How Autophagy Shapes the Tumor Microenvironment in Ovarian Cancer

Abstract

Ovarian cancer (OC) is characterized by a high mortality rate due to the late diagnosis and the elevated metastatic potential. Autophagy, a lysosomal-driven catabolic process, contributes to the macromolecular turnover, cell homeostasis, and survival, and as such, it represents a pathway targetable for anti-cancer therapies. It is now recognized that the vascularization and the cellular composition of the tumor microenvironment influence the development and progression of OC by controlling the availability of nutrients, oxygen, growth factors, and inflammatory and immune-regulatory soluble factors that ultimately impinge on autophagy regulation in cancer cells. An increasing body of evidence indicates that OC carcinogenesis is associated, at least in the early stages, to insufficient autophagy. On the other hand, when the tumor is already established, autophagy activation provides a survival advantage to the cancer cells that face metabolic stress and protects from the macromolecules and organelles damages induced by chemo- and radiotherapy. Additionally, upregulation of autophagy may lead cancer cells to a non-proliferative dormant state that protects the cells from toxic injuries while preserving their stem-like properties. Further to complicate the picture, autophagy is deregulated also in stromal cells. Thus, changes in the tumor microenvironment reflect on the metabolic crosstalk between cancer and stromal cells impacting on their autophagy levels and, consequently, on cancer progression. Here, we present a brief overview of the role of autophagy in OC hallmarks, including tumor dormancy, chemoresistance, metastasis, and cell metabolism, with an emphasis on the bidirectional metabolic crosstalk between cancer cells and stromal cells in shaping the OC microenvironment.

Expression and molecular profiles of the AlkB family in ovarian serous carcinoma

“…Cumulative evidence has reported that ovarian serous carcinoma (OV) has the highest mortality among all histological subtypes of ovarian cancer. As shown in a recent study, we found that the survival data have not changed since 1980 in many areas [ 6 – 8 ]. Consequently, molecular markers will play an essential role in diagnosing OV at an early stage and assist in the treatment of patients.…”

Cancer-Associated Fibroblast-Derived IL-6 Determines Unfavorable Prognosis in Cholangiocarcinoma by Affecting Autophagy-Associated Chemoresponse

“…It is now accepted that the actual level and functional outcome of autophagy in cancer cells depend on several factors [ 50 ], precisely: (1) the genetic background (i.e., the mutation in relevant oncogenes and tumor suppressor genes as well as in genes controlling the regulatory pathways) of the cancer cell; (2) the presence of growth factors, and the level of inflammation and of secreted inflammatory factors in the TME; (3) the structural and metabolic status of the TME (vascularization, availability of nutrients and of oxygen); and (4) the presence of epigenetic modifiers in the TME. Further, autophagy is a dynamic process that adjusts its regulation in the cells depending on the microenvironment.…”

Interleukin‑8 released by cancer‑associated fibroblasts attenuates the autophagy and promotes the migration of ovarian cancer cells

“…Autophagy, a lysosomal catabolic process with homeostatic and pro-survival functions, influences the behavior of ovarian cancer cells, affecting a variety of processes, such as survival in metabolic harsh conditions, invasive growth, the development of immune- and chemo-resistance, the maintenance of stem-like properties and dormancy ( 3 , 11 ). Autophagy is dysregulated in ovarian cancer ( 12 , 13 ), and the autophagy-related proteins BECLIN-1 and LC3 are in fact prognostic factors for ovarian cancer ( 14 - 17 ).…”