Moss - What genes cant do - 2003 (522929), страница 39
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Consider the case of colon carcinoma, whichhas been used as the basis of a more recent multistep genetic model ofcarcinogenesis (Fearon & Vogelstein 1990). The basic schema proposedfor tumor progression in the colon is one which begins with lesions tothe gene APC followed by an activating lesion to the oncogene ras and154Chapter 4then sequential loss of the DCC and p53 tumor suppressor genes. Whileostensibly another attempt to make good on the “genetic orchestrationof cancer” concept, a closer examination of the evidence suggests the lossand/or disruption of stabilizing functions and a permissive rather thandeterminative model of the role of mutations.One in 10,000 individuals in the United States, Europe, and Japansuffers from an autosomal-dominant disease known as familial adenomatous polyposis (FAP). Individuals with this affliction develop thousands of benign adenomatous polyps of the colon during the second andthird decade of life, with a small percentage of these becoming carcinomas of the colon.
The gene APC, located at chromosome 5q21, was identified as the site of the relevant lesion (Levine 1993). Recent studies haveindicated that the APC gene product appears to participate in the proteincomplexes associated with cell-to-cell binding and tissue-stabilizing junction formation (Hulsken, Behrens et al. 1994). Along similar lines theDCC (deleted in colorectal cancer) gene which is found to be lostin more than 70 percent of colorectal cancers has a gene product withsignificant amino acid homology to that of the neural cell adhesionmolecule (NCAM) (Levine 1993).
Reminiscent of Harris’s constructedfibronectin mutation, the identification of APC and DCC as cell-cellinteraction related genes suggests that such interaction is a requirementfor successful colon cell differentiation and that these genetic lesionsrepresent a loss of this function.According to the colon carcinoma model, homozygous deletion of thetumor suppressor gene p53 occurs at the latter stages of the carcinogenicsequence. Thus far, p53 has been implicated in a greater array of humancancers than any other gene. Like Rb (the retinoblastoma tumor suppresser gene), and the oncogene myc, the p53 gene product binds to DNAand appears to be an effector of transcriptional activity (Haffner andOren 1995). The effects of p53, like that of myc, Rb—and probably alltransciptional regulators—are highly complex, being capable of eitherup-regulating or down-regulating transciptional activity, depending onthe physiological-biochemical context.
The gene product of myc, forexample, may serve either in the stimulation of cell proliferation or inapoptosis (described as programmed cell death), depending on the prevailing state of cytokines6 (Wyllie 1995). Increasing amounts of attentionDialectics of Disorder: Normalization and Pathology as Process155have been directed toward evidence of cancer-relevant roles of p53in cellular responses to genetic damage. Two different pathways, onetoward arrested growth and the other toward apoptosis, appear to beconcerted responses to genotoxic challenge, in which the p53 proteinplays a role (Haffner & Oren 1995).Following Harris, we have explored the possibility that the most reliable correlation of genetic damage with cancer can be best interpretedas a loss of some developmental resource (Gene-D) which had becomenecessary for the continuation (or retention) of development specificto a particular path of differentiation.
The identification of importanttumor suppresser genes as putative cell adhesion molecules corroboratesthis view. The p53 gene, which thus far has shown the widest range ofapplicability to human cancers, may do so because it serves as a necessary developmental resource in a kind of meta-differentiation which transcends tissue-specific differences. Apoptosis may be best conceptualizedas a meta-level form of terminal differentiation that can be induced bygenetic damage and other events.
In this model of p53 action, as well asthat of APC and DCC, the significance of genetic damage is that of apermissive and in no manner directive relationship to carcinogenesis. Thelesson to be learned from Harris and the tumor suppressor researchprogram is that the question of the driving force of carcinogenesis eithercannot be answered at the level of genetic analysis or perhaps is just notthe right question at all.Life at the Margins: Adapting to Altered CircumstancesI have argued that a bifurcation took place in thinking about cancerearly in the 20th century with the main trend toward that which I havereferred to as “the phylogenetic turn” and also as gene-centrism.
Thelegacy of the nineteenth century developmentalist outlook on cancerwas that of grappling with the consequences that would follow from thefact of any cell being invested with the Keime und Anlagen of the wholeorganism. If cells retain the potential of the whole, then the fate of agiven cell cannot be determined solely from within but must be largelythe consequence of subsequent interactions with other cells and acellular elements of its surround (including environmental irritants). I156Chapter 4have also suggested that the gene concept that arose in the twentiethcentury had roots in a need to chop up the Keime und Anlagen in orderto square it with the apparent requirements of Darwinian evolutionarytheory.
