Biochemical Markers Associated with the Stages of Promotion and Progression during Hepatocarcinogenesis in the Rat

Abstract

JSTOR is a not-for-profit service that helps scholars, researchers, and students discover, use, and build upon a wide range of content in a trusted digital archive. We use information technology and tools to increase productivity and facilitate new forms of scholarship. For more information about JSTOR, please contact support@jstor.org.. The National Institute of Environmental Health Sciences (NIEHS) and Brogan & Partners are collaborating with JSTOR to digitize, preserve and extend access to Environmental Health Perspectives. Specific biochemical changes occurring during hepatocarcinogenesis have been sought by many investigators. The development of multistage models for hepatocarcinogenesis in the rodent has renewed interest in such marker alterations in preneoplastic as well as neoplastic hepatocytes. Preneoplastic altered hepatic foci (AHF) exhibit specific histomorphologic changes as viewed with tinctorial stains and show a variety of biochemical changes as evidenced by enzyme and immunohistochemistry and by other histochemical markers. During the reversible stage of promotion when AHF are scored by multiple markers, the distribution of markers within these lesions differs with the use of different promoting agents. One interpretation of this finding is that each promoting agent stimulates the replication of a set of initiated cells exhibitingthe phenotypic characteristics of a specific programmed phenotype. The same markers score AHF during the stage of progression, but many AHF in this stage are phenotypically heterogeneous, exhibiting in tissue sections a "focus-in-focus" pattern of marker alteration. These latter changes can be correlated with the appearance of karyotypic alterations in preneoplastic hepatocytes. On the other hand, it has been difficult to demonstrate the activation, either mutational or transcriptional, of proto-oncogenes until this stage of progression in rat hepatocarcinogenesis. Thus, a study of biochemical and molecular markers during the stages of hepatocarcinogenesis may lead to a better understanding of potential mechanisms involved in the development of neoplasia through the stages of initiation, promotion, and progression.

Review Article: Experimental Chemical Carcinogenesis in Fish

“…The roles of the membrane-associated cell adhesion molecules in fish carcinogenesis is unknown and an area of research worth exploring as the integrins and cadherins are integrally related to neoplastic growth and development. One of the most important enzyme markers in rodent carcinogenesis is altered GGT activity (153). GGT is a membrane-bound enzyme with increased activity in the neoplastic rodent liver, signaling reversion of affected cells to a more fetal phenotype and possibly conferring increased protection from the toxic microenvironment (72).…”

“…An assessment of these changes using tissue homogenates, enzyme chemistries, or immunological methods can help define the molecular mechanisms of neoplastic development and progression. While the numbers of markers are vast (152,153), some of the more common rodent markers have been studied in fish. The most commonly reported are gamma-gluta-myl transpeptidase (GGT), glutathione-S-transferase (GST), the cytochrome P-450s, iron exclusion, and oncogene/tumor suppressor gene expression.…”

Peroxisome proliferator-activated receptor γ ligands suppress liver carcinogenesis induced by diethylnitrosamine in rats

“…These three stages of tumor formation have been characterized in many mammalian tissues, particularly in the liver [2,3] . According to the concept of multistage carcinogenesis, clones of cells arise with increasing autonomy from normal growth regulation at each stage of development, and from these selected populations of cells, neoplasms ultimately develop [4] . The placental form of rat glutathione S-transferase (rGST P) positive foci is thought to be preneoplastic lesions of the liver [5][6][7][8][9][10][11][12] .…”

Absence of p53 mutations and various frequencies of ki‐ras exon 1 mutations in rat hepatic tumors induced by different carcinogens

“…When rats are continuously treated with hepatic carcinogens or given a single dose of carcinogen followed by treatment with hepatocarcinogenic promoters, numerous hyperplastic foci (HF) or hyperplastic nodules (HPNs) consisting of altered hepatocytes increase within the liver, and a few hepatocellular carcinomas (HCCs) may finally develop [1,2]. It is thought that multiple genetic alterations may be required for normal hepatocytes to progress from an altered to neoplastic state, but very little is known about the molecular mechanisms involved.…”