Environment Industrial

One of the important reasons for examining this paradigm is that in considering from whence a cancer cell is derived, two possible answers can be offered:  namely, from any one of the hundreds of billions of cells in the body or from only a few special kinds of cells in each organ.  Two major theories which capture these ideas are the “stem cell theory” (or “disease of differentiation” or “ontogeny as partially blocked ontogeny” theories) and the “dedifferentiation” or “retro-differentiation” theory of cancer (Markert, 1986; Pierce, 1974; Trosko and Chang, 1989a).  Before one can distinguish the two, more definitions will be needed.  The fertilized egg can be considered a totipotent stem cell, since it can give rise to every type of cell in the human body.  Pluripotent stem cells are those derived from the totipotent cell but are restricted to give rise to only those cells found in certain organs (i.e., liver and pancreas).  Committed stem or progenitor cells are those derived from the pluripotent stem cells, which now give rise to a specialized series of cells within the organ.  A terminally differentiated cell is one, by definition, that is clonally dead.  That is, it cannot divide to give rise to another cell like itself or one that will be a derivative of it.  A neuron, red blood cell or a lens cell would be examples.  A cell could be called differentiated if it has highly specialized functions yet still have limited division potential, e.g., a hepatocyte.  The concept of cancer as a stem cell disease or disease of differentiation has its roots in many different observations; (a) the similarity of stem cells and tumor cells, such as tissue origin, extensive proliferative potential and tissue-specific differentiation potential; (b) the implication of small target size for tumor control with radio-or chemotherapy; (c) the demonstration that clonogenic potential, self-renewal capacity and cell differentiation features are restricted to subpopulations of cells in tumors; (d) the ability to induce terminal differentiation of some neoplastic cells in vitro by various nature differentiation factors or exogenous chemical compounds (Chang et al., 1987).

While there have been several major observations prompting support for the stem cell theory, one of the relevant observations to this analysis is the finding of Nakano and Ts’o (1991).  They demonstrated, in an in vitro hamster transformation system, that a small subpopulation of less differentiated and contact-insensitive cells was more susceptible to neoplastic transformation than populations of cells depleted of these “presumptive” stem-like cells.  In brief, not all cells could be transformed when exposed to various “carcinogens”.  Moreover, this subpopulation of transformable cells decreased with the developmental age of the animal.  These observations not only relate to the stem cell theory but also to cancer risk assessment.  If the same phenomenon exists in the human body, then, assuming not all cells are equal targets for carcinogenesis, the risk associated with exposure to carcinogenesis would be a function of that population of cells.  In addition, if that stem cell population in various organs is differentially modulated by genetic, developmental or environmental factors, the n the risk at the time of exposure would have to take this into account. (More will be said on this later.)

Evidence has been accruing recently suggesting that these stem cells do exist in human tissue.  Chang et al., (1987; 1990) have isolated contact insensitive cells from normal human kidney and breast tissue.  Several important features related to these cells provide linkages to additional hypotheses concerning the carcinogenic process.  The first is that these cells, while normal, appear to be immortal, i.e., they do not have the so-called “Hayflict” lifespan (Hayflict, 1965).  The second is that they do not have functional gap-junctional intercellular communication which is normally found in the differentiated normal cells.  The former is of some philosophical as well as scientific importance.  The latter will be discussed later.

It is conventionally assumed that a normal cell is mortal while a cancer cell is immortal.  It is understandable, from an experimental biologist’s perspective since most normal human cells in tissue culture appeared to “senesce”, while most cancer cell could be grown indefinitely.  However, it now appears that the culture conditions in which normal tissue was placed did not favor the growth of stem cells.  Therefore, the senescence of the cells was probably due to the terminal differentiation of the cells and the loss of the stem cell pool.  If the stem cell is fundamentally immortal when it is naturally induced to terminally differentiate, it then becomes “mortal”.  Consequently, although recent molecular oncology studies continue to view the early process of carcinogenesis as one needing to “immortalize” a normal.  “Mortal” cell (Land et al., 1983; New bold and Overell, 1983), it has been hypothesized that the process is just the opposite (Trosko and Chang, 1989a).  This would also fit the stem cell theory very well.  If the stem cell is immortal, and if the first step in the carcinogenic process blocks the cell’s ability to terminally differentiate or become “Mortal”, the cell would still be able to proliferate and self-renew the error that is the inability to terminally differentiate.