The role of caspase-8 in the tumor microenvironment of ovarian cancer
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CLINICAL
The role of caspase-8 in the tumor microenvironment of ovarian cancer Izabela Kostova 1 & Ranadip Mandal 1 & Sven Becker 1 & Klaus Strebhardt 1,2,3 Received: 7 May 2020 / Accepted: 23 September 2020 # The Author(s) 2020
Abstract Caspase-8 is an aspartate-specific cysteine protease, which is best known for its apoptotic functions. Caspase-8 is placed at central nodes of multiple signal pathways, regulating not only the cell cycle but also the invasive and metastatic cell behavior, the immune cell homeostasis and cytokine production, which are the two major components of the tumor microenvironment (TME). Ovarian cancer often has dysregulated caspase-8 expression, leading to imbalance between its apoptotic and non-apoptotic functions within the tumor and the surrounding milieu. The downregulation of caspase-8 in ovarian cancer seems to be linked to high aggressiveness with chronic inflammation, immunoediting, and immune resistance. Caspase-8 plays therefore an essential role not only in the primary tumor cells but also in the TME by regulating the immune response, B and T lymphocyte activation, and macrophage differentiation and polarization. The switch between M1 and M2 macrophages is possibly associated with changes in the caspase-8 expression. In this review, we are discussing the non-apoptotic functions of caspase-8, highlighting this protein as a modulator of the immune response and the cytokine composition in the TME. Considering the low survival rate among ovarian cancer patients, it is urgently necessary to develop new therapeutic strategies to optimize the response to the standard treatment. The TME is highly heterogenous and provides a variety of opportunities for new drug targets. Given the variety of roles of caspase-8 in the TME, we should focus on this protein in the development of new therapeutic strategies against the TME of ovarian cancer. Keywords Tumor microenvironment . Caspase-8 . Non-apoptotic functions . Macrophages . TAMs . Ovarian cancer treatment
1 Ovarian cancer Ovarian cancer is the fifth most common cause of death among female cancer patients and the most lethal malignancy of the female reproductive tract [1]. The poor disease outcome is primarily due to the lack of appropriate methods for early detection, increasing chemoresistance and limited surgical debulking [2]. More than 75% of the patients are already at an advanced stage of the disease at the time of diagnosis. Despite the surgical removal of the tumor and aggressive * Klaus Strebhardt [email protected] 1
Department of Gynecology, University Hospital, Goethe-University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
2
German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
3
German Cancer Consortium (DKTK) partner site, Frankfurt, Germany
chemotherapy, most patients experience recurrence within the next 16 to 22 months. As a result, ovarian cancer has a 5-year survival rate of only 46% [3]. Histologically, ovarian cancer is divided into four subgroups: serous,
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