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.
Highlights
On average a human adult body encompasses fifty trillion cells (~5x1013) with a daily turnover of hundred billion cells (~1011) within which each contains two copies of ~three billion base-pair DNA haploid genome
The Von-Hippel Lindau (VHL)-hypoxia inducible factor (HIF)-hypoxia-metabolism Studies on oxygen sensing led to the discovery of HypoxiaInducible Factors (HIFs) [34]
HIF1/2 is prolyl hydroxylated by EGLN, ubiquitinated by VCB-Cul2-VHL, and rapidly degraded by the 26S Proteasome [36]; whereas under low oxygen conditions such as high altitude or ischemia, HIF is stabilized to initiate a myriad of hypoxia-specific transcriptional programs [34, 36,37,38]
Summary
On average a human adult body encompasses fifty trillion cells (~5x1013) with a daily turnover of hundred billion cells (~1011) within which each contains two copies of ~three billion base-pair DNA haploid genome. Generally speaking ccRCC is a VHL-loss kidney cancer, and complete VHL inactivation is the quintessential first functional/genetic truncal event [7].
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.