Environment Industrial

By phrasing the question in this fashion, one can see that the paradigm to understand the cancer problem is fundamentally wrong.  Our current understanding of genetics shapes the concept that DNA, the genetic information, must interact with environmental signals in order to express that information.  In other words, the phenotype of an organism is the result of the genotype interacting with the environment, e.g. nature and nurture, rather than nature versus nurture.  There is no question that genes are involved in carcinogenesis, since it has long been known that there were many genetic syndromes associated with predispositions to cancer, i.e., Down syndrome, xeroderma pigmentosum, Fanconi’s anemia, etc.  On the other hand, physical and chemical agents, such as ultraviolet light and cigarette tar condensates, were known to induce cancers in animals.  Xeroderma pigmentosum, a skin cancer predisposed syndrome, lacks, genetically, enzymes in the cells which are needed to repair damage done in the DNA of ultraviolet light-exposed skin cells.  Cells from normal individuals can repair ultraviolet induced DNA damage under normal conditions, preventing is damage from causing alterations, i.e., mutations, in the newly replicated DNA.  Without these repair enzymes, these ultraviolet induced DNA lesions can cause mutations (Glover et al., 1979; Maher and McCormick, 1976).

In addition, new evidence has identified specific genes, which if mutated, over expressed, abnormally expressed or lost, can influence the carcinogenic process.  These genes, the proto-oncogenes and tumor suppressor genes play critical roles in normal cells by regulating cell proliferation or differentiation (Sager, 1986; Weinberg, 1985).  When altered, these two fundamental processes, which are needed for the survival of all multicellular organisms, contribute to the general characteristics of all cancer cells, namely, these cannot control their growth, nor can they terminally differentiate under normal conditions.  Returning to the xeroderma example, by inheriting mutated genes at conception, the xeroderma individual cannot repair its DNA if exposed to sunlight.  If the cell are not exposed to sunlight, the DNA will not be damaged (ignore for the moment, damage done to these cells by UV-mimicking chemicals).  If the DNA is damaged, mutations will occur in many genes, including the proto-oncogenes [Nature and Nurture].  By inheriting a mutation in this case, more mutations can occur in the body after exposure to the environmental agent, sunlight.  Some of these mutations then can start the cancer process (Glover et al., 1979; Maher and McCormick, 1976).  That is, these mutations, if they occur in the proper oncogene in a stem cell, could prevent the terminal differentiation of the stem cell when it is stimulated to divide and differentiate.  If the amount of UV-induced DNA damage is severe in the terminally-differentiated cells, these cells would die since the XP cells do not repair their DNA very efficiently.  This cell death of the differentiated cell population would force the surviving initiated stem cell to proliferate, but not to terminally differentiate (Trosko, 1981).  This clonal expansion of the initiated cell would be the result of a cell death-type of promotion process.  As these initiated cells accumulate on the skin surface, additional exposure could induce another mutation in one of the initiated cells, thereby providing a second “hit” which might be needed to complete the carcinogenic process in this case.  In other words, xeroderma pigmentosum might represent an “initiation-promotion-progression” or “complete carcinogen” syndrome.

Skin cancer can, of course, be induced in non-xeroderma pigmentosum individuals.  When normal individuals get exposed to massive amounts of ultraviolet light, such that their DNA repair capacities are unable to repair all the damage, some of the damage would then act as substrates for mutations as in the case of xeroderma pigmentosum.  Either repeated exposures to large amounts of sunlight to induce cell killing to act as promoting and progression agents or exposure to non-cytotoxic mitogenic agents would ultimately bring about the skin cancer.

This xeroderma pigmentosum syndrome can further illustrate the “nature and nurture” model when one examines the internal tumors of these individuals.  While all the cells of these XP individuals are deficient in DNA repair, and while there have been reports of internal tumors found in these individuals (Kraemer, 1980), the numbers are small in comparison to the skin tumors.  Some would argue that is because they do not live long enough to develop internal tumors.  While that is probably true, it points out that the environmental exposure to chemical mutagens is far lower than exposure to the physical mutagen, sunlight.  Chemical mutagen exposure would probably never exceed levels which would induce massive cell killing as exposure to sunlight would do.  Therefore, internal initiated cells in the XP individual would have to be exposure to a high enough level, in a sustained, chronic manner, of noncytotoxic mitogenic stimuli to act as a promoter.

Recent molecular findings on the retinoblastoma, Wilms’ and Li-Frameni syndromes might suggest that these could represent “initiator-prone” syndromes (Malkin et al., 1990), if one assumes that the inheritance of one mutated gene through the germ line as the “initiating” event.  On the other hand, Downs and neurofibromatosis syndromes, which have not been sh;own to have defects in DNA repair (Trosko et al., 1985; Yotti et al., 1980), might be conceptualized as “promoter-prone” syndromes (Trosko et al., 1985).  In general, there are genes which could enhance or prevent environmental mutagen-induced DNA damage (e.g.,albinism or dark pigmented individuals, respectively) and genes which stimulate or reduce cell proliferation in certain tissues (e.g. genetic imbalanced growth regulators and hormones).