Endometriosis and ovarian cancer: a review of clinical, pathologic, and molecular aspects

Endometriosis-associated ovarian cancer has been and will continue to be a major focus of research efforts into the causes of ovarian cancer. Several recent review articles have discussed endometriosis and ovarian cancer ( 1 , 21 , 22 , 115 – 118 ). This review discussed the stepwise tumor progression of endometriotic-associated carcinoma and focused on studies in the roles of sex steroid hormones, inflammatory processes, and genetic alterations in the progression from endometriosis, atypical endometriosis, ovarian borderline tumor, and endometriotic-associated carcinoma. The World Endometriosis Society and the World Endometriosis Research Foundation recently endorsed a workshop to develop a global consensus statement of research directions and priorities in endometriosis (the 10th World Congress on Endometriosis held in Melbourne, Australia, March 2008). One of the major recommendations from the workshop with regard to basic research is to identify the mechanisms and risk factors underlying the transformation of ovarian endometriosis to ovarian cancer. This task first requires a better understanding of the pathophysiological processes of endometriosis, including histology, immunohistochemistry, and molecular and proteomics approaches. Development of new biomarkers based on genetic alterations identified in endometriotic-associated carcinoma will eventually benefit the clinical evaluation, diagnosis, and management of patients at various stages along the continuum of the endometriosis-associated ovarian carcinoma.

Estrogen seems to be a mitogen both for endometriosis and ovarian cancer. Direct and indirect epidemiologic evidence suggest that estrogen may be carcinogenic to the ovary ( 103 ). However, laboratory evidence does not support this concept, and a plausible mechanism that links estrogen to ovarian carcinogenesis has not yet been developed. There is evidence supporting a role of estrogen in the etiology of endometriosis and enhancement of inflammation. Estrogen production plays a key role in the pathology of endometriosis because its inhibition by GnRH analogs, oral contraceptives, progestins, or aromatase inhibitors significantly reduces pelvic disease and pain ( 104 ). Steroidogenic acute regulatory protein (STAR) facilitates the initial step of estrogen formation ( 105 ). The key step, the conversion of C19 steroids to estrogens, is catalyzed by CYP19A1 (aromatase), inhibition of which effectively eliminates all estrogen production. Three major body sites produce estrogen in women with endometriosis. First, estradiol is secreted by the ovary. Second, aromatase enzyme in peripheral adipose and skin tissue catalyzes the conversion of circulating androstenedione to estrone. Finally, cholesterol is converted to estradiol locally in endometriosis. Peripheral and/or local aromatase activity in endometriosis may be particularly important because a combination of a GnRH agonist and an aromatase inhibitor is significantly superior to only GnRH agonist for providing long-lasting pain relief in patients with severe endometriosis ( 106 ). Two basic pathologic processes, namely cell survival and inflammation, are responsible for the primary symptoms of endometriosis. Estrogen enhances the survival or persistence of endometriotic tissue, whereas prostaglandins and cytokines mediate pain, inflammation, and infertility ( 107 , 108 ). A link between inflammation and estrogen production in endometriosis was recently uncovered and describes a positive feedback cycle that favors overexpression of key steroidogenic genes, most notably aromatase, overexpression of COX2, and continuous local production of estradiol and PGE2 in endometriotic tissue ( 109 – 112 ). PGE2 coordinately stimulates the expression of all necessary steroidogenic genes, thus enabling the endometrial stromal cell to synthesize estradiol from cholesterol ( 105 ). Among the 6 steroidogenic genes, the regulation of STAR and aromatase has been characterized extensively. Both endometriotic and endometrial stromal cells express similar levels of the PGE2 receptor subtypes ( 113 ). PGE2 or a cAMP analog stimulates STAR and aromatase levels and activity in endometriotic cells, but not in endometrial stromal cells ( 105 , 109 , 111 ). Thus, PGE2-cAMP-dependent steroidogenesis in endometriotic stromal cells requires downstream effectors and its absence in endometrial stromal cells is mediated by inhibitory mechanisms or a lack of stimulatory effectors downstream of cAMP. The nuclear receptor NR5A1, which is present in endometriosis and absent in endometrium, serves as the key transcription factor responsible for mediating the PGE2-cAMP-dependent induction of STAR, aromatase, and possibly other steroidogenic genes in endometriotic stromal cells. The absence of NR5A1 in endometrial cells plays a major role in the lack of responsiveness of steroidogenic genes to PGE2 or cAMP analogs. In addition, the redundant presence of a number of transcriptional inhibitors of STAR and aromatase promoters in endometrial cells provides a fail-safe system for silencing these steroidogenic genes. In the absence of NR5A1, a transcriptional complex that consists of these repressors occupies the steroidogenic promoters and suppresses them in endometrial cells ( 105 ). In summary, on PGE2 induction, coordinated recruitment of NR5A1 to the promoters of the essential steroidogenic genes is the key event for estradiol synthesis in endometriotic stromal cells. A suitable therapeutic target among the steroidogenic enzymes is aromatase, which is encoded by a single gene, because its inhibition blocks all estradiol biosynthesis. Aromatase inhibitors diminish or eradicate endometriotic implants and associated pain that is refractory to currently available treatments ( 114 ).