Endometriosis-Associated Ovarian Carcinomas: How PI3K/AKT/mTOR Pathway Affects Their Pathogenesis

Abstract

Ovarian clear cell (OCCC) and endometrioid (EnOC) carcinomas are often subsumed under the umbrella term “endometriosis-associated ovarian cancer” (EAOC), since they frequently arise from ectopic endometrium settled in the ovaries. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is known to be aberrantly activated both in endometriosis and EAOC; however, its role in the progression of endometriosis to ovarian cancer remains unclear. In fact, cancer-associated alterations in the mTOR pathway may be found in normal uterine epithelium, likely acting as a first step towards ovarian cancer, through the intermediary stage of endometriosis. This review aims to summarize the current knowledge regarding mTOR signaling dysregulation in the uterine endometrium, endometriosis, and EAOC while focusing on the interconnections between the PI3K/AKT/mTOR pathway and other signaling molecules that give rise to synergistic molecular mechanisms triggering ovarian cancer development in the presence of endometriosis.

Refractory ovarian squamous cell carcinoma arising from a seromucinous borderline tumor with squamous overgrowth: A case report

“…In addition, we also identified ARID1A and PIK3R1 pathogenic mutations (Q439* and S460_R461 > G) that have not been previously reported in SCC derived from ovarian teratomas ( Tamura et al, 2020 ). These mutations are common in endometrial and endometriosis-associated ovarian cancers ( Cancer Genome Atlas Research Network et al, 2013, Driva et al, 2023 ). In addition, an ARID1A mutation may be linked to the molecular biology of SMBTs ( Wu et al, 2012 ).…”

Endometriosis-Associated Ovarian Cancer: From Molecular Pathologies to Clinical Relevance

“…Altogether, the PI3K/AKT/mTOR pathway is a major regulator of the cell cycle; thus, alterations in gene regulation due to mutations contribute to the development and progression of ovarian cancer (reviewed by Aziz et al [62]) as well as in the transformation process from a healthy endometrium to endometriosis and EAOC (reviewed by Driva et al [63]). In contrast, the activity of the phosphatase and tensin homolog (PTEN), the counterpart of the PI3K/AKT pathway, was reduced due to PTEN silencing in EAOC, thus alleviating the negative control of PTEN on cell growth and division [64][65][66].…”

The mysterious association between adiponectin and endometriosis

“…Another important factor downstream of the PI3K/Akt pathway is mTOR, an evolutionarily conserved serine/threonine protein kinase ( Driva et al, 2023 ). Researchers have reported an upregulation in mTOR signaling in endometriotic foci ( Choi et al, 2014 ), and the protein is involved in the modulation of key pathophysiological processes such as proliferation, differentiation, apoptosis, autophagy, and decidualization of endometrial cells ( Guo and Yu, 2019 ; Driva et al, 2022 ).…”