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Journal of Molecular Cancer

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James E. Trosko PhD
Department Pediatrics and Human Development, College of Human Medicine, Michigan State University, 1355 Bogue Street, Room B240, East Lansing, Michigan 48824, USA

Received Date: Oct 16, 2018 / Accepted Date: Nov 20, 2018 / Published Date: Nov 30, 2018

Citation: James E. Trosko. How evolution of quorum sensing must fit into the understanding of the origin, prevention and treatment of cancer. J Mol Cancer. 2018;1(3):22-24.

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Gap junctional intercellular communication; Adult stem cells; Epigenesis; evolution of cancer; OCT4A; Mutagenesis; Multi-step process of carcinogenesis.

This review applies the mechanism of “cell-cell signaling in sustaining and perpetuating homeostasis, starting with the reduction in intracellular entropy as the organizing principle for metazoan evolution”[1].

How Evolutionary Mechanisms of Mutagenesis and Epigenesis at the Organ-Specific Adult Stem Cell Level in the Multi-Cellular Metazoans Contribute to the Resistant “Cancer Stem Cells”

Currently, cancer is still a major global health problem, whether the disease is strongly correlated to smoking, alcohol, diet, viruses, exposure to sun light, lack of exercise, inherited cancer-predisposing genes, exposure to mutagenic or epigenetic chemicals, etc.; whether the types of cancers varies from nation to nation, ethnic group to ethnic group; or whether it seems to be somewhat resistant to prevention or therapy. In the paper to which I would like to add a “Commentary”, I wanted to point out that in the basic cancer research field and translational- therapeutic field, the success or failure of the new fields of “bioinformatics”, “precision medicine”, “cancer stem cells”, together with extremely sophisticated technologies of CRISPR, or single cell molecular analyses, will depend on a much broader view of human carcinogenesis than what traditional approaches can provide. This was seen by Hanahan and Weinberg [2]: “Some would argue that the search for the origin and treatment of this disease will continue over the next quarter century in much the same manner as it has in the recent past, by adding further layers of complexity to a scientific literature that is already complex beyond measure. But we anticipate otherwise: those researching the cancer [or any other disease] problem will be practicing a dramatically different type of science than we have experienced over the last 25 years. Surely much of this change will be apparent on the technical level. But ultimately, the more fundamental change will be conceptual.”

In general, so many concepts need to integrate the various scientific disciplinary fields (evolution; genetics; epigenetics; stem cell biology, microbiology (viruses, microbiome), immunology; nutrition, etc.) with psychological, social, economic, political, and cultural factors. First, cancer is clearly not a new disease [3], simply because human DNA, which plays several roles in the carcinogenic process, either by specific genes being mutated or epigenetically altered, is not immune to these potentially disrupting molecular processes [4]. Second, the cell, in a multi-cellular organism, is the unit by which the evolutionary forces act to maintain homeostasis for health. Third, the human carcinogenic process is a multi-step, multimechanism process [5-7], consisting of the “initiation” of a single normal cell to an “immortalized” cell; the “promotion” or clonal amplification of this initiated cell by the stimulation of proliferation and the blockage of apoptosis [8], and the “progression” state, where an initiated cell in this promoted clone acquires the ability to invade tissues and to metastasize. Fourth, while each cancer starts from a single cell, by the time an invasive metastatic cancer appears, the population of the tumor is both genotypically and phenotypically heterogeneous, consisting of “cancer stem cells” and “cancer non-stem cells”, interacting with each other and the other normal stromal and immune cells, as well as the extra-cellular matrices [9,10]. This complexity of cell interactions, as seen by Potter [11], creates that major challenge to the erroneous idea that a single preventive and therapeutic approach to cancer management can be performed. “The cancer problem is not merely a cell problem, it is a problem of cell interaction, not only within tissues, but also with distal cells in other tissues. But in stressing the whole organism, we must also remember that the integration of normal cells with the welfare of the whole organisms is brought about entirely by molecular messages acting on molecular receptors” [11].

The major objective of my original paper on “Quorum Sensing” [12] tried to point out that during the evolution of single cell organisms, primitive communication signals between the population of these single cells was selected to protect both the individual cell and the species by forcing them to go into a dormant phase when nutrients or other conditions, needed for life, would jeopardize their survival if ignored. Obviously, the so-called “drugresistant” bacteria appeared when that survival mechanism was disrupted and when the quorum signal was ignored. Today, this same phenomenon of cancer drug resistance has been a typical phenomenon found in cancer therapy. Until recently, the common explanation has been that the drug resistance of cancer cells was the result of radiation/chemotherapy and immunotherapy ability to induce mutations in the cancer population by the therapy itself. More recently, with the concept of stem cells, based on some stem cell biology [13-16], the appearance of therapy-resistant cancer cells is probably due to a selection of therapy resistant “cancer stem cells”, either because of better DNA repair [17], or of expressed drug transporter genes [18,19]. In both cases of drug resistant bacteria or therapy- resistant cancer cells, there is a biologically- based evolutionary basis for this phenomenon.

