2840 Hypothesis/Commentary Inflammation and Endometrial Cancer: A Hypothesis Francesmary Modugno,1,2 Roberta B. Ness,1,2 Chu Chen,3,4,5 and Noel S. Weiss3,5 1Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh; 2University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania; 3Program in Epidemiology, Public Health Sciences Division, Fred Hutchinson Cancer Research Center; 4Department of Otolaryngology: Head and Neck Surgery; and 5Department of Epidemiology, School of Public Health and Community Medicine, University of Washington, Seattle, Washington Abstract Endometrial cancer is the most common gynecologic early menarche, and late menopause—may be viewed as malignancy in the United States. Substantial epidemiologic factors increasing the exposure of the endometrium to data implicate an imbalance of estrogens and progestogens inflammation, whereas pregnancy and smoking, two likely in the etiology of this disease. We propose that inflamma- protective factors, have the opposite effect. Chronic inflam- tion also plays a role in endometrial cancer development. mation can induce rapid cell division, increasing the Emerging laboratory data suggest that elevated levels of possibility for replication error, ineffective DNA repair, prostaglandin E2 may underlie the transformation of normal and subsequent mutations. A proinflammatory milieu can endometrium to neoplastic tissue and that in vitro nonste- also directly increase estrogen production. Hence, inflam- roidal anti-inflammatory drugs may inhibit endometrial mation may work in conjunction with or in addition to cancer cell growth. In this review, we suggest that the risk estrogen exposure in the development of endometrial factors for endometrial cancer—unopposed estrogens, anov- cancer. (Cancer Epidemiol Biomarkers Prev 2005;14 ulation, polycystic ovary syndrome, excessive menstruation, (12):2840–7) Introduction Substantial epidemiologic data implicate an imbalance of cycle resembles an inflammatory process, that unopposed estrogens and progestogens in the etiology of endometrial estrogens have an inflammatory effect on the endometrium, cancer (Table 1): early menarche (1, 2), late menopause (3, 4), and that many of the established risk factors for endometrial anovulation (5, 6), prolonged menstruation, obesity (7-9), poly- cancer can be viewed as producing inflammation in the cystic ovary syndrome (10), and diabetes mellitus (11-13), endometrium. This proinflammatory milieu can initiate and characteristics or conditions involving a relative increase promote neoplastic transformation directly. It can also increase in exposure to endogenous estrogens, have been associated estrogen production, which may facilitate carcinogenesis by with an increased risk of the disease. All three prospective disrupting the estrogen-progestogen balance. studies that have examined hormone levels observed an increase in endometrial cancer risk with increasing circulating The Inflammation-Cancer Link levels of estrogen (14-16). Unopposed estrogen therapy (17-19) and tamoxifen (20, 21), both of which exert proliferative effects Epidemiologic studies have documented a relationship be- on the endometrium, have also been associated with an tween local tissue inflammation and cancer development at that elevated incidence of the disease. Conversely, increased parity site. Examples include hepatitis and liver cancer (28) and colitis (4, 11, 22, 23) and combination oral contraceptive use (4, 24-26), and colon cancer (29). The inverse association between long- both characterized by a relatively high degree of exposure to term use of nonsteroidal anti-inflammatory drugs (NSAID) and progestogens, are associated with reduced risk of endometrial reduced risk of several cancers (30-34) further supports an cancer. Exposure to endogenous or exogenous estrogens not inflammation-cancer link. Although the means by which local adequately opposed by progestogens leads to an increase in inflammation facilitates cancer development is unknown, the mitotic activity of endometrial epithelial cells (27). This inflammatory cells and, in particular, the production of proin- excessive activity results in increased DNA replication and flammatory cytokines, such as tumor necrosis factor-a (TNF-a), repair errors, which, in turn, can lead to somatic mutations that by both local tissue and infiltrating inflammatory cells, seem to may ultimately give rise to endometrial hyperplasia and play a key role (reviewed in refs. 35-40). These inflammatory subsequent malignancy. In this review, we propose that cells induce rapid cell division and produce increased concen- inflammation may work in conjunction with or in addition to trations of free