Exploiting the circuit breaker cancer evolution model in human clear cell renal cell carcinoma
Authors:James J. Hsieh1 and Emily H. Cheng2,3,4
1 Molecular Oncology, Department of Medicine, Washington University, St. Louis, MO 63110, USA.
2 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
3 Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
4 Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, Cornell University, New York, NY 10065, USA.
Keywords:
kidney cancer evolution, circuit breaker, VHL, HIF, PBRM1, MTOR.
Abbreviations:
CB – circuit breaker;
ccRCC – clear cell RCC;
HIF – hypoxia inducible factor;
OG – oncogene;
mccRCC – metastatic ccRCC;
RCC – renal cell carcinoma;
TSG – tumor suppressor gene;
VHL – Von-Hippel Lindau.
Corresponding Author(s):
Conflict of interest statement:
JJH has received consulting fees from Eisai Inc., Japan; clinical trial funding from Merck & Co., Inc., USA, and AstraZeneca Pharmaceuticals, UK; and research funding from BostonGene, USA.
Please cite this article as:
James J. Hsieh and Emily H. Cheng (2020). Exploiting the circuit breaker cancer evolution model in human clear cell renal cell carcinoma. Cell Stress 4(8): 191-198. doi: 10.15698/cst2020.08.227
© 2020 Hsieh and Cheng. This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and re-production in any medium, provided the original author and source are acknowledged.
Abstract:
The incessant interactions between susceptible humans and their respective macro/microenvironments registered throughout their lifetime result in the ultimate manifestation of individual cancers. With the average lifespan exceeding 50 years of age in humans since the beginning of 20th century, aging – the “time” factor – has played an ever-increasing role alongside host and environmental factors in cancer incidences. Cancer is a genetic/epigenetic disease due to gain-of-function mutations in cancer-causing genes (oncogene; OG) and/or loss-of-function mutations in tumor-suppressing genes (tumor suppressor genes; TSG). In addition to their integral relationship with cancer, a timely deployment of specific OG and/or TSG is in fact needed for higher organisms like human to cope with respective physiological and pathological conditions. Over the past decade, extensive human kidney cancer genomics have been performed and novel mouse models recapitulating human kidney cancer pathobiology have been generated. With new genomic, genetic, mechanistic, clinical and therapeutic insights accumulated from studying clear cell renal cell carcinoma (ccRCC)–the most common type of kidney cancer, we conceived a cancer evolution model built upon the OG-TSG signaling pair analogous to the electrical circuit breaker (CB) that permits necessary signaling output and at the same time prevent detrimental signaling overdrive. Hence, this viewpoint aims at providing a step-by-step mechanistic explanation/illustration concerning how inherent OG-TSG CBs intricately operate in concert for the organism’s wellbeing; and how somatic mutations, the essential component for genetic adaptability, inadvertently triggers a sequential outage of specific sets of CBs that normally function to maintain and protect and individual tissue homeostasis.