The other side of the coin: The tumor-suppressive aspect of oncogenes and the oncogenic aspect of tumor-suppressive genes, such as those along the CCND–CDK4/6–RB axis

Abstract

Although cancer-regulatory genes are dichotomized to oncogenes and tumor-suppressor gene s, in reality they can be oncogenic in one situation but tumor-suppressive in another. This dual-function nature, which sometimes hampers our understanding of tumor biology, has several manifestations: (1) Most canonically defined genes have multiple mRNAs, regulatory RNAs, protein isoforms, and posttranslational modifications; (2) Genes may interact at different levels, such as by forming chimeric RNAs or by forming different protein complexes; (3) Increased levels of tumor-suppressive genes in normal cells drive proliferation of cancer progenitor cells in the same organ or tissue by imposing compensatory proliferation pressure, which presents the dual-function nature as a cell-cell interaction. All these manifestations of dual functions can find examples in the genes along the CCND-CDK4/6-RB axis. The dual-function nature also underlies the heterogeneity of cancer cells. Gene-targeting chemotherapies, including that targets CDK4, are effective to some cancer cells but in the meantime may promote growth or progression of some others in the same patient. Redefining "gene" by considering each mRNA, regulatory RNA, protein isoform, and posttranslational modification from the same genomic locus as a "gene" may help in better understanding tumor biology and better selecting targets for different sub-populations of cancer cells in individual patients for personalized therapy.

Protecting the normal in order to better kill the cancer

“…The first wave was centralized on targeting fast‐proliferating cells because it has been, until now, a widespread misconception that cancer cells are fast‐proliferating. Actually, most cancer cells, especially those in highly lethal solid tumors, proliferate relatively slowly, but a tumor mass often has a large portion of cells at the proliferating status and thus manifests a fast enlargement, as explained recently . In contrast, many normal cells in such tissues as bone marrow, hair‐follicles, gastrointestinal (GI) tract, and epidermal skin proliferate much faster than most cancer cells .…”

“…Actually, most cancer cells, especially those in highly lethal solid tumors, proliferate relatively slowly, but a tumor mass often has a large portion of cells at the proliferating status and thus manifests a fast enlargement, as explained recently . In contrast, many normal cells in such tissues as bone marrow, hair‐follicles, gastrointestinal (GI) tract, and epidermal skin proliferate much faster than most cancer cells . For this reason, chemo drugs developed in the first wave have severe side effects on these normal fast‐proliferating cells , exhibited as cytopenia, alopecia, skin itch, nausea, vomiting, and diarrhea, etc., although some drugs such as 5‐fluorouracil (5FU) may stimulate certain immune cells that have anticancer activities.…”

Is Type 2 Diabetes One of Such Aging Phenomena That Lack an Irreversible Structural Change?

“…Expression of mitochondrial RNAs and proteins from mitochondrial DNA (mtDNA) in eukaryotic cells involves proteins encoded on the nuclear genome, making mitochondrial functions reversible and controlled indirectly by the nuclear DNA. Although mutations of nuclear DNA sometimes can be spontaneously reversed to the normal, as clearly seen in some genetic diseases [1], such "reverse mutation" or "mutation of mutation" occurs as rare events. Epigenetic alterations may also alter cellular functions,mutation in the genome.…”

“…Liver cancer is also rare unless there exists hepatitis, alcoholism or a chemical carcinogen as a constant exogenous inducer or enhancer for the liver injury and carcinogenesis [37,38]. Brain neurons and heart muscle cells hardly develop tumors during adulthood [1,3]. On the other hand, catabolic cells may more easily develop IR than anabolic ones, although this is still purely hypothetical and awaits experimental verification, because they, especially the striated muscle cells and neurons, are much longerlived and consume much more glucose.…”

“…Actually, for this reason, most classic chemotherapeutic drugs target fast-proliferating cells, and therefore many, but not all, anabolic cells are also those responsible for the common side effects of chemotherapy, including hair loss, low blood cell counts, skin itch, nausea, vomiting, diarrhea, etc. [1,2]. In many cells of the anabolic type, especially in cancer and embryotic cells, glucose is usually metabolized via a so-called glycolysis, in which one glucose molecule is converted to not only two molecules of adenosine-5'-triphosphate (ATP) to provide energy but also two molecules of pyruvate and two molecules of reduced Nicotinamide Adenine Dinucleotide (NADH) that can be used as construction materials for building new cells [32,33].…”