Abstract
Simple SummaryOvarian cancer is a complex pathology for which we require effective screening and therapeutical strategies. Apart from the cancer cell portion, there exist plastic immune and non-immune cell populations, jointly constituting the context-adaptive tumor microenvironment, which is pivotal in tumorigenesis. Estrogens might be synthesized in the ovarian tumor tissue and actively contribute to the shaping of an immunosuppressive microenvironment. Current immune therapies have limited effectiveness as a multitude of factors influence the outcome. A thorough understanding of the ovarian cancer biology is crucial in the efforts to reestablish homeostasis.Ovarian cancer is a heterogeneous disease affecting the aging ovary, in concert with a complex network of cells and signals, together representing the ovarian tumor microenvironment. As in the “Schrödinger’s cat” thought experiment, the context-dependent constituents of the—by the time of diagnosis—well-established tumor microenvironment may display a tumor-protective and -destructive role. Systemic and locally synthesized estrogens contribute to the formation of a pro-tumoral microenvironment that enables the sustained tumor growth, invasion and metastasis. Here we focus on the estrogen biosynthetic and metabolic pathways in ovarian cancer and elaborate their actions on phenotypically plastic, estrogen-responsive, aging immune cells of the tumor microenvironment, altogether highlighting the multicomponent-connectedness and complexity of cancer, and contributing to a broader understanding of the ovarian cancer biology.
Highlights
Ovarian cancer (OC) is a group of diseases affecting the aging ovary
Epithelial ovarian tumor tissue and the ovarian vein draining from the tumorous ovary contain several folds greater estrogen levels than serum [14,59], and intriguingly, serum estradiol concentration seems to decrease after tumor surgery [60,61]
We explore the emergence of the ovarian tumor-permissive microenvironment, with a focus on its immune portion, and highlight the role of estrogens in the building of inhospitable conditions that exhaust the effector immune cells, granting the cancer cells an escape from immune recognition (Figure 3)
Summary
Ovarian cancer (OC) is a group of diseases affecting the aging ovary. The disease is usually detected at an already advanced stage due to its non-specific symptoms and deficiency of effective screening strategies. The pool of estrogens available to the ovarian tumor might be modulated by the changing microbiome [15,16]. Despite these indications of association between OC and estrogens, therapeutic approaches targeting estrogen receptors or inhibitors of the estrogen biosynthesis pathway are modestly beneficial for a certain group of OC patients [17]. The heterogeneity of the disease, as well as its diagnosis usually at an already advanced stage, when an immunosuppressive microenvironment has been well established beforehand, might be an explanation for the limited effectiveness of these therapeutic approaches, or other single-agent therapeutic approaches. Contrary to the cat, whose fate is decided by a single random subatomic event that may or may not occur, the fate of the microenvironment is influenced by a plethora of factors, and estrogens are one of them
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