Moss - What genes cant do - 2003 (522929), страница 42
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There is strikingevidence that the tissue context in which many human cancers develop isdifferent from that of normal tissue. A gradient of biochemical and cytological abnormality has been observed extending some distance from theedge of bladder tumors (Rao et al. 1993). The abnormality of adjacenttissue may include genetic features, or it may not.
Ostensibly normalbreast tissue adjacent to breast tumors shows loss of alleles (Deng et al.1996). Victims of Barrett’s esophageal cancer have chromosomal changesin large areas of the esophagus in which cancer later arises. By contrastmucous tissue around colorectal cancers display various phenotypicabnormalities but no genetic changes (Boland et al. 1995).The incidence of human cancer is highly correlated with increasingage. In an attempt to sort out the heterogeneity of age correlations thatdoes exist, human cancers were classified into two groups (Dix & Cohen1980).
Class 1, which comprises the great majority of human cancer(including tumors of the mouth, esophagus, stomach, colon, rectum,liver, pancreas, bladder, brain, bronchus, trachea, myeloid and other nonlymphatic leukemias, prostate, and penis), shows a smooth logarithmicincrease in incidence between ages 10 and 80 years. The second class,which includes lymphatic leukemia, bone, testes, and Hodgkin’s cancers,shows two peaks of incidence, one around the age of 35 and the otherat greater than 50 years. The most pronounced correlation would be thatof prostate cancer (class 1); 80 percent of American men are found tohave clinical prostate cancer by the age of 80.Experimental studies on tumor-age correlations support the epidemiological findings.
When the environmental carcinogen N-methyl-N¢nitrosourea was inoculated into mice at 3, 12, and 24 months of age,Dialectics of Disorder: Normalization and Pathology as Process167only the oldest group developed pancreatic cancer (Zimmerman et al.1982). Pancreatic cancer is extremely rare in humans below the age of40. Age-based differences in susceptibility to cancer can even be seen incells in culture. Cells from the bladder epithelium of old mice are farmore susceptible to chemical carcinogenesis than those from young mice(Summerhayes & Franks 1979).While aging may result in a gradual loss of tissue durability and plasticity and thus the ability to assimilate perturbations, loss of the organizational stability of tissues may also be the result of adaptive responsesto acute challenges. Liver biology provides a purchase upon organizational dynamics that appears to be instructive on a number of levels.Liver cell cancer affects hundreds of millions of people, ranking it secondworldwide, although unlike most of the “top ten” cancers it is lesscommon in the Western world.
There is increasing evidence that in partsof China and Africa it is correlated with exposure to mycotoxins (toxinsproduced by fungi) such as aflotoxin, and in Western countries there isa similar but less pronounced correlation with alcohol consumption andcirrhosis of the liver (Farber 1987). The mechanisms by which etiological agents are involved in the causation of liver cancer are unknown, butwhat does appears to be uniformly the case—whether it be mycotoxins,alcohol, or hepatitis B virus—is that hepatocellular carcinoma (livercancer) is a long process, requiring 30 to 60 years from the time of initialexposure. Liver cancer is evidently a multistep process, and attemptshave been made, beginning with Sasaki and Yoshida (1935), to establishan experimental model by means of which the sequential stages of livercancer can be characterized.Beginning in 1976 Farber and coworkers identified the initiation ofliver cancer with the formation of a “resistant hepatocyte.” A successfulexperimental model for the study of cancer development requires anability to identify the initiation of cancer through some form of assayand a sufficient degree of synchrony in the subsequent progression of initiated cells such that discrete stages can be identified and characterized(Farber, 1987).
The rat liver afforded Farber and coworkers just such anopportunity. With exposure to over 75 different chemical carcinogens asmall number of liver cells were seen to take on a new phenotypedescribed as “resistant.” This resistant phenotype could be characterized168Chapter 4in three ways: (1) Resistant cells can be induced to grow, whereasthe majority of hepatocytes are growth-inhibited by the carcinogen. (2)Resistant cells exhibit highly enhanced tolerance for cytotoxins. (3)Resistant cells have a distinctive profile of enzymes consistent with theirability to withstand cytotoxic challenge (Farber 1991).