The somatic mutation hypothesis put forward by Boveri broughtthis turn of mind to bear on cancer research and established a conceptionof the cancer cell as determined from within. From these twolegacies arose two distinctly different conceptions of the autonomouscell, as discussed above. Sections 2 through 4 largely followed the fortunes of the somatic cell hypothesis with its equation of cellular autonomy and the so-called cancer cell. The somatic mutation hypothesisreached its apex with the Bishop and Varmus oncogene model but ultimately failed to support its most interesting claims against challenges,both implicit and explicit, that arose from parallel studies on the role ofrecessive genes in carcinogensis. Section 5 “thematized” the nature ofthese challenges.The subject of cancer raises with poignancy this question: At whatlevel of biological order can the distinction between normal and pathological be properly made? The prevalent focus on the nature of the cancercell has been misleading to the extent that it has masked a more divergent and interesting conflict over the locus of normality-abnormality.While somatic mutation theories have attempted to implicate genes asbeing the right level for this analysis—that is, the subcellular level—theolder idea that it must be at the supercellular level that normal versuspathological growth trajectories are determined, was never completelyvanquished.A particularly vociferous attack on the reductivism of the cancer celltheory was launched in 1962 by the British radiologist D.
W. Smithersin the prestigious medical journal The Lancet. As the epigraph at thehead of this chapter suggests, Smithers presented what could well bedescribed as a manifesto calling for not just a new cancer biology butalso a new biology of the life process and organization without which,he would claim, cancer could never be adequately comprehended. Hisstyle of attack was eminently straightforward. He enumerated the components of the mainstream reductionist view then laid out the incompatibilities between it and the accumulated experience of his own careerin pathology and clinical radiology. He then adumbrated the elements ofDialectics of Disorder: Normalization and Pathology as Process157his alternative model.
Despite the passage of over 35 years, his renditionof the mainstream view still sounds strikingly familiar, his anomalies arestill anomalies, and his alternative model is still alternative and still interesting. I will present all three.Smithers’s characterization of the traditional view of cancer (by “traditional” Smithers really means the mainstream view of his day andcertainly not anything prior to Boveri) is as follows (Smithers 1962):1. Cancer is a special disease of cells.2. A cancer cell is one that has been permanently changed and is nolonger capable of behaving like a normal cell.3.
Cancer cells multiply without restraint and produce tumours servingno useful purpose in the body.4. Cancer cells grow at the expense of normal tissues, actively invadingand destroying them.5. Cancer cells can gain access to cavities and to lymphatics and bloodvessels and be carried off, each one being capable of developing into anew tumour wherever it may come to rest.6. If the cause of cancer in the cancer cell could be discovered, the wholeproblem might be resolved.7. Cancer cells must be removed or destroyed in situ if patients are tobe cured.8. If one viable cancer cell remains, treatment will fail.9. A chemical poison specific to the cancer cell may one day be foundto replace all present treatment methods.10.
When disease has spread beyond the scope of local removal or irradiation, any nonspecific cell poison may be worth trying until somethingbetter comes along.This list provides a strikingly apt representation of the suppositions thathave guided both basic and clinical research in oncology over the last 35years. Item number 6, the idea that if we could ascertain the determination of the cancer phenotype within the cell we would solve the problemof cancer, is exactly the guiding motivation behind all the research inmolecular oncology.
In this respect, both the oncogene and the tumorsuppresser gene concepts partition squarely on the far side of Smithers’s158Chapter 4divide. Smithers’s analysis well describes all the implications of theautonomous-cell-as-cancer-cell equation and in so doing highlights howmany taken-for-granted “facts” about cancer may have to be made problematic if the basic notions expressed in, for example, numbers 1 and 6were to be reconsidered.Smithers’s list of incompatibilities is as follows:1. The multicentric origin of neoplasia. (Many cancers appear to bederived from more than one cell.)2.
The long prediagnostic natural history and the many predisposingfactors in the development of tumours. (Histologists never see a radicaltransition in cancer, only gradual changes along a continuum over time.)3. Age incidence and geographical variation.4. Progression and regression in tumor behaviour. (The experience ofspontaneious regression is of particular interest in this regard.)5. The conditional persistence of some tumors. (Some tumors appear tocontinue to be dependent on certain environmental conditions.)6.
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