Abstract
Renal cell carcinoma (RCC) and autosomal dominant polycystic kidney disease (ADPKD) share several characteristics, including neoplastic cell growth, kidney cysts, and limited therapeutics. As well, both exhibit impaired vasculature and compensatory VEGF activation of angiogenesis. The PI3K/AKT/mTOR and Ras/Raf/ERK pathways play important roles in regulating cystic and tumor cell proliferation and growth. Both RCC and ADPKD result in hypoxia, where HIF-α signaling is activated in response to oxygen deprivation. Primary cilia and altered cell metabolism may play a role in disease progression. Non-coding RNAs may regulate RCC carcinogenesis and ADPKD through their varied effects. Drosophila exhibits remarkable conservation of the pathways involved in RCC and ADPKD. Here, we review the progress towards understanding disease mechanisms, partially overlapping cellular and molecular dysfunctions in RCC and ADPKD and reflect on the potential for the agile Drosophila genetic model to accelerate discovery science, address unresolved mechanistic aspects of these diseases, and perform rapid pharmacological screens.
Highlights
Abnormal neoplastic growth underlies benign and malignant neoplasms or tumors.While benign tumors may grow slowly and do not spread to other sites, malignant cancerous growth displays variable propensity to form metastases to other tissues
Similar mTOR-driven metabolic regulation was found in another renal cell carcinoma (RCC) type in a kidney-specific Cre (KspCre) Tsc1 mutant restricted to a segment of renal tubule; in this case, mTOR has been found to downregulate the TCA cycle enzyme fumarate hydratase leading to fumarate accumulation, and driving tumor cell progression [46,116]
Abnormal neoplastic growth in clear cell RCC (ccRCC) and autosomal dominant polycystic kidney disease (ADPKD) appears to result from the accumulation of several mutational hits that cooperate to change fundamental cell properties, metabolism, and behavior
Summary
Abnormal neoplastic growth underlies benign and malignant neoplasms or tumors. While benign tumors may grow slowly and do not spread to other sites, malignant cancerous growth displays variable propensity to form metastases to other tissues. Genetic models of neoplastic growth in RCC and ADPKD are expected to help advance our understanding of the underlying molecular lesions and their possible cooperation in disease etiology. We examine the current knowledge of RCC and ADPKD, with particular interest in the molecular lesions underpinning the abnormal cell growth and discuss the potential to use the genetic tools in Drosophila to address unresolved mechanistic aspects and to accelerate drug discovery and testing. RCC accounts for 90% of all adult kidney malignant tumors and 10% of all cancers [4,5,6]. It is twice more frequent in men than women [7]. RCC has a 40% fatality rate [17,18,19]
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