During the past 20 years, research in the behavioral sciences has become increasingly sophisticated. New findings concerning the brain and behavior have forced upon us the unpleasant necessity of reexamining our models. Concepts once useful, such as "the unconscious," "regression," and "motivation," no longer serve to adequately encompass the data. Ashby is a representative of this new order of sophistication in research, as he proceeds to investigate the problem of the brain's orderliness. He accepts, as fact, that the nervous system behaves adaptively and assumes that it is, in its essentials, mechanistic. These two data are approached as not irreconcilable. From this point, he proceeds to examine dynamic systems from the standpoint of rigorous scientific —dominantly mathematical—logic until he has evolved a theoretical counterpart of brain functioning. He then builds and experiments with a prototype electronic model, which he names the "Homeostat," and tests various aspects of his theories of

Design for a Brain

Publisher Summary This chapter reviews the sequence of cellular and other changes during cancer development in selected sites in experimental animals and in humans. It highlights the similarities and differences among the carcinogenic processes and discusses the evident generalities and working hypotheses derived from the analyses. It also discusses some perspective concerning the possible relationship of carcinogenesis to other types of chronic pathological processes such as some forms of adaptation and evolution. Major emphasis is given to three sites—namely, skin, liver, and breast. Several other sites or types of neoplasms are also discussed in the chapter, including urinary bladder, brain, kidney, uterine cervix, and foreign-body sarcoma. It focuses on the development of cancer with chemicals in experimental animals and in humans. To date, the major evidence for a beneficial role for new cell populations occurring during the preneoplastic phase of carcinogenesis concerns the liver. However, it seems appropriate to explore other systems from this point of view. In other organs or tissues, appropriate physiological or environmental factors should be sought as possible influences on early carcinogen-induced new cell populations. These influences might well constitute naturally occurring “promoting” environments in at least some carcinogenic process.

The sequential analysis of cancer development.

The stages of initiation and promotion in hepatocarcinogenesis.

CURRENT understanding of the pathogenesis of neoplasia rests principally on the demonstration1–3 that the induction of carcinomas of mouse skin by hydrocarbons can be separated into at least two stages. There is evidence of similar stages in the natural history of carcinogenesis of nonepidermal tissues4–7. For example, Peraino et al.6 have shown that short term feeding of acetylaminofluorene to rats followed by a long term diet containing 0.05% phenobarbital results in 100% incidence of hepatomas, whereas animals receiving acetylaminofluorene and no phenobarbital developed 10 times fewer hepatocarcinomas. Peraino's procedure and that of Kitagawa et al.7, who fed rats azo dye followed by phenobarbital, required that the carcinogen be fed to the rats for 3–8 weeks. On the other hand, Scherer and Emmelot8 have shown that a single large dose of diethylnitrosamine given to rats within 24 h of partial hepatectomy can induce hepatocellular carcinomas, whereas low doses (< 30 mg kg−1), given in the same way, give rise only to small foci of cells deficient in ATPase, comparable with those described earlier9,10. Further, Solt and Farber11 have reported that a single dose of diethylnitrosamine followed by acetylaminofluorene and partial hepatectomy rapidly produces foci containing γ-glutamyl transpeptidase, in contrast to the situation in normal liver which exhibits no histochemical activity of that enzyme. By combining the procedure of Scherer and Emmelot8 with that of Peraino et al.6, we have been able to distinguish clearly between two stages in the genesis of liver cancer in rats.

Biochemical characterisation of stages of hepatocarcinogenesis after a single dose of diethylnitrosamine

