Moss - What genes cant do - 2003 (522929), страница 40
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The hormonal dependence of other tumors. (The status of a cell as acancer cell may be hormone-dependent.)Smithers’s list consists of those frequently observed aspects of carcinogenesis that point away from a strictly internal (to-the-cell) basis ofcancer and toward the relevance of higher levels of organization. Noneof these six points has become irrrelevant during the ensuing 35 years;rather, attempts have been made to accommodate such observations withsomatic mutation hypotheses such that they do not appear to be whollyanomalous.
But this would be the pattern seen for any number ofresearch programs that begin to run out of explanatory steam. Even ifalleged contradictions can be eased or softened, there is still the dangerof each new emendation to the model increasingly taking on an ad hoccharacter. As an alternative to piecemeal attempts to fix the somaticmutation theory Smithers offered what amounts to the reassertion of adevelopmental-organizational perspective as follows:1. Cancer is a disease of organization.2.
The word “cancer,” however, merely covers the most disorganizedend of a progression in disorganization extending from maldevelopment,Dialectics of Disorder: Normalization and Pathology as Process159malformation, metaplasia, hyperplasia, dedifferentiation, and neoplasiato disintegration.3. There is no such thing as a cancer cell—only cells behaving in amanner arbitrarily defined as being cancerous.4.
There being no such thing as a cancer cell, there can be no cause ofcancer to be found within it.5. Organization is measured by the amount of information in a system,and the entropy of a system is a measure of its degree of disorganization; gradual increases in entropy occur, not sudden cellular malignancy.6. Organizational breakdown commonly leads to progressive loss ofgrowth control, with released cell division producing an excess of tissuesno longer coordinated with the whole.7.
Organization can become more or less disorganized, and the resulting tumours may progress or regress in behaviour patterns.8. An abnormal cell, particularly a stem cell, may produce a cloneof cells reacting abnormally with the environment and so promotedisorganization.9. Environmental stress may disorganize the behaviour of many cellswithin a sphere of influence which may be local or widespread, depending on the character and distribution of the particular cells concerned.10. There are many causes of organismal disorganization; understanding depends on the explanation of tissue dependencies and relationshipswhich are complex, changing, and never likely to be totally foreseeable.At first blush, Smithers’s view would appear to be far outside thecurrent consensus, holding as it does that cancer is unmistakably theresult of genetic lesions; many would be inclined to dismiss it simply forbeing hopelessly outdated. Yet, with critical examination we can see thatthis is misguided. Smithers suggests that carcinogenesis is a gradualprocess, whereas the somatic mutation viewpoint has traditionallyfocused on the idea of oncogenic mutation as an all-or-nothing event.Current thinking however, has once again rejected the idea that cancercan be caused by a single somatic mutation.
The leading exemplar of amultistep somatic mutation model of cancer, colon carcinoma, is understood to require four to six, or even more, sequential mutations. Clearly,160Chapter 4this must constitute a gradual process. One may well try to argue thatwhile sequential and gradual, the colon model still describes an entirelyintracellular process. Yet even this can no longer be considered a securepresumption.
The (cellular) genome is quickly emerging as a far moredynamic system than had even recently been imagined. Geneticrearrangement, on many levels, is mediated by active cellular processes.Once it becomes established that mutations are not exclusively, orperhaps even principally, the result of biologically blind physiochemicalchance (e.g., quantum fluctuations in electron distribution) but rather theresult of biological processes such as enzyme systems, then the sharpintracellular versus extracellular distinction becomes untenable becausethe processes that are mediating genetic rearrangements are themselvessusceptible to the influences of the larger extracellular field.
Even mutations that are the result of a general downregulation in mutation repairsystems can be linked to the effects of the larger extracellular field uponthe mutation-repair state of the cell. By “extracellular field” I am referring to the sum total of cell-cell, cell-matrix, receptor-ligand, chemicalmessenger, local ionic concentrations, and so forth, which influence allthe activities of a cell.Perhaps a particularly compelling illustration of this point is the emergence of gene amplification as a major type of somatically based geneticrearrangement found to be associated with human cancers. Amplification refers to the actual multiplication of the number of gene copieswithin the DNA of a cell.
