Progress in clinical and biological research最新文献

This review focuses on etiologic factors and hormonal correlates of the three major gynecologic cancers-uterine cervix, uterine corpus and ovary- and breast cancer. The incidence rate of the three gynecologic cancers combined is only 40 percent of the breast cancer rate (43.6 vs 109.5 per 100,000), whereas the combined mortality rate is half that for breast cancer (14.3 vs 27.3 per 100,000). Cervical cancer is distinctive in that it's hormonal correlates are few; it exhibits the epidemiologic characteristics of a sexually transmitted disease. Integration of Human Papilloma Virus DNA types 16, 18 (or other) within the cellular genome has been identified in more than 80% of high grade cervical intraepithelial neoplasias and invasive carcinomas. Epithelial ovarian cancers occur most commonly in nulliparous, infertile women and familial carriers of BRCA1. Oral contraceptive (OC) use reduces ovarian cancer risk by at least one-half, a benefit which increases with increasing duration of use and persists for at least 15 years after discontinuation. Pregnancy and OCs suppress gonadotropin secretion, whereas fertility drugs enhance follicle-stimulating hormone production. These indicators of alterations in the hypothalmic-pituitary-ovarian axis provide some support for both the excess gonadotropin and the incessant ovulation theories of ovarian carcinogenesis. Endometrial carcinoma is the prototype hormonally-determined disease. Increased estrogen from either endogenous or exogenous sources increases risk. Lowering the estrogen load or adding progestin reduces risk. This explains the marked protection achieved by combined estrogen/progestin OC's and the dramatic increased risk uncurred by long-term estrogen replacement therapy (ERT). Breast tissue, also a target for sex steroid hormones, displays a more complex risk profile. Current ERT use increases breast cancer risk by about 30%; adding a progestin to the estrogen does not improve the situation (40% increased risk). Furthermore, OCs do not reduce breast cancer risk, but may increase it for current OC users under age 45. The magnitude of these hormonal effects is much smaller than that exhibited with endometrial cancer.

Most breast cancer has a complex, multifactorial etiology. One consequence of this multifactorial phenomenon is that etiological heterogeneity may exist. This heterogeneity implies simply that two or more groups of breast cancer cases in the general population may have been caused by different sets of events. The ability to define etiologically heterogeneous subgroups in the population may facilitate a number of research and clinical issues. Studying etiologically homogeneous subgroups in the general population may improve the ability to identify etiologic agents. Identification of a homogeneous group of breast cancer cases may also aid breast cancer diagnosis or treatment, and may allow a more effectively application of cancer prevention and control strategies. Defining etiologic heterogeneity in the general population is one initial step in the process of understanding cancer etiology. Using knowledge such as that provided in the two examples presented here, formal case-control or cohort studies can be undertaken to examine whether the factors that define etiologic heterogeneity are involved in etiology. Furthermore, the results of studies of etiologic heterogeneity can point toward potential gene-gene or gene-environment interactions. The type of studies presented here can therefore serve a useful role in leading to more formal molecular epidemiological analyses.

Breast cancer is a complex disease in which numerous genetic aberrations occur. It is unclear which, if any, of these abnormalities are causative of breast tumorigenesis. However, on the basis of the currently accepted view of breast cancer as a multistep process, it is possible that specific abnormalities may be required in the progression from a normal breast epithelial cell to an invasive tumor cell. Figure 3 shows a schematic putative model of breast cancer progression based primarily on epidemiological and histopathological studies (Page and DuPont, 1992). Advances in methodology have allowed us to more precisely determine the approximate chronology of some of these aberrations and the possible roles each plays in the formation of malignancy. Simplistically, one could speculate that it is the early loss of cell cycle control in the presence of a mitogenic stimulus that allows a cell to divide unchecked. Such uncontrolled proliferation in the absence of wild type p53 would yield a high level of genomic instability. As proliferation continues, numerous additional chromosomal abnormalities occur, and increased tumor heterogeneity would be observed as distinct subpopulations emerge in the evolution toward a progressively more aggressive phenotype. However, much still remains to be learned to gain a full understanding of the key players behind the genetic evolution of breast cancer. Only by analyzing preinvasive and putative early stages of breast cancer will we be able to characterize the most probable sequence of genomic abnormalities.