radicals (41) that may subsequently damage estrogen exposure in the development of endometrial cancer DNA. Increased rates of cell turnover are associated with a (Fig. 1). Support for our hypothesis comes from several greater likelihood of replication errors and ineffective DNA observations, including the fact that the effect of the menstrual repair at key regulatory sites, such as within tumor suppressor genes, which may increase the probability of converting DNA lesions to mutations (42). Moreover, inflammatory cytokines Received 7/6/05; revised 9/19/05; accepted 9/27/05 induce a range of inflammatory enzymes, including cyclooxy- Grant support: National Cancer Institute grant K07-CA80668. genase-2 (COX-2). COX-2 cyclizes and oxygenates arachidonic The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. acid, eventually producing prostaglandin E2 (PGE2; ref. 43). Section 1734 solely to indicate this fact. PGE2 can facilitate tumorigenesis by increasing production of Requests for reprints: Francesmary Modugno, Department of Epidemiology, Graduate School cytokines and growth factors necessary for tumor growth, of Public Health, University of Pittsburgh, 516A Parran Hall, 130 DeSoto Street, Pittsburgh, PA 15261. Phone: 412-383-2601; Fax: 412-383-2653. E-mail: modugno+@pitt.edu invasion, and metastases, including interleukin (IL)-6, IL-8, Copyright D 2005 American Association for Cancer Research. vascular endothelial growth factor, and matrix metalloproteases doi:10.1158/1055-9965.EPI-05-0493 (44). PGE2 also increases production of inducible nitric oxide Cancer Epidemiol Biomarkers Prev 2005;14(12). December 2005 Downloaded from cebp.aacrjournals.org on September 27, 2021. © 2005 American Association for Cancer Research. Cancer Epidemiology, Biomarkers & Prevention 2841 Table 1. Risk factors for endometrial cancer in relation to the estrogen/progestogen imbalance hypothesis and the proposed inflammation hypothesis Risk/protective factor Proposed mechanism—estrogen/ Proposed mechanism—inflammation hypothesis progestogen imbalance hypothesis* Risk factors Unopposed estrogen therapy use Unopposed estrogen exposure Increased exposure to estrogens in the endometrium increases inflammatory response in the endometrium Obesity Increased systemic exposure Increased proinflammatory to unopposed systemic milieu estrogens via aromatization of androgens in adipose tissue and via decreased sex hormone–binding globulin production Decreased progesterone exposure leading to unopposed estrogen exposure due to anovulation Diabetes mellitus ? Increased proinflammatory systemic milieu Polycystic ovary syndrome Increased systemic exposure Increased proinflammatory to unopposed estrogens via systemic milieu aromatization of androgens Early menarche/late menopause Increased lifetime exposure Increased lifetime exposure to to estrogen in the endometrium inflammation via increased number of menstruations Anovulation Decreased progesterone production Decreased exposure to progesterone leading to unopposed estrogen increases inflammatory response exposure in the endometrium in endometrium Menorrhagia ? Increased exposure to inflammation via menstruation Protective factors Pregnancy Increased exposure to progesterone Decreases exposure to menstruation Increased exposure to anti-inflammatory effect of progesterone Decreased inflammatory milieu in the uterus Smoking Decreased exposure to estrogens Production of anti-inflammatory due to increased metabolic clearance estrogen metabolite and production of less estrogenic metabolites Oral contraceptive use Increased exposure to progestins Increased exposure to anti-inflammatory progestins Decreased exposure to menstruation *Adapted from ref. 145. synthetase, an enzyme involved in free radical generation (44). activation is a hallmark for inflammatory diseases (50). Further evidence for a role of COX-2 in cancer formation comes Liberated NF-nB protein may also activate malignancy- from the observation that carcinogenesis is inhibited in mice promoting signaling pathways in both cancer cells and treated with COX-2-selective inhibitors and in COX-2 knockout tumor-associated inflammatory cells (51), and aberrant NF- mice (45, 46). Hence, neoplastic transformation may be initiated nB activity has been reported for several cancers, including by DNA damage incurred by cells as a result of free radical estrogen-associated breast cancer (52, 53). Recently, animal generation. These initiated cells may be further promoted via models have further elucidated the role of NF-nB in tumori- COX-2-mediated up-regulation of PGE2, which causes the pro- genesis. In an inflammation-associated murine model of liver duction of factors supporting