Complement Pathway Is Frequently Altered in Endometriosis and Endometriosis-Associated Ovarian Cancer

Abstract

Purpose Mechanisms of immune dysregulation associated with advanced tumors are relatively well understood. Much less is known about the role of immune effectors against cancer precursor lesions. Endometrioid and clear cell ovarian tumors partly derive from endometriosis, a commonly diagnosed chronic inflammatory disease. We performed here a comprehensive immune gene expression analysis of pelvic inflammation in endometriosis and endometriosis-associated ovarian cancer (EAOC). Experimental design RNA was extracted from 120 paraffin tissue blocks comprising of normal endometrium (n=32), benign endometriosis (n=30), atypical endometriosis (n=15) and EAOC (n=43). Serous tumors (n=15) were included as non-endometriosis associated controls. The immune microenvironment was profiled using Nanostring and the nCounter® GX Human Immunology Kit, comprising probes for a total of 511 immune genes. Results One third of the endometriosis patients revealed a tumor-like inflammation profile, suggesting that cancer–like immune signatures may develop earlier, in patients classified as clinically benign. Gene expression analyses revealed the complement pathway as most prominently involved in both endometriosis and EAOC. Complement proteins are abundantly present in epithelial cells in both benign and malignant lesions. Mechanistic studies in ovarian surface epithelial (OSE) cells from mice with conditional (Cre-loxP) mutations show intrinsic production of complement in epithelia and demonstrate an early link between Kras- and Pten-driven pathways and complement upregulation. Downregulation of complement in these cells interferes with cell proliferation. Conclusions These findings reveal new characteristics of inflammation in precursor lesions and point to previously unknown roles of complement in endometriosis and EAOC.

Immune-inflammation gene signatures in endometriosis patients

“…In addition, expression of genes for cell adhesion molecules, such as ICAM-1, VCAM-1 , and SELL , were also increased, potentially aiding adhesion or invasion of ectopic tissues onto peritoneum or other surfaces. Interestingly, in concordance with the recent report by Suryawanshi et al, genes encoding for complementary proteins were significantly increased in the ectopic tissues compared with the control tissues (27). The contribution of complement proteins toward the pathogenesis of endometriosis is unknown; however, we can speculate, from its known functions, that they participate not only as a part of immune surveillance system in identifying diseased tissues, but also participate in the processes of angiogenesis, hematopoietic stem cell mobilization, and regeneration of damaged tissues (28).…”

Complement component 7 (C7), a potential tumor suppressor, is correlated with tumor progression and prognosis

“…On the contrary, Suryawanshi et al observed that the C7 in tumor-related endometriosis had higher expression levels than in normal endometrium [19]. The further reasons underlying the difference need to be explored.…”

Innate immune mediators in cancer: between defense and resistance

“…Abnormalities in the activation of the classical pathway have been described in patients with chronic lymphatic leukemia . Finally, complement components, compatible with classical pathway activation, were abundantly present in endometriosis and ovarian cancer, whereas normal endometrium showed little to no expression of these factors . Activation of other complement pathways has also been reported in certain tumor types.…”