Moss - What genes cant do - 2003 (522929), страница 41
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Oncogene activation would be seen not as the determinant of cancer but as the proximate initiator of some kind of abnormality, the consequences of which are contingently determined by therelevant context. Bishop did not choose to turn down that interpretivepath, and the mainstream of cellular cancer research has continued tofocus on the strictly intracellular, genetic determination of the cancerphenotype. Yet the evidence for the context specificity of cancer has notdeclined in the slightest; nor, given the emerging knowledge of the biologically mediated nature of somatic genome alterations, can Smithers’sidea that carcinogensis may begin with tissue disorganization be ruledout.
If Smithers’s (1962) view appears ostensibly to undervalue or ignorethe significance of intracellular events, it would seem that molecularoncologists up to the present have persisted in dogmatically adhering toa gene-versus-all-else dichotomy, when precisely it is the need to understand the multidirectional vectors of causality that is indicated. A stunning illustration of the inextricability of carcinogenesis from the largerdevelopmental field can be found in the biology of those vertebrates thathave retained substantial regenerative capability.Substantial somatic regenerative ability is restricted in vertebrates tomembers of the Urodele amphibians, which includes newts and otherssalamanders. An adult newt can regenerate its tail and limbs as well asupper and lower jaw and ocular tissues such as the lens.
This process,Dialectics of Disorder: Normalization and Pathology as Process163which is called “epimorphic regeneration,” begins with the formation ofa local growth zone called a “blastema.” Urodeles can reverse the differentiated state of tissues in response to amputation or tissue removal(Brockes 1998). De novo undifferentiated cells proceed to undergoseveral rounds of division before redifferentiating into a new lens or limbmesenchyme.Urodeles in general, and especially the particular Urodele tissue thatis possessed of regenerative capacity, show striking resistance to tumorformation. Evidence suggests that in response to experimental exposureto carcinogens, supernumerary regenerates form. It is conventionallyheld, in concert with the somatic mutation model of carcinogenesis, thatcell senescence—the apparent limitation on the number of times a cell iscapable of dividing—is a built-in safeguard against cancer, resulting fromthe accumulation of multiple mutations.
Yet the tissues of the Urodeles,which are capable of forming a blastema and thus have indefinite growthpotential, are the vertebrate tissues that are most resistant to tumor formation. There is no basis for imagining that these tissues are any lesssusceptible to somatic mutations, indeed only more so owing to theirgrowth capacity. It is thus suggestive that tumor resistance is a functionof the ability of the multicellular milieu to enter into a de novo morphogenetic pathway. Brockes (1998) described the cellular response ofUrodele tissue to “oncogenic activation or loss of tumor suppressor function” as the return of differentiated cells to the cell cycle, dedifferentiation and then participation in regeneration type patterns of behaviorrather than tumor formation. “It is possible .
. . that if tumorigenic mutations arise, the cells are somehow constrained within the regulatoryframework of epimorphic regeneration” (Brockes 1998).With additional experimental data the Urodele example couldwell provide powerful support for a renewed version of Smithers’sthesis. It appears likely that no number of oncogenetic mutations canturn a blastemal cell into a cancer cell because cancer is simply not determined at a single cell level, and the higher-order structure of blastemaforming tissues is in effect poised to elicit the behavior of newlyproliferative cells (whatever route, mutational or otherwise, to newlyproliferative status they followed) such as to result in de novo organizational integration.164Chapter 4More recent consideration of the kind of kinetics and possible mechanisms associated with chemical carcinogensis lends even further supportto Smithers’s view.
Experimentally proven carcinogens are actually highlyvariable with respect to their mutagenicity. But regardless of whether achemical carcinogen is shown to be mutagenic or not, there are a numberor characteristics of chemical carcinogens that are virtually invariant.Chemical carcinogens are not promoters of cell growth but ratherinhibitors of cell growth.