Ataxia-Telangiectasia (A-T) is an autosomal recessive disorder which presents a wide array of clinical symptoms including enhanced cancer predisposition and progressive cerebellar degeneration leading to general neuromotor dysfunction. The A-T cellular phenotype consists of higher levels of chromosome breakage, increased sensitivity to ionizing radiation and radiomimetic drugs, and defective cell cycle checkpoints in response to genome damage. Positional-cloning of the gene mutated in A-T, designated ATM, identified a 13 kb transcript encoding a 3056 amino acid protein which possesses a carboxy-terminal domain with distinct homology to phosphatidylinositol-3 kinase. Furthermore, ATM related proteins have been identified in yeast, Drosophila and other mammalian species which are involved in cell cycle control and cellular responses to DNA damage. Development of cellular and animal models for A-T can serve to better dissect the role and involvement of ATM in cell cycle regulation, cancer development, neuronal cell death and other hallmark symptoms of this disorder.

Inappropriate estrogen exposure during critical periods of development will cause numerous abnormalities in the female reproductive tract. Epigenetic effects on the expression of estrogen-regulated genes is proposed to be one of the mechanisms by which neonatal estrogen elicits teratogenic and carcinogenic effects. Of note is the existence of an integral relationship between the regulation of members of the epidermal growth factor (EGF) gene family and estrogen effects on the growth and differentiation of the reproductive tract. To determine whether the EGF gene family plays a critical role in mediating the pathogenic effects of estrogen, we have used transforming growth factor-alpha (TGF alpha) transgenic mice to investigate the effects of constitutive TGF alpha expression in the reproductive tract and whether TGF alpha would potentiate carcinogenesis induced by the potent estrogen, diethylstilbestrol (DES), and by the carcinogen, 7,12-dimethylbenz[a]anthracene (DMBA). The animals were homozygous TGF alpha transgenic female mice from the MT42 line and the parental CD-1 outbred mice. Constitutive TGF alpha expression was found to augment the effects of both DES and DMBA in eliciting hyperplastic and differentiation changes in the reproductive tract. The presence of the TGF alpha transgene significantly increased the incidence of DES-induced vaginal adenosis, uterine endometrial hyperplasia, hypaspadia, and benign ovarian cysts. In addition TGF alpha potentiated the effects of DMBA in eliciting uterine polyps and benign ovarian cysts, and in the retention of Wolffian Duct remnants. However, the incidence of reproductive tract neoplasia was not promoted by the presence of the TGF alpha transgene. This study indicates that TGF alpha plays a role in the developmental and morphogenic events of both the Müllerian duct and urogenital sinus, and that deregulation is associated with pathogenesis of these tissues. Furthermore, the fact that constitutive expression of the TGF alpha did not substitute for DES as a reproductive tract carcinogen or act as a promoter of DES-induced uterine neoplasia suggest that DES carcinogenesis involves more than aberrant expression of this single growth factor.

Biochemical and genetic studies of the estrogen-induced pituitary tumors of the F344 rat provide a new model for understanding cancer biology. Because a genetic difference in tumor susceptibly already exists in this animal model it is possible to search for the underlying mechanisms. Interestingly, thus far marked changes in expression of known or unknown oncogenes do not appear to be involved in the formation of this tumor. Similarly, known angiogenic factors have not been implicated in this model's dramatic angiogenic response to estrogen. It will be very informative to dissect out the critical genes and the products that are involved in this system and then to determine whether similar genes are involved in human, estrogen-induced cancers.