Cell Reversal From a Differentiated to a Stem-Like State at Cancer Initiation

Abstract

Even if the Somatic Mutation Theory of carcinogenesis explains many of the relevant experimental results in tumor origin and development, there are frequent events that are not justified, or are even contradictory to this widely accepted theory. A Cell Reversal Theory is presented, putting forward the hypothesis that cancer is originated by reversal of a differentiated cell into a non-differentiated stem-like state, by a change of its intrinsic epigenetic state, following a perturbation on the cell and/or its microenvironment. In the current proposal a cluster of cancer stem cells can be established, without the strict control mechanisms of a normal stem cell niche, and initiate a tumor. It is proposed that a reversal to a pluripotent state is at tumor origin and not tumor progress that prompts cell dedifferentiation. The uncontrolled proliferation of cancer stem cells causes a microenvironment disorganization, resulting in stressful conditions, like hypoxia and nutrient deprivation, which induces the genetic instability characteristic of a tumor; thus, in most cases, mutations are a consequence and not the direct cause of a tumor. It is also proposed that metastases result from dedifferentiation signaling dispersion instead of cell migration. However, conceivably, once the microenvironment is normalized, the stem cell-like state can differentiate back to a mature cell state and loose its oncogenic capacity. Therefore, this can be a reversible condition, suggesting important therapeutic opportunities.

A Review on Cancer Stem Cells in Vasculogenic Mimicry Formation: A New Dimension for Targeted Therapy

“…In solid tumor, cancer cells exist in different states of differentiation and this can be expressed by the cell surface markers in various tumors. 11,12 Cancer stem cell theory states that a small subset of cells within a tumor characterized by stem-like properties can lead to tumor initiation, progression, and metastases. The self-renewing and differentiating capacity of CSC are responsible for tumor heterogeneity.…”

A bioelectric model of carcinogenesis, including propagation of cell membrane depolarization and reversal therapies

“…The present hypothesis has many contact points with the Tissue Organization Field Theory (TOFT) 32 , 33 , in the sense that it considers cancer a disease of tissue organization, and a tumor can originate from a perturbation on the tissue environment, not of a single or reduced number of cells, leading to a transition from normal to pluripotent like cells 34 . The bioelectrical communication is then a mechanism for tissue cells homeostasis but also, in case of a major perturbation, a process driving a global cells’ state change.…”

MicroRNAs and Stem-like Properties: The Complex Regulation Underlying Stemness Maintenance and Cancer Development

“…In some tumors, noncancer cells can even dedifferentiate into cells with a stem-cell phenotype, forming the dedifferentiated cancer cells [19,20]. Although the circumstances in which the dedifferentiation occurs are not completely clear, it has been reported that stress, wounding, or hypoxia can be responsible for this process [21]. Moreover, it has been hypothesized that the dedifferentiation of noncancer cells in cells with stem-cell phenotype could represent a further event for tumor initiation [21].…”

“…Although the circumstances in which the dedifferentiation occurs are not completely clear, it has been reported that stress, wounding, or hypoxia can be responsible for this process [21]. Moreover, it has been hypothesized that the dedifferentiation of noncancer cells in cells with stem-cell phenotype could represent a further event for tumor initiation [21]. Stem-cell phenotypes in cancer can also be derived from paracrine effects from other cells; for example, endothelial cells can induce the CSC phenotype of human colorectal cancer cells by secreting factors promoting the CSC phenotype and Notch activation [22].…”