Cancer development, as demonstrated with theuse of chemical carcinogens (as well as radiation, DNA viruses, and someRNA viruses), is a prolonged process requiring from one-third to twothirds the life span of an organism (Farber, 1991). Initiation (of theprocess of carcinogenesis) with a carcinogen is never immediately followed by spontaneous or autonomous proliferation of cells of any organ.The unrestrained growth characteristic of cancer is a property of thelatter stages of the process of tumorigenesis.
The kinetics of autonomousgrowth as seen in experimental systems using chemical carcinogenswould thus support Smithers’s idea that cancer is not the result of a rapidchange within the cell that causes it to become autonomous. What thencauses the onset of chemically induced carcinogenesis if (1) the mutagenicity of a chemical carcinogen is not relevant to its carcinogenicity,(2) chemical carcinogens do not promote growth but rather inhibit it,and (3) the acquisition of unrestrained growth occurs only late duringthe course of a very lengthy process? Could the biological significance ofcarcinogens be not that of inducing uncontrolled growth through bringing about somatic mutation but rather that of serving as an organizational irritant or disrupter which triggers adaptive but destabilizingresponses in cells and tissues?A possible clue was derived from the cell culture studies of Mondaland Heidelberger (1970).
By exposing cells derived from mouse prostateto the potent carcinogen methylcholanthrene, they found that all exposedcells gave rise to clonal populations out of which some minority of cellsgave rise to transformed foci. Studies showed that some alteration hadtaken place in 100 percent of the exposed cells. Each and every exposedcell had become capable of giving rise to progeny cells, out of which thena smaller subset produced transformed (tumorigenic) colonies.
Of nontreated control cells by contrast, only 6 percent would ultimately giveDialectics of Disorder: Normalization and Pathology as Process165rise to colony producing progeny cells. Population-wide (100 percent)responses do not fit the profile of a mutation (which is always a lowprobability event) but rather are suggestive of a physiological (epigenetic)phenomenon, although a general tendency toward diffuse, nonspecificgenetic damage might also fill the bill).
Observations, such as those ofSmithers, that carcinogenesis often begins from a whole (multicentric)field of cells, have been made in parallel with findings that have supported the theory of the monoclonal (from one cell) origins of cancer.How best to reconcile this apparent contradiction has been given littleattention; rather, evidence of the monoclonality of cancers has just beentaken as confirmation of the somatic mutation model and thus of thepurely internally determined cancer cell, leaving the question of fieldeffects largely ignored. Yet there are many possible explanations for howcancer could begin at the level of a disrupted field and lead to a monoclonal tumor, which would highlight rather than dismiss the importanceof cellular interactions within an organizational field.The principal difference between an organizational field model forexplaining carcinogenesis versus a somatic mutation model is that of thehierarchical level which is being examined.
An organizational field storycannot and should not attempt to exclude intracellular events, and intracellular events would certainly include changes in the structure andactivity of DNA and chromosomes. What an organizational fieldapproach would demur would be an attempt to treat an intracellularevent as a self-sufficient determination of a carcinogenic trajectory, whichis exactly what the somatic mutation tradition has attempted to putforward.
So the question for an organizational field analysis is notwhether genetic alterations occur in carcinogenesis—they surely do—buthow to situate them in the complex nexus of causes and effects. Tumorprogression entails increasing genetic instability. Genetic instability andits consequences are in turn largely mediated by the organizationalcontext of the cell.The age of a tissue (and its developmental status) has long been seenas highly significant with respect to both the likelihood of giving rise toa tumor cell and also with respect to its receptivity to tumor growth.
Inclassic early studies, Mintz et al. (1978) produced a mouse teratocarcinoma by transplanting 6-day-old mouse embryos to under the testis166Chapter 4capsule of an adult male mouse. If these cells were then subsequentlyinjected under the skin of a mature mouse, they were seen to formtumors. Yet if the same cells were inoculated into a very early embryothey became integrated into the developmental matrix of the embryo,becoming normal constituents of many different tissues.In a conceptually similar and more recent set of experiments(McCullough et al. 1997) liver cancer cells from a rat were transplantedinto the livers of both older and younger mice. In the older mice the cancercells were highly likely to produce a tumor. In the younger mice the samecells were prone to differentiate into normal liver cells.
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