Progress in clinical and biological research最新文献

Approximately 20% of all deaths in the United States are due to cancer. Cancers of the hormonal tissues such as breast, uterus, ovary in women and prostate in men account for about 8% and 5% of total mortality and 30% and 11% of cancer mortality in women and men, respectively. Diet is considered to be a major and important environmental factor contributing to cancers of hormonal tissues. Breast, uterus, and ovary cancers in women and prostate cancers in men were positively correlated with high fat consumption, high body weight (body mass), body fat, and obesity. A major mechanism for development of these cancers appears to be mediated through increased levels of hormones, especially estrogens. Adipose tissue is considered to be one of the major sources of extraglandular estrogen, produced by aromatization of androgen precursors. Weight reduction decreases the estrogen levels possibly due to a decrease in body fat, thus decreasing the risk for cancers of the hormonal tissues. Dietary fiber may modify the risk for these cancers by influencing estrogen metabolism, recirculation, and excretion. Vitamin A and its precursors may decrease the risk for prostate cancer. Iodine deficiency may increase the risk for thyroid neoplasms in humans and experimental animals. Tumors of the hormonal tissues are the most common tumors in laboratory rodents, especially rats and mice. Incidences of mammary and anterior pituitary tumors had significant and positive correlation with body weight in rats and mice. Lowering the body weight by either decreased caloric intake or other means (e.g., exercise, increased fiber consumption) markedly lowered the incidences of these tumors in laboratory rodents. Laboratory studies indicated that mammary tumor rates in rats may not depend on the amount of fat consumed per day. The mammary tumor-promoting effect of fat may be due to complex interactions involving energy intake and energy retention (body mass) mediated through paracrine, endocrine, and neurohormonal mechanisms. Dietary protein may influence chemically induced tumors by affecting the metabolism of chemicals through enzyme induction. Thus, environmental factors such as diet are considered to be major and important factors for tumors of the hormonal tissues such as breast, uterus, and ovary in women and prostate in men. Diet and associated body weight are considered to be the major factors for tumors of hormonal tissues such as mammary and pituitary glands in rodents, especially rats. Modification of diet and a decrease in caloric intake may markedly decrease the incidence or delay the development of tumors of hormonal tissues in humans and in experimental animals.

The field of comparative carcinogenesis has expanded greatly during the last decade. During this decade, the advent of molecular biology techniques allowed the isolation and identification of several oncogenes and tumor suppressor genes. Analysis of genetic alterations in these genes enabled the first dissection and comparison of carcinogenesis pathways in humans and rodents at the molecular level. The results showed that most of the oncogenes-/tumor suppressor genes found to be altered in humans were also altered in rodents. Even the molecular pathways involved in carcinogenesis appear to be similar in some organs. Unfortunately, there are still many unknown steps in the process of carcinogenesis. However, overall, the results still indicate that in spite of the differences between rodents and humans, the use and comparison of rodent models with human tumorigenesis is one of the best ways to 1) examine the mechanisms of carcinogenesis, 2) to identify potential carcinogenic compounds, and 3) to help determine potential carcinogenic risk for humans. The potential validity of the comparative carcinogenesis approach should become even more valuable as it becomes more fine-tuned due to the application of new approaches and the identification of new genes for study. The rapid pace of genomic mapping, the use of loss of heterozygosity studies, and the use of genetically susceptible populations (rodents and humans) has and will continue to allow the localization, isolation, and identification of new cancer genes. As each gene is analyzed in human and rodent tumors, the molecular pathway comparisons will become more accurate and detailed. This combined with molecular epidemiological and transgenic approaches will assure that the field of comparative carcinogenesis will continue to grow and be important in the next decade.

It is proposed that the kidney cytotoxicity or tubular damage and the subsequent regenerative cell proliferation elicited by estrogens after chronic hormone treatment is driven specifically by the intrinsic estrogenic property of these agents. The sequence of events leading to estrogen-induced renal tumorigenesis in the hamster is presented in Figure 2. There are a number of events that occur rapidly and nearly simultaneously. First, there is an alteration in kidney proximal tubule (PCT) cells that is manifested by an elevation in both ER and PR at about 1.5 and 3 months, respectively. This clearly demonstrates an increased responsiveness of the kidney tubule to estrogen. Second, there is a progressive PCT cytotoxicity or cell injury, occurring as early as 1.5 months, which increases in severity with continued estrogen exposure. Initially, when the tubular damage is not severe, the reparative hyperplasia occurs mainly in the mature proximal tubules. Third, with increased severity in renal tubular cell damage, committed epithelial interstitial stem cell populations, shown to be the origin of this tumor, begin to proliferate in an effort to repair the increasing cell damage induced by chronic estrogen treatment. As a consequence of this regenerative cell proliferation, in both mature proximal tubules (limited) and primitive interstitial stem cells, aneuploid cells in both dividing mature and primitive kidney cells are significantly elevated. This view is consistent with the specific estrogen-induced cell proliferation in culture cited earlier. Evidence has recently been provided in our laboratory that suggests that chromosomal instability as a result of nonrandom chromosomal alterations (trisomies, tetrasomies, monosomies) as well as other chromosomal aberrations contribute critically to early events in renal tumorigenesis in the hamster. Moreover, overexpression of protooncogenes and suppressor genes occurs as early as 4 months of estrogen treatment. Therefore, the nongenotoxic estrogen-induced neoplastic transformation in the hamster kidney is suggested to occur in a series of discrete molecular events that is now believed to be primarily hormonally driven and hormonally dependent.