All three of thesefeatures are suitable for assay.Farber defined the process of initiation as follows:Initiation is a change in a target tissue or organ, induced by exposure to a carcinogen, that can be promoted or selected to develop focal proliferations, one ormore of which can act as sites of origin for the ultimate development of malignant neoplasia (Farber 1987).It should be noted that the first stage in Farber’s model of carcinogenesis need not itself be an aberrant response to a challenge. Indeed, theresistant phenotype has the earmarks of a physiologically adaptiveresponse to hepatotoxic insult. What signifies the resistant phenotype asa stage in the process of carcinogenesis is not its morbidity but rather isits relationship to other stages in the process.
The subsequent stages arenot inevitable. As has been seen since the earliest work on experimentalmodels of carcinogenesis, initiated tissue only proceeds towards malignancy under conditions of promotion.Promotion is the process whereby an initiated tissue or organ develops focalproliferations (such as nodules, papillomas, polyps, etc.), one or more of whichmay act as precursors for subsequent steps in the carcinogenic process (Farber1987).Promotion may be accomplished in the rat liver model by meansof renewed exposure to cytotoxins, dietary deficiencies, or some otherregime of protracted metabolic stress. Depending upon the nature of theregime, microscopic foci or islands of resistant cells may predominate inthe liver for weeks or even months or may rapidly give rise to visiblenodules.
Several lines of evidence suggests that nodule formation constitutes a highly organized developmental process which serves a physiologically adaptive function in protecting the organism from exposureto toxins. Chief among such evidence is exactly the newly acquiredability of the organism to withstand high doses of hepatotoxins.Rats with hepatocyte nodules are unusually resistant to a lethal dose of a potenthepatoxic agent, carbon tetrachloride. Rats with nodules show a complete resist-Dialectics of Disorder: Normalization and Pathology as Process169ance to a dose of carbon tetrachloride that is lethal for 100% of normal rats(Farber 1991).Further support for the physiologically adaptive nature of the hepatocyte nodules is found in the ability of the majority of the nodules toundergo a complex process of redifferentiation, becoming normal adultlike hepatocytes.
That the majority of nodule hepatocytes are capable ofreturning to a normal phenotype provides strong evidence that the formation of the resistant phenotype, with its ability to proliferate intonodules, is a process that lies within the normal developmental prerogatives of the liver cell. And yet the diminished vulnerability to hepatotoxins that the liver nodule affords the organism may be purchased at aprice. In Farber’s rat liver model, 2 to 5 percent of the nodules do notredifferentiate into normal adult liver tissue but rather persist.
It appearsto be at this point that the phenotype of the nodular hepatocytes is nolonger a response to ambient conditions but begins to represent anuncoupling from its microenvironment and a shearing off to an independent developmental trajectory.The persistent nodules acquire a new property—“spontaneous” or seemingly“autonomous” cell proliferation of their hepatocytes—and become the origin fora slow evolution to hepatocellular carcinoma (Farber 1987).The path from persistent nodules to malignancy is characterized bya stagewise progression, albeit one that eventually becomes difficult tocategorize.
Two months after initiation, a 10-fold greater propensity forgrowth among hepatocytes of persistent nodules is observed relative tothat of the surrounding liver, but growth is still largely synchronous andwell organized. By 6 months the baseline percentage of proliferatinghepatocytes was seen to double. Between 2 and 6 months changes in thegrowth potential of the nodule hapatocytes was observed. All hepatocytes at 2 months (control, nodule, or nodule surrounding) can be stimulated to grow by use of mitogens or partial hepatectomy, but all threethen return to basal growth rates soon thereafter. However similar treatment of 6-month nodules resulted in a proliferative response on the partof 60 to 80 percent of the hepatocytes, with a significant number failingto return to the baseline rate for several weeks thereafter (Farber, 1987).The persistent nodules at 6 months also show another new property—generation of nodules and hepatocellular carcinoma on transplantation to the spleen.170Chapter 4The earlier nodules, like normal live hepatocytes, grow slowly in the spleen withgradual replacement of the splenic pulp but without nodules or cancer (Farber1987).The legendary baseball player Mickey Mantle, publicly famous forhome runs and enduring pain, and privately distinguished for sustainedalcohol consumption, became fond of saying that if he knew he wasgoing to live so long, he would have taken better care of himself.7 Mantledied in his early sixties of liver cancer soon after having received a somewhat controversial liver transplant.
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