Cellular Origin of Cancer: Dedifferentiation or Stem Cell Maturation Arrest?

Abstract

Given the fundamental principle that cancer must arise from a cell that has the potential to divide, two major nonexclusive hypotheses of the cellular origin of cancer are that malignancy arises a) from stem cells due to maturation arrest or b) from dedifferentiation of mature cells that retain the ability to proliferate. The role of stem cells in carcinogenesis is clearly demonstrated in teratocarcinomas. The malignant stem cells of teratocarcinomas are derived from normal multipotent stem cells and have the potential to differentiate into normal benign mature tissue. A widely studied model supporting dedifferentiation has been the putative origin of hepatocarcinomas from "premalignant" foci and nodules induced in the rat liver by chemicals. However, the dedifferentiation concept for hepatocarcinogenesis is challenged by more recent interpretations indicating that hepatocellular carcinoma arises from maturation arrest caused by aberrant differentiation of determined stem cells. Either hypothesis is supported by the cellular changes that occur in the rodent liver after different hepatocarcinogenic regimens. The formation of foci and nodules from altered hepatocytes supports dedifferentiation; the proliferation of small oval cells with the potential to differentiate into either biliary ducts or hepatocytes supports arrested maturation of determined stem cells. It is now postulated that foci and nodular change reflect adaptive changes to the toxic effects of carcinogens and not "preneoplastic" stages to cancer. The stem cell model predicts that genotoxic chemicals induce mutations in the determined stem cell which may be expressed in its progeny. Proliferation of initiated cells is induced by promoting events which also allow additional mutations to occur.

Metaplasia, intraepithelial neoplasia and early cancer of the stomach are related to dedifferentiated epithelial cells defined by cytokeratin-7 expression in gastritis

“…Review articles have suggested that malignancy could arise either from stem cells due to a maturation arrest, or from a dedifferentiation of mature cells that regain the ability to proliferate [43,44]. Although present considerations about gastric carcinogenesis usually prefer the stem cell hypothesis, a definite proof of it is lacking [14].Our study suggests that an origin of gastric carcinomas from dedifferentiated gastric cells is also possible.…”

Elevate Level of Glycosaminoglycans and Altered Sulfation Pattern of Chondroitin Sulfate Are Associated with Differentiation Status and Histological Type of Human Primary Hepatic Carcinoma

“…The ‘maturation arrest’ hypothesis [27] states that genetic alterations occurring in a hepatic progenitor, or its immediate progeny, cause aberrant proliferation and prevent its normal differentiation. Further accumulation of genetic alteration can eventually lead to malignant transformation of these incompletely differentiated cells.…”

The mutator phenotype theory can explain the complex morphology and behaviour of cancers

“…The abnormality involving differentiation might be either arrest of the maturation of stem cells, or dedifferentiation of mature cells which retain their ability to proliferate [16]. However, detailed comparisons of cell lines taken from the same primary tumours showed that there are often marked differences in the metastatic capabilities of these proliferating cells.…”

“…Tumours are characterised by variable degrees of incomplete differentiation-related change of appearance. This has been discussed in terms of dedifferentiation, or stem cell arrest [16]. Either process could be affected by genetic instability in terms of randomly variable modifications of the genes required for the relevant steps.…”