The sequence of possible cellular, tissue, biochemical, and molecular changes that are important during the development of experimental liver cancer with chemicals is reviewed from the viewpoint of the author's experience in carcinogenesis over the past 25 years. The development of a new model for the analysis of liver carcinogenesis, the resistant hepatocyte model, is briefly described, as are the known steps between exposure to an initiating dose of a chemical carcinogen to the appearance of hepatocellular carcinoma. These steps include: (a) the interactions with DNA; (b) the dependence on a round of cell proliferation for initiation; (c) one type of initiated hepatocyte, a resistant hepatocyte; (d) the selection of these new hepatocytes, probably by clonal expansion, to form synchronously the first type of hepatocyte nodules, early nodules; (e) the election of the majority of these nodules to undergo remodeling to normal-appearing liver by differentiation ("redifferentiation"); (f) the election of a minority of early nodules to persist; (g) the slow growth of the few persistent nodules; and (h) the precursor role of persistent nodules in the development of hepatocellular carcinoma. The evidence for such a precursor role includes: (a) the common occurrence in persistent nodules of a subsequent precancerous step, "nodules in nodules"; (b) the occurrence of metastasizing cancer inside nodules without cancer elsewhere in the liver; and (c) the high rate of evolution to cancer of persistent nodules, but not of early nodules, when transplanted to the spleen. Based on the common architecture, organization, blood supply, and biochemical pattern of properties relating to the metabolism of xenobiotics in hepatocyte nodules in six different models of liver carcinogenesis and on the common occurrence of a highly programmed redifferentiation pattern of carcinogen-induced hepatocyte nodules, it is concluded that heterogeneity and diversity seen in many phenotypic properties of cancers, including liver cancers, is preceded by a precursor population that is unusually homogeneous and uniform in phenotype. Thus, the heterogeneity and diversity of cancers are probably late manifestations in carcinogenesis. The available evidence is very suggestive that the hepatocyte nodules are an expression of physiological adaptation to exposure to hazardous xenobiotics and not a form of aberration or mutation. The data also suggest that hepatocyte nodules are an additional pattern of liver differentiation and that liver cancer, to be understood, should be compared with this precursor new state rather than the conventional adult, fetal, or embryonic states.(ABSTRACT TRUNCATED AT 400 WORDS)

https://cancerres.aacrjournals.org/content/canres/44/12_Part_1/5463.full.pdf

Cellular Biochemistry of the Stepwise Development of Cancer with Chemicals: G. H. A. Clowes Memorial Lecture

Continued administration of several hepatocarcinogens led to an increase in the concentration of glutathione (GSH) in the livers of intact, but not of hypophysectomized or adrenalectomized rats. The concentration of GSH remained high untill the development of hyperplastic nodules. Subsequently, the concentration of GSH dropped to the normal level or below. A single dose of 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB) produced an increase of GSH which, within a certain range, depended upon the amount of the carcinogen. In well differentiated, slowly growing hepatomas, the concentration of GSH approached the level in normal adult rat liver. On the other hand, in nondifferentiated and rapidly growing hepatomas, GSH was only 30-40% of that in normal liver. The activity of gamma-glutamyl transpeptidase (GTase) increased within 24-48 hours after a single large dose of 3'-Me-DAB. Continued feeding of 3'-Me-DAB led to an exponential increase of GTase. During hepatocarcinogenesis, the level of GTase activity corresponded to the degree and size of pathologic changes produced in rat liver. Chloramphenicol partially inhibited the increase of GTase induced by 2-acetylaminofluorene. Pretreatment with 3-methylcholanthrene partially inhibited the increase of GTase that had been induced by a single dose of 3'-Me-DAB. Puromycin partially inhibited the increase of GTase induced by several doses of dimethylnitrosamine. These observations indicated a close connection between the activation of GTase and chemical carcinogenesis in rat liver. Measurements of GTase activity in 12 Morris hepatomas supported this conclusion; their GTase levels were greatly elevated compared with that in normal adult rat liver.

Glutathione and Gamma Glutamyl Transpeptidase in Rat Liver During Chemical Carcinogenesis

It was shown experimentally that ACTH causes an increase of cytoplasmic RNA and subcellular granules of the adrenal cortex shortly after administration. This effect was found to be concentrated primarily on the basophilic cytoplasmic granules and to be largely independent of cell division. The increase of nuclear RNA, DNA, and nuclear mass followed that of the cytoplasm. The observations indicate also that the mass increase of mitochondrial and chromidial systems is closely related to the increase in cytoplasmic, largely chromidial RNA.

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The action of corticotropin (ACTH) on nucleic acids and subcellular elements of the adrenal cortex.

Intracellular Localization of Carcinogen and its Relationship to the Mechanism of Carcinogenesis in Rat Liver

Intracellular localization of carcinogen and its relationship to the mechanism of carcinogenesis in rat liver.

On the Correlation between Metabolic and Structural Changes During Carcinogenesis in Rat Liver

Anna E. Fiala

Papers

Glutathione and Gamma Glutamyl Transpeptidase in Rat Liver During Chemical Carcinogenesis

The action of corticotropin (ACTH) on nucleic acids and subcellular elements of the adrenal cortex.

Intracellular localization of carcinogen and its relationship to the mechanism of carcinogenesis in rat liver.

On the correlation between metabolic and structural changes during carcinogenesis in rat liver.

Deoxynucleotidase Activity in Rat Liver and Certain Tumors