Abstract
Cancer and stromal cells, which include (cancer‐associated) fibroblasts, adipocytes, and immune cells, constitute a mixed cellular ecosystem that dynamically influences the behavior of each component, creating conditions that ultimately favor the emergence of malignant clones. Ovarian cancer cells release cytokines that recruit and activate stromal fibroblasts and immune cells, so perpetuating a state of inflammation in the stroma that hampers the immune response and facilitates cancer survival and propagation. Further, the stroma vasculature impacts the metabolism of the cells by providing or limiting the availability of oxygen and nutrients. Autophagy, a lysosomal catabolic process with homeostatic and prosurvival functions, influences the behavior of cancer cells, affecting a variety of processes such as the survival in metabolic harsh conditions, the invasive growth, the development of immune and chemo resistance, the maintenance of stem‐like properties, and dormancy. Further, autophagy is involved in the secretion and the signaling of promigratory cytokines. Cancer‐associated fibroblasts can influence the actual level of autophagy in ovarian cancer cells through the secretion of pro‐inflammatory cytokines and the release of autophagy‐derived metabolites and substrates. Interrupting the metabolic cross‐talk between cancer cells and cancer‐associated fibroblasts could be an effective therapeutic strategy to arrest the progression and prevent the relapse of ovarian cancer.
Highlights
Ovarian cancer is the seventh most common cancer in women, with the incidence of around 9.4 and 5.0 agestandardized rate per 100,000 in developed and developing countries, respectively.[1,2] Despite the progress in drug discovery and improvement in the management, ovarian cancer remains the leading cause of death from gynecological cancer.[2,3] Worldwide, as many as 240,000 women are diagnosed with ovarian cancer, and approximately half of them die each year.[2]
Understanding how cancer-associated fibroblast (CAF) and ovarian cancer cells reprogram each other's metabolism and, in particular, how autophagy is modulated in both these cells might shed lights on novel signaling pathways that could be targeted for the treatment of ovarian cancer
The conversion of adipose-derived and bone marrow derived mesenchymal stem cell (MSC) and of peritoneal fibroblasts into CAFs was observed in a xenograft transplant of human ovarian cancer SKOV3 cells transgenically expressing the homeobox gene HOXA9.67 This effect was mediated by the release into the peritoneum of TGF-β2 driven by HOXA9 from the ovarian cancer cells.[67]
Summary
Ovarian cancer is the seventh most common cancer in women, with the incidence of around 9.4 and 5.0 agestandardized rate per 100,000 in developed and developing countries, respectively.[1,2] Despite the progress in drug discovery and improvement in the management, ovarian cancer remains the leading cause of death from gynecological cancer.[2,3] Worldwide, as many as 240,000 women are diagnosed with ovarian cancer, and approximately half of them die each year.[2]. Recent studies support the view that a “metabolic symbiosis” exists between CAFs and cancer cells In this model, cancer cells induce a rise of autophagy in CAFs, which in turn provide the cancer cells with energetic metabolic substrates and so reducing their autophagy needs.[24,25] the metabolic crosstalk between stromal and cancer cells reciprocally affects autophagy regulation,[26] which might reflect in behavioral changes driving cancer relapse and metastasis as we will see later. Understanding how CAFs and ovarian cancer cells reprogram each other's metabolism and, in particular, how autophagy is modulated in both these cells might shed lights on novel signaling pathways that could be targeted for the treatment of ovarian cancer
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