Destabilization of Abnormal Methylation Enzymes as the Only Viable Option for the Elimination of Cancer Stem Cells to Save Cancer Patients

Abstract

Cytotoxic chemotherapy was a tragic by-product of World War II. It was the major therapeutic modality employed but failed to win the War on Cancer during 1971-1976 declared by President Nixon. Despite the failure, killing of cancer cells (CCs) remained the commanding principle of cancer establishments to guide development of cancer therapies throughout. Apparently, this commanding principle is incorrect, since cancer mortality continues to increase. Wound unhealing leads to the evolution of cancer. Progenitor stem cells (PSCs) must proliferate and undergo terminal differentiation in order to complete wound healing. PSCs are cells that possess aberrant methylation enzymes (MEs), which provide them a significant growth advantage. In order to safeguard cells with aberrant MEs and maintain control over them, nature produces chemo-surveillance, which is composed of wound healing metabolites, differentiation inducers (DIs), and differentiation helper inducers (DHIs). The breakdown of chemo-surveillance, which prevents PSCs from undergoing terminal differentiation, is the cause of wound unhealing. The nature does not have a mechanism to detect the breakdown of chemo-surveillance to make the correction. PSCs are forced to proliferate, which is limited by contact inhibition, another protection mechanism the nature created to limit the buildup of normal stem cells. PSCs are then forced to evolve into cancer stem cells to escape contact inhibition. It takes a single hit to silence TET-1 enzyme, an enzyme responsible to direct lineage transitions, to turn PSCs into cancer stem cells (CSCs). The evolution of CSCs from PSCs is quite easy, since PSCs are equipped with very active abnormal MEs. The propagation of CSCs still cannot heal the wound, because the problem is the collapse of chemo-surveillance. The CSCs will be forced to progress to faster growing CCs by chromosomal abnormalities such as translocations to activate oncogenes, or deletions to inactivate suppressor genes. So, the correct solution of cancer is to restore chemo-surveillance by providing DIs and DHIs to destabilize abnormal MEs to achieve terminal differentiation of PSCs and CSCs which are closely linked to wound unhealing. Killing of CSCs and PSCs cannot heal the wound. Therefore, destabilization of abnormal MEs to achieve terminal differentiation of CSCs is the only viable option to take out CSCs by healing the wound to save cancer patients. The elimination of CSCs is essential to the success of cancer therapy. We have carried out extensive studies of natural and unnatural DIs and DHIs for the manufacturing of CDA formulations to save cancer patients.