The Concept of “Cancer Stem Cells” in the Context of Classic Carcinogenesis Hypotheses and Experimental Findings

Abstract

In this Commentary, the operational definition of cancer stem cells or cancer initiating cells includes the ability of certain cells, found in a heterogeneous mixture of cells within a tumor, which are able to sustain growth of that tumor. However, that concept of cancer stem cells does not resolve the age-old controversy of two opposing hypotheses of the origin of the cancer, namely the stem cell hypothesis versus the de-differentiation or re-programming hypothesis. Moreover, this cancer stem concept has to take into account classic experimental observations, techniques, and concepts, such as the multi-stage, multi-mechanism process of carcinogenesis; roles of mutagenic, cytotoxic and epigenetic mechanisms; the important differences between errors of DNA repair and errors of DNA replication in forming mutations; biomarkers of known characteristics of normal adult organ-specific stem cells and of cancer stem cells; and the characteristics of epigenetic mechanisms involved in the carcinogenic process. In addition, vague and misleading terms, such as carcinogens, immortal and normal cells have to be clarified in the context of current scientific facts. The ultimate integration of all of these historic factors to provide a current understanding of the origin and characteristics of a cancer stem cell, which is required for a rational strategy for prevention and therapy for cancer, does not follow a linear path. Lastly, it will be speculated that there exists evidence of two distinct types of cancer stem cells, one that has its origin in an organ-specific adult stem cell that is ‘initiated’ in the stem cell stage, expressing the Oct4A gene and not expressing any connexin gene or having functional gap junctional intercellular communication (GJIC). The other cancer stem cell is derived from a stem cell that is initiated early after the Oct4A gene is suppressed and the connexin gene is expressed, which starts early differentiation, but it is blocked from terminal differentiation.

Cancer cell cycle heterogeneity as a critical determinant of therapeutic resistance

“…These concepts are well discussed in other scientific literature, such as in a review article written by Trosko. 114 Moreover, Ryl et al discovered that arrest in an early cell-cycle phase supports later re-entry into unhindered proliferation providing an exciting twist to the cancer stem cell hypothesis. They suggested that the transient G1 arrest of cells born at the start of chemotherapeutic treatment ultimately supports therapy resistance.…”

Stemming Tumoral Growth: A Matter of Grotesque Organogenesis

“…Several studies confirm that tumours can develop from single clones which acquire a set of mutations driving overgrowth [ 52 , 53 ]. These mutations are of diverse origins: they can be inherited in the autosomal or mitochondrial DNA, induced by chemical carcinogens or environmental factors, or modulated by the individual’s microbiome [ 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 ] ( Figure 1 ). Tumours, while growing, increase by volume and thus the contact area with the wild-type host tissues also increases.…”

Fusobacterium & Co. at the Stem of Cancer: Microbe–Cancer Stem Cell Interactions in Colorectal Carcinogenesis

“…Cancer stem cells (CSC) may represent normal resident stem cells undergoing oncogenic transformation or instead arise from the mutation-induced de-differentiation of more mature or even fully differentiated cell elements [8,9]. Indeed, random mutations occurring during the physiologic division of stem cells may account for up to two-thirds of cancer risk variations among tissues.…”

“…The remainder is related to genetic or environmental factors, such as cigarette smoke, pollutants, radiation, or infectious agents [10,11]. Carcinogens, including viruses and onco-bacteria, may directly target cells endowed with stem cell capacity; alternatively, they could primarily target non-stem tumor cells and turn them into cancer stem-like cells [8].…”