Human adult stem cells as the target cells for the initiation of carcinogenesis and for the generation of "cancer stem cells"

Abstract

The inference to stem cells has been found in ancient myths and the concept of stem cells has existed in the fields of plant biology, developmental biology and embryology for decades. In the field of cancer research, the stem cell theory was one of the earliest hypotheses on the origin of a cancer from a single cell. However, an opposing hypothesis had it that an adult differentiated somatic cell could "de-differentiate" to become a cancer cell. Only within the last decade, via the "cloning" of Dolly, the sheep, did the field of stem cell biology really trigger an exciting revolution in biological research. The isolation of human embryonic stem cells has created a true revolution in the life sciences that has led to the hope that these human stem cells could lead to (a) basic science understanding of gene regulation during differentiation and development; (b) stem cell therapy; (c) gene therapy via stem cells; (d) the use of stem cells for drug discovery; (e) screening for toxic effects of chemicals; and (f) understand the aging and diseases of aging processes.

Keywords: Adult stem cells; De-differentiation theory; Initiation/promotion/progression hypothesis of carcinogenesis; Oct-4; Re-programming; Stem cell theory of carcinogenesis; iPS cells.

Fig. 1.

Diagram illustrating the potential origin of two types of non-gap junctional communicating cancer cells, either due to the original target cell being an adult stem cell that did not transcriptionally express its connexin genes (HeLa and MCF-7- type tumors). Many cancer cells have expressed connexins, but they have non-functional gap junctions. This could be due either to mutations or posttranslationally modified connexin proteins, caused by expressed oncogenes. These tumor cells might have been derived from adult stem cells that expressed connexins before the loss of Oct-4A expression, due to induced partial differentiation by micro-environment changes.

Fig. 2.

In this diagram, a normal adult stem cell is shown dividing asymmetrically to form one daughter that is committed to ultimately terminally differentiate. The other daughter is designated to be identical to its mother adult stem cell (Oct-4+). If that adult stem cell is exposed to some condition that prevents asymmetrical cell division, but does not suppress the Oct-4 expression, it is operationally an initiated cell. That is, if mitotically stimulated to divide, it divides symmetrically to form two initiated, non-terminally differentiated cell. Initiation is, then, defined as the process that prevents an “immortal” normal adult stem cell to terminally differentiate or become “mortal”. These adult initiated stem cells are still Oct-4 positive or benign cancer stem cells. As these initiated Oct-4+ cells are stimulated to proliferate and resist apoptosis, the growing benign tumor micro-environment changes, some of these initiated Oct-4+ cells can partially differentiate into “cancer non-stem cells” [Oct-4 negative]. Eventually, additional stable mutational or epigenetic events occur, providing the benign Oct-4+ cancer stem cells to become invasive, metastatic “cancer stem cells”.

Fig. 3.

The diagram tries to incorporate a “systems” aspect of how a physical, chemical or biological agent could affect a multi-cellular organism. At non-cytotoxic concentrations or doses, an agent could simultaneously trigger oxidative stress in both the cells of the immune tissues and the epithelial/ endothelial/ stromal cells in various organs. Upon induction of reactive oxygen species (ROS) and of oxidative stress induction of intra-cellular signaling in various cell types of the complex immune system, various cytokines would interact on tissues, containing the three fundamental cell types (adult stem cells, progenitor and terminally-differentiated cells). Given that these cells would have been exposed to the toxic agent and that they, also, would have reacted to the agent differentially because of their different physiological/phenotypic state, the interaction of all three types could be very different (e.g., the normal stem cells might be induced to proliferate asymmetrically; any initiated pre-cancerous stem cell might proliferate symmetrically; the progenitor cells might be induced to proliferate symmetrically and to migrate, as in wound healing; and the terminally differentiated cell might adaptively respond or to apoptose) in response to the inflammatory signal. In summary, each cell type of the immune system and of the various organ tissues, with their different expressed genes and cellular physiology, will respond differently to sub-lethal exposure to agents inducing oxidative stress triggered intra-cellular signaling and epigenetic alterations. The interaction of inflammatory agents on pre-exposed organ epithelial cells could be an additive effect, a synergistic response or possibly, even an antagonistic effect. This could explain the wide range of diseases in which the inflammatory process seems to play a prominent role.