Inflammation and Endometrial Cancer: A Hypothesis

Abstract

Endometrial cancer is the most common gynecologic malignancy in the United States. Substantial epidemiologic data implicate an imbalance of estrogens and progestogens in the etiology of this disease. We propose that inflammation also plays a role in endometrial cancer development. Emerging laboratory data suggest that elevated levels of prostaglandin E 2 may underlie the transformation of normal endometrium to neoplastic tissue and that in vitro nonsteroidal anti-inflammatory drugs may inhibit endometrial cancer cell growth. In this review, we suggest that the risk factors for endometrial cancer-unopposed estrogens, anovulation, polycystic ovary syndrome, excessive menstruation, early menarche, and late menopause-may be viewed as factors increasing the exposure of the endometrium to inflammation, whereas pregnancy and smoking, two likely protective factors, have the opposite effect. Chronic inflammation can induce rapid cell division, increasing the possibility for replication error, ineffective DNA repair, and subsequent mutations. A proinflammatory milieu can also directly increase estrogen production. Hence, inflammation may work in conjunction with or in addition to estrogen exposure in the development of endometrial cancer. (Cancer Epidemiol Biomarkers Prev 2005;14 (12):2840 -7)

Inflammatory events in endometrial adenocarcinoma

“…Production of this cytokine, in both the KLE and RL95 endometrial adenocarcinoma cell lines after oestrogen stimulation, has also been demonstrated (He et al 2009). Other inflammatory mediators upregulated by oestrogen include IL1, TNF-a, and matrix metalloproteinases (MMPs) (Modugno et al 2005, He et al 2009, and IL1B can enhance the actions of oestrogen (King et al 2009). Oestrogen can also activate nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB) signalling in endometrial cancer, a key transcription factor regulating the expression of many inflammatory mediators (Seo et al 2004).…”

“…Progesterone also stimulates the production of prostaglandin dehydrogenase and inhibits cytokine-induced transcription of cyclooxygenase2 (COX2), thereby reducing prostaglandin production and consequent inflammation (Ishihara et al 1995, van der Burg & van der Saag 1996 Therefore, as endometrial adenocarcinoma is characterised by increased oestrogen to progesterone signalling, an increase in inflammatory mediators may occur, thus promoting tumour growth. The pro-inflammatory milieu in endometrial cancer can also directly increase oestrogen production (Modugno et al 2005). IL6 can stimulate oestrogen synthesis and can act synergistically with TNF-a to increase aromatase, 17b-hydroxysteroid dehydrogenase and oestrone sulfatase activity, thus increasing local oestrogen biosynthesis (Modugno et al 2005, Salama et al 2009).…”

“…The pro-inflammatory milieu in endometrial cancer can also directly increase oestrogen production (Modugno et al 2005). IL6 can stimulate oestrogen synthesis and can act synergistically with TNF-a to increase aromatase, 17b-hydroxysteroid dehydrogenase and oestrone sulfatase activity, thus increasing local oestrogen biosynthesis (Modugno et al 2005, Salama et al 2009). TNF-a increases local oestrogen biosynthesis in human endometrial glandular epithelial cells and directs oestrogen metabolism to produce more hormonally active and carcinogenic metabolites.…”

Molecular biology of oncogenic inflammatory processes. I. Non-oncogenic and oncogenic pathogens, intrinsic inflammatory reactions without pathogens, and microRNA/DNA interactions (Review)

“…The transforming tissues exude prostaglandins and cyclooxygenases. Irreversible malignant proliferation of the endometrium takes place (413,414).…”

Prenatal TCDD Exposure Delays Differentiation and Alters Cell Proliferation and Apoptosis in the Uterus of the Sprague-Dawley Rat

“…These white blood cells are often associated with the combating of infection and are also associated with inflammation. Inflammation may be associated with endometrial cancer and cell transformation [30]. An infiltration of eosinophil leukocytes has been reported in the uterus of rats after exposure to M. spicata, which causes lipid peroxidation and uterine damage [31].…”