The Fundamental Assumption of the Origin of Cancer-Resistant Cells

In the original paper on “Quorum Sensing” in multi-cellular organisms, it was assumed that, of the two opposing hypotheses of the single cell origin of the “cancer stem cell”, namely the normal cell, that was “initiated”, was an organ-specific adult stem cell (the Stem Cell hypothesis) [20-24] or that it was a somatic differentiated cell that was “de-differentiated” or “re-programmed” [25]. Further, because the “initiation” event in that cell was an “irreversible” event, it was assumed that a mutagenic event had occurred [26]. Now, here is the critical fact that seems to be missed. Mutations can occur as a result of an “error of DNA repair”, best exemplified by the skin cancer prone, “Xeroderma Pigmentosum Syndrome” [27-30] after the skin is exposed to ultraviolet light. Yet, normally, one rarely sees any discussion of another means by which a mutation can occur, namely by the process of an “error of DNA replication”, as seen in the cancer prone, Blooms syndrome [31,32]. In other words, every time an adult stem cell is stimulated to proliferate, there is always a finite chance that a mutation could occur, without any pre-existing DNA damage. This implies that, while stem cells are, under normal conditions usually quiescent, under rapid tissue growth or under several tissue injury or cell death or removal, stem cells are recruited into compensatory hyperplasia. One of the major epidemiological questions raised in the case of human cigarette -induced lung cancer, “How does one explain lung cancers in nonsmokers?” While exposure to “downstream” smoke is one explanation, the fact that initiated cells exist in all of us, some due to “errors of DNA repair”, others are due to errors in DNA replication”. It might be that non-smokers have lung cancers because they have been exposed to epigenetic, tumor promoting conditions/chemicals that stimulated the clonal expansion of the pre-existing, spontaneously- generated initiated lung adult stem cells, which were generated by “errors of DNA replication”.

Are All Cancer Stem Cells Alike?

Of course, while we still are not sure of the biological nature of any or all cancer stem cells, there is some strong evidence that cancer stem cells did originate from normal adult organ-specific stem cells [33,34]. Moreover, Loewenstein and Kanno [35] first speculated that there seemed to be a universal phenotype of cancer cells, namely they did not “contact inhibit”; did not have growth control; did not terminally differentiate and were seemingly “immortal”. One major characteristic, they argued, was a lack of Gap Junctional Intercellular Communication (GJIC). At that time, Loewenstein and Kanno did not know about one characteristic of normal stem cells, namely they did not express connexin or gap junction genes [36]. Nor did Loewenstein and Kanno [35] know that tumor promoting, epigenetic chemicals, such as phorbol esters or DDT, could reversibly inhibit GJIC [37]. Further, Loewenstein and Kanno did not know that various viruses (SV-40; HPV) or oncogenes (H-Ras; Src, Neu, etc) could stably inhibit gap junction function) [38-40]. Since the Oct-4A gene has been associated with both normal adult stem cells and many cancer stem cells [33,41], the question is , “If all cancer cells lack growth control, lack terminal differentiation and lack GJIC function, could there be two kinds of cancer stem cells that lack GJIC?” [42]. The answer would seem to be, “Yes”. There are those that originated in the adult undifferentiated organ-specific stem cell, expressing the OCT4A gene but not the connexin genes. These would be very “embryonic-like”, such as the “flat-type” human colon cancer cells [43]. The other cancer stem cells might have originated in an early-differentiated adult stem cell, whose Oct4A gene has been repressed and its gap junction gene, needed for differentiation, has been expressed, but that the gap junction function has been rendered non-functional by some oncogene or virus [44,45]. The “polyp-type” human colon tumor might represent this type. The implication of this interpretation explains why two tumors might not respond to the same therapy, since a stem cell-derived Oct4A expressing, non-connexin expressing, and a drug transporter gene- cancer stem cell would require a cancer drug to repress the Oct4A gene and the drug-transporter gene but to express the transcription of the connexin gene to establish functional gap junctional intercellular communication [46]. On the other hand, the cancer stem cells, which expresses the connexin genes, but also has expressed oncogenes or oncogenic viruses, post-translation- inhibitors to the SV40, HPV or other viral proteins would be needed to re-establish GJIC.


The essence of the original “Quorum Sensing” paper was that through the evolutionary process, both single cell and multi-cellular organisms developed adaptive communication mechanisms that allowed these cells to survive during moments of stress. However, in both cases of the single cell organism and of the multi-cellular organism, the “Quorum Sensing” mechanisms could be disrupted, causing the homeostatic regulation of proliferation (and differentiation in the case of multi-cellular organisms). Drug-resistance bacteria and therapeutic resistant cancer cells are the ultimate end result of this disruption of quorum sensing. Based on the original “Quorum Sensing” paper, this “Commentary” has tried to re-emphasize the fact that the initiation of a normal organ-specific adult stem cell is the inevitable consequence of the evolutionary process of mutagenesis, that can occur by either an “error of DNA repair” of damage caused by some environmental agent or by an “error of DNA replication” in adult stem cells when they are forced to expand their population for tissue growth or by “compensatory hyperplasia”, after there has been significant cell death or cell removal. In other words, mutagenesis is a double-edge sword both the creation of new adaptive genes that leads to evolutionary survival of the species, and for the disruption of genes, needed to maintain homeostatic control of cells for health of somatic cells, but could lead to diseases.

The evolution of multi-cellularity also gave rise to stem cell niches, organspecific stem cells, and the dual process of symmetrical and asymmetrical stem cell division; new mechanisms (“Epigenesist”) to regulate the expression of specific sets of genes in the total genome, required for tissue differentiation, and senescence of cells.

Lastly, all cancer stem cells seem to lack GJIC, however, there are two types, those that never express their connexin genes but express OCT4A, and those that do express the connexin genes, but not OCT4A gene, yet the connexin proteins are unable to form functional gap junctions, because they have been inactivated by some viral proteins or activated oncogenes. This implies, anticancer therapy has to be designed to attack these two very different “cancer stem cells”, such that the phenotypes of these two cancer stem cells would be very different. Lastly, health or pathologies are the result of evolution, via mechanisms of mutagenesis and epigenetic alteration of genes, acting on the cell level via the integrated cell-cell communication mechanisms in multicellular metazoans.


To all my former undergraduate, graduate and medical students, postdoctoral fellows, Visiting Scholars and Collaborating Colleagues, I wish to thank you for providing the experimental results and stimulating discussions over my 50 years of laboratory research.