It turns out that amplification of protooncogenes is one of the major pathways by which the proto-oncogene isactivated. Amplification is found to result in from 5 to more than 500copies of the original gene becoming present and does not typically entaila change in DNA sequence, i.e., a classical mutation (Schwab 1998).
Theactivation of proto-oncogenes by amplification is a matter of genedosage. The oncogene ERBB2, for example (also known as HER2 andNeu) is found to be amplified in 20 to 25 percent of primary breastcancers although no sequence mutation is associated with it (Schwab1998). While all the mechanisms associated with gene amplification arenot known there can be little doubt that it involves an array of complexbiological activities. Enzymes, in all likeliehood, mediate the polymerization of new DNA using the old gene as a template, and additionalDialectics of Disorder: Normalization and Pathology as Process161enzyme systems must make the necessary incisions and ligations neededto result in a continuous strand of de novo elongated DNA.At this level of biological complexity the idea that such events takeplace at random in hermetic isolation from all the ambient factors thatinfluence every other biological process is simply untenable.
The emerging consensus of a multistage multimutational basis of cancer makesreference to an increasingly complex shopping list of factors, oncogenes,tumor suppresser genes, cell-adhesion molecules, and so forth that areessential ingredients of malignancy. But where is the line between causeand effect? On what basis can it be held that subsequent alterations ofcellular DNA, amplifications, rearrangements, and the like, which arethemselves mediated by biological subsystems, are not the effects of biological factors, including the larger extracellular field, every bit as muchas they are the effectors of subsequent biological events?Smithers may not have been privy to the wide array of genetic eventsthat have since been shown to be associated with carcinogenesis, but itis the very nature of these genetic events that are beginning to point theway back to the significance of the larger extracellular field.
Particularlystriking in this regard is the emergence of members of every class of celladhesion molecule (those cell surface components which are mostdirectly involved in mediating cell-cell and cell-matrix interactions), i.e.,the integrins, cadherins, and the immunoglobin superfamily, in cancerrelated alterations. Changes in the composition or character of celladhesion molecules may directly affect both the influence of a cell on itsextracellular surround and how it in turn is affected by that surround.That somatic alterations of cell-adhesion molecule genes are emerging asfrequent factors in carcinogensis would strongly suggest that the internal milieu of a cell can’t be separated from its larger context when considering the etiology of cancer.The somatic rearrangement of various genes in carcinogensis has beenwell established and yet neither the onset of these rearrangementsnor the consequences of these rearrangements occurs in isolation fromthe larger extracellular milieu.
Smithers’s idea that cancer is principallya disease of extracellular organization is thus not overruled by the last20 years of findings in cancer genetics. Nor has thinking along these linesgone entirely unnoticed by the genetic mainstream. Consider, for162Chapter 4example, the following early reflection from leading oncogene investigator and Nobel Laureate J. Michael Bishop:Each oncogene induces tumors in only a limited and characteristic set of tissues:transformation of cells in culture follows the same selective pattern. We cannotat present explain the selectivity of oncogene actions, but the phenomenon hascontributed to the view that transformation by retrovirus oncogenes is fundamentally a disturbance of differentiation.
According to one prevalent view, oncogenes may act by arresting cellular development within a specific compartmentof one or another developmental lineage; tumorigenesis ensues because the immature cells that constitute the compartment continue to divide, as is their nature,and become a continuously expanding population (Bishop 1982).Smithers (point no. 8) allowed for the possibility of an abnormal cellwhich results in a clone of cells that react aberrantly with their environment. The anonymous, yet prevalent, view to which Bishop referswould appear to be akin to a kind of deflationary account of the role ofoncogenes in cancer.
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