BERKELEY, CA (UroToday.com) - We recently published an article regarding our investigation into the role of autophagic pathways in clear cell renal cell carcinoma (ccRCC). This work identified a novel mechanism by which VHL mediates the cell-maintenance processes of autophagy and how this is divided into tumor-promoting autophagy via LC3B, and tumor-suppressing autophagy via LC3C. This work on autophagy in RCC is interesting as we learn more about the role of various other energy and metabolic perturbations leading to renal malignancy. The role of autophagy fits into that global picture as an alternative mechanism for malignant cells to derive energy under conditions of starvation by “cannibalizing” their own organelles and molecules to produce the necessary nutrients to survive despite environmental limitations that thwart tumor growth.
Autophagy is a complex process that provides an example of how mechanisms of VHL’s tumor suppression are well beyond the scope of HIF regulation. The description of VHL’s role in regulating expression of microRNA 204 (miR-204) and its cytotoxicity via control of LC3B demonstrates how VHL loss leads to a multitude of alterations, culminating in tumor growth. Interestingly, this activity appears to be paired to a tumor-suppressing mechanism by which VHL, via HIF, controls LC3C autophagy - which can protect from the pro-tumorigenic effects of LC3B.
This investigation analyzed the role of these pathways in a number of cell lines as well as human tumor tissue. Repeatedly we observed the same phenomena. Thus, it is our belief that these pathways are integral to the development and progression of ccRCC. In the current feverish interest in identifying “targetable” pathways and “actionable” cellular processes in order to develop novel therapeutics, we believe that the process of autophagy may hold great promise. While the overall picture will undoubtedly be more complex than currently imagined, it is interesting to postulate that these autophagic pathways, and their control of a source of cellular energy, may provide an “escape” mechanism for malignant cells to avoid the “energy starvation” induced by our current targeted agents. Studying post-therapy tumor tissue may reveal an increase in pro-tumorigenic autophagy. Similarly, we postulate that metastatic tumors may utilize pro-tumorigenic autophagy to survive the arduous process of metastasis, and specifically, periods of limited energy.
In conclusion, our recent investigation into autophagy in RCC provides another mechanism by which altered VHL leads to malignancy. As we study the various faces of RCC, from low- to high-grade tumors, and from local to recurrent or metastatic disease, we hope to understand exactly what role, and at what time in tumorigenesis, autophagy plays its part. Our hope is that this will present an additional opportunity to develop a targeted assault on RCC.
Written by:
Nicholas G. Cost, MD and Maria F. Czyzyk-Krzeska, MD, PhD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
Department of Cell and Cancer Biology
University of Cincinnati College of Medicine
Cincinnati, OH 45267-0056, USA
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