperate need for development of novel targeted therapies and diagnostic methods. In this thesis we describe a new cell type intermingled between the proximal tubular cells of the nephron in normal human kidney. These cells share marker expression with regenerating tubules and display stem cell-like abilities as well as distinct morphological properties, such as low mitochondrial content and extensive structural and anchorage protein expression. By developing a novel human explant model of ATN ex vivo we also show that these cells are more resilient to injury. These cells were detected in normal chimpanzee and pig kidney, but not in mice, not even after induced renal injury. Additionally, the transcriptional profile of these cells is similar to that of papillary renal cell carcinoma (pRCC), and correlate to worse prognosis in clear cell RCC (ccRCC). These results indicate that these cells survive renal insults to a higher extent than bulk proximal tubule cells, and become activated to repopulate the tubule, but also suggest that pRCC might originate from oncogenic transformation of these cells. In the second part of this thesis we show that the dopamine transporter SLC6A3 is highly expressed and functional in ccRCC, while only being expressed at very minute levels in normal kidney and other cancer forms. Additionally, we show that the SLC6A3 expression is affected by hypoxia inducible factor 2 alpha (HIF-2α), an important protein in the cellular oxygen sensing system, which is ubiquitously expressed in the constantly pseudohypoxic ccRCC tumors. We further demonstrate that hypoxia induces SLC6A3 expression in normal kidney cells, but not in cells from other normal tissues like breast or vessels. These results show that SLC6A3 is a highly specific biomarker for ccRCC and that the endogenous features of this dopamine transporter may be utilized for the development of novel treatment modalities in ccRCC.
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