On the potential origin of the zygote-like cancer stem cell with a focus on fusion for cell rescue

Cancer is conventionally viewed as a disease of accumulated somatic mutation and epigenetic dysregulation leading to cell de-differentiation and uncontrolled proliferation. With few exceptions, malignant tumors develop from a single damaged cell. However, there is also strong evidence for the involvement of more than one cell in the initiation of oncogenesis. Oncogenic mutations may be insufficient by themselves to trigger oncogenesis as somatic cells harboring driver mutations are often seen in nonmalignant tissues. We review experimental evidence for the reactivation of embryonic genes, emergence of cancer stem cells, and therapy resistance by the developmental programme hijack via cell fusion. Furthermore, based on our previous findings on fetal-maternal microchimerism, in this hypothesis article we delve into the potential mechanisms of activation of the early totipotent program by unselective stem cell fusion for cell rescue, centering the primitive pluripotent stem cells residing in postnatal human tissues as potential pivotal drivers of tumorigenesis that could recapitulate incomplete stages of embryogenesis and cell migration after triggering nuclear reprogramming toward a totipotent zygote-like cancer stem cell state, potentially amenable to genomic instability, somatic mutation, defective histogenesis and tumor-host microchimerism.