Possible Role of Ovarian Epithelial Inflammation in Ovarian Cancer

Abstract

Ovarian cancer is a commonly fatal disease for which prevention strategies have been limited, in part because of a lack of understanding of the underlying biology. This paper reviews the epidemiologic literature in the English language on risk factors and protective factors for ovarian cancer and proposes a novel hypothesis that a common mechanism underlying this disease is inflammation. Previous hypotheses about the causes of ovarian cancer have attributed risk to an excess number of lifetime ovulations or to elevations in steroid hormones. Inflammation may underlie ovulatory events because an inflammatory reaction is induced during the process of ovulation. Additional risk factors for ovarian cancer, including asbestos and talc exposure, endometriosis (i.e., ectopic implantation of uterine lining tissue), and pelvic inflammatory disease, cannot be directly linked to ovulation or to hormones but do cause local pelvic inflammation. On the other hand, tubal ligation and hysterectomy act as protective factors, perhaps by diminishing the likelihood that the ovarian epithelium will be exposed to environmental initiators of inflammation. Inflammation entails cell damage, oxidative stress, and elevations of cytokines and prostaglandins, all of which may be mutagenic. The possibility that inflammation is a pathophysiologic contributor to the development of ovarian cancer suggests a directed approach to future research

Menstrual and reproductive factors in relation to ovarian cancer risk

“…Early menarche is associated with a more rapid onset of ovulatory cycles, and with the tendency to sustain higher levels of luteal phase estradiol and progesterone (Vihko and Apter, 1984). Thus, a protective effect of late menarche, observed here in premenopausal women, is consistent with hypotheses regarding incessant ovulation (Fathalla, 1971;Casagrande et al, 1979) and ovarian inflammation (Ness and Cottreau, 1999), but inconsistent with the hypothesis that higher levels of progesterone are associated with reduced risk (Risch, 1998). Similar to most previous reports (for example, Hartge et al, 1988;Chen et al, 1992), we found no evidence of an association between age at natural menopause and ovarian cancer risk.…”

“…The gonadotrophin hypothesis proposes that excessive gonadotropin secretion and consequent increases in oestrogen stimulation lead to proliferation and malignant transformation of ovarian epithelium . More recent hypotheses have suggested a role for chronic ovarian inflammation (Ness, 1999), androgens and progesterone (Risch, 1998), and the possibility that pregnancies reduce risk by clearing transforming cells from the ovaries (ovarian clearance) (Adami et al, 1994). …”

Expression of interleukin‐18 in human ovarian carcinoma and normal ovarian epithelium: Evidence for defective processing in tumor cells

“…26 In addition, normal ovarian epithelial cells themselves have been previously reported to produce several proinflammatory cytokines, such as monocyte colony-stimulating factor (M-CSF), IL-1, IL-6 and TNF-␣ in response to injury or inflammatory stimuli. 27,28 On the basis of epidemiologic studies, it has been proposed that chronic inflammation may play a role in the development of ovarian tumors, 29 and IL-18 has been considered an important mediator of chronic inflammation in other areas. 30 In keeping with previous reports of IL-18 expression in epithelial layers that line the mucosal surface of the body, we report for the first time that normal ovarian epithelial cells express both IL-18 and ICE and have the potential to produce mature IL-18.…”

Inflammation-associated gene expression is altered between normal human ovarian surface epithelial cells and cell lines derived from ovarian adenocarcinomas

“…Repeated episodes of ovulation-associated injury and repair are presumed to underlie the high frequency of ovarian carcinoma arising from the OSE (Fathalla, 1971;Salazar et al, 1996), which account for 90% of all ovarian cancers (Ozols, 1991). Since ovulation is a natural inflammatory process (Espey, 1980a, b), factors related to inflammation of the OSE have been associated with increased risk of ovarian cancer (Ness and Cottreau, 1999;Ness et al, 2000). It is therefore critically important to understand how inflammatory cell damage is normally resolved in the OSE.…”

“…Mutations responsible for generating cancerous cells are believed to arise from DNA replication/repair errors during subsequent rounds of OSE cell proliferation. The rate of mutation is further believed to increase in the presence of toxic oxidants that are released during such an inflammatory response (Ness and Cottreau, 1999).…”