Modeling Neoplastic Growth in Renal Cell Carcinoma and Polycystic Kidney Disease

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.

Identifying Hypoxia Characteristics to Stratify Prognosis and Assess the Tumor Immune Microenvironment in Renal Cell Carcinoma

“…Von Hippel-Lindau tumor suppressor (pVHL) and HIFs are critical factors in these pathways. With tumor cell proliferation and growth, RCC results in hypoxia with the activated HIF-α signaling in response to oxygen deprivation (Millet-Boureima et al, 2021). On the other hand, the VHL gene is lost in ∼90% of ccRCC tumors (Linehan and Ricketts, 2019).…”

Empowering Melatonin Therapeutics with Drosophila Models

“…However, the incomplete knowledge of the myriad of melatonin roles and dosage effects still limits precise manipulation in diseased states. The potential for melatonin treatment is widely recognized in neurological disease and oncology, there is new promise for ADPKD and there appears to be an untapped capacity also in renal cell carcinoma, a malignancy sharing pathological aspects with ADPKD (reviewed in [321,344]). Considering that the complexity and redundancy of the mammalian melatonin pathways substantially complicate mechanistic studies, model organisms may be deployed to probe specific questions and mechanisms.…”

“…ADPKD is characterized by the progressive formation of fluid-filled cysts along the length of the renal tubules (nephrons). Cystic growth disrupts normally regulated proliferation and apoptosis of the epithelial cells forming the renal tubule and it displays some neoplastic characteristics (reviewed in [321]). The first-in-kind Drosophila model of PKD harbors a mutation in the Bicaudal C (BicC) gene [231].…”

“…Melatonin is also known to regulate several pathways implicated in neoplastic growth (e.g., mTOR (reviewed in [337]), MAPK [338,339], JAK/STAT3 [339][340][341], ERK [337,342], and TGF-β/Smad [343]). Several of these pathways are also altered in ADPKD tissue and related neoplastic renal cell carcinoma (reviewed in [321,344]). Thus, the observed improvements in the melatonin treated cystic BicC flies may result from the simultaneous correction of several cellular defects.…”

“…These melatonin-mediated effects have been found to rescue cell metabolism in oncology [349] and may also contribute to ameliorating the Warburg-like effects in the renal cyst and ADPKD. Considering that all these pathways are well-conserved in Drosophila (reviewed in [321,327,350]), and corresponding gene knockout and knockdown flies exist, it should be possible to decipher the molecular bases of melatonin efficacy as a cyst-reducing drug candidate. Overall, our Drosophila studies gave insight into a potential novel treatment for ADPKD, that being non-toxic, could likely be administered indefinitely to alleviate symptoms of chronic ADPKD.…”