A state-of-the-art consensus report on what is known about peroxisome proliferation, the mechanisms involved, and their relevance to carcinogenesis. Peroxisomes are single, membrane-limited, cytoplasmic organelles that are found in cells of animals, plants, fungi, and protozoa. Peroxisome proliferators include certain hypolipidaemic drugs, phthalate ester plasticizers, industrial solvents, herbicides, food flavours, leukotriene D4 antagonists, and hormones. Numerous studies in rats and mice have demonstrated the hepatocarcinogenic effects of peroxisome proliferators, and these compounds have been unequivocally established as carcinogens. Since humans are exposed to peroxisome proliferators to a significant extent, assessment of the adverse biological effects of this group of compounds, and particularly their potential carcinogenicity, has become an important issue. The report has two parts. The first records the consensus reached by a group of eleven experts, including several of the leading investigators in this field. Questions addressed include the mechanisms by which peroxisome proliferators exert their carcinogenic effects in rodents, the relevance of animal studies to the evaluation of carcinogenic risk in humans, and the potential use of peroxisome proliferation as a biological marker for liver cancer. The report concludes that compounds inducing peroxisome proliferation in rats and mice have little, if any, effect on human liver. The report also issues advice on the interpretation of peroxisome proliferation, demonstrated in animal studies, when evaluating the carcinogenic risk to humans. The second part consists of three background papers presented by members of the working group.

Provides an update on several new aspects of peroxisome biology, including the role of the peroxisome proliferator activated receptor. The book covers morphilogical, biochemical and molecular biological aspects of peroxisomes.

All three peroxisome proliferator-activated receptor (PPAR) subtypes share a high degree of structural homology while exhibiting differences in function, tissue distribution, and ligand specificity. In Peroxisome Proliferator-Activated Receptors: Discovery and Recent Advances, the authors trace the history of PPAR discovery and detail the receptor structure and its posttranslational modifications. Furthermore, endogenous ligands as well as various classes of exogenous ligands, subtype-selective, dual and pan agonists as well as antagonists, are discussed. In addition, the tissue distribution and versatile functions of PPAR subtypes in major organs are described. As PPARs play critical roles as regulators of numerous physiological as well as pathophysiological pathways, Peroxisome Proliferator-Activated Receptors: Discovery and Recent Advances aims to help researchers to develop safer and more effective PPAR modulators as therapeutic agents to treat a myriad of diseases and conditions.

Peroxisome proliferator-activated receptor / (PPAR/) is an important regulator in various physiological processes, including lipid metabolism and glucose homeostasis. However, its role in cancer remains controversial. Although PPAR/ is highly expressed in the intestines of normal adults, it has been reported to be up- or down-regulated during colon tumorigenesis. Researchers have not reached a consensus for whether PPAR/ is beneficial, detrimental, or unrelated to colon cancer initiation, survival, growth, and metastasis, in mouse or and human cancer models.One of the first mechanisms described that PPAR/ promotes carcinogenesis was the hypothesis that PPAR/ is a target gene of the oncogenic APC/-CATENIN pathway, a major pathway that is activated by mutations in colon cancer. However, subsequent studies did not observe a correlation between PPAR/ expression and -CATENIN activation, and questioned whether PPARD (gene coding for PPAR/) is a bona fide APC/-CATENIN target protein. Moreover, the functionality of PPAR/ as influenced by the APC/-CATENIN pathway, has not been critically examined to date. Therefore, in the first part of this thesis, the hypothesis that PPAR/ is functionally regulated by the APC/-CATENIN pathway as a tumor-promoting protein was tested. We first investigated whether mutations of the APC/CTNNB1 (-CATENIN) genes or overexpression of functional -CATENIN modulate PPAR/ cellular retention and its response to ligand activation in human colon cancer cell lines. We further examined the effect of ligand activation of PPAR/ using a classic agonist, as well as selective repression of PPAR/ using ligands that stimulate its transcriptional repression activity, on the growth of colon cancer cells with wild-type or mutant APC/CTNNB1. We observed that cytosol and nuclear retention of PPAR/, with or without ligand activation, were not different between cell lines with wild-type or mutant APC/CTNNB1 (gene coding for -CATENIN). Second, target gene activation of PPAR/ following ligand activation occurred faster in cell lines with mutant APC/CTNNB1 compared to a non-mutant cell line, although this difference was not observed with transient overexpression of -CATENIN. Third, ligand activation and selective repression of PPAR/ inhibited growth in several APC/CTNNB1 mutant cell lines but had no effect on the non-mutant cell line. These results suggest that cellular retention and transcriptional activity of PPAR/ are not directly regulated by the APC/-CATENIN pathway. However, the results also suggest that PPAR/ may be enhanced by the presence of APC/CTNNB1 mutations in human colon cancer cell lines.The role of PPAR/ in colon cancer invasion and metastasis also remains elusive. In the second part of this thesis, the influence of PPAR/ activation on malignancy-related features of colon cancer was examined. We hypothesized that ligand activation or selective repression of PPAR/ would inhibit anchorage-independent growth, migration, invasion, epithelial to mesenchymal transition (EMT), and metalloprotease (MMP) activity. Results, some preliminary in nature, showed that selective repression of PPAR/ reduced anchorage-independent growth by inducing apoptosis, inhibited migration, and reduced EMT marker expression, but did not change TNF/TGF-induced MMP activity. By contrast, ligand activation of PPAR/ reduced migration and TNF/TGF-induced MMP activity, but did not affect anchorage-independent growth and EMT marker expression. These results suggest that both ligand activation and selective repression of PPAR/ reduce the malignant potential of colon cancer, although the underlying mechanisms could be different. Combined, results from this study indicate that PPAR/ is not functionally regulated by the APC/-CATENIN pathway. Further, ligand activation or selective repression of PPAR/ using synthetic ligands may modulate colon cancer growth and malignancy-related features, in particular in cells with APC/CTNNB1 mutations.

These conference proceedings reflect the resurgence of public awareness and research interest in the field of hormonal carcinogenesis, a phenomenon that is largely the result of the widespread use of therapeutic hormonal agents and the causal association of hormones and a variety of cancers, such as breast, prostatic, unterine and cervical. Significant attention is paid to the popular use of oestrogen therapies in women's health care.

Induction of drug (xenobiotic)-metabolizing enzymes is a common biological response to xenobiotics, the mechanisms and consequences of which are important in academic, industrial, and regulatory areas of pharmacology and toxicology. This monograph, for the first time, has brought together researchers who deal specifically with drug-metabolizing enzymes and peroxisome proliferators. It contains an up-to-date review of peroxisome proliferation, with detailed tables on the 100 known peroxisome proliferators and studies on their hepatocarcinogic capacity. It provides current material from 12 different laboratories doing cutting-edge research on the effect of peroxisome proliferators on drug-metabolizing enzymes.The book covers the response of cytochrome P450s, UDP-glucuronosyltransferases, epoxide hydrolases, glutathione S-transferase, DT-diaphorase, and other enzymes.