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.
Highlights
Caspase-8 is an aspartate-specific cysteine protease, which is best known for its apoptotic functions
G-CSF and granulocyte macrophage colony stimulating factor (GM-CSF) do not induce caspase-8 activation. These results suggest that caspase8 activation is required for the differentiation of macrophages and prevention of the sustained activation of NFκB during the process
Based on our knowledge about the regulating functions of caspase-8 in the cytokine secretion by cancer and non-cancer cells, immune response, and homeostasis of immune cells, we propose, that Caspase-8 is a possible new link in the interactions between the tumor and their surrounding environment
Summary
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 C3 subtype is characterized by low malignant potential (LMP) These tumors show enhanced expressions and mutations of the mitogenactivated protein kinase pathway genes KRAS and BRAF. The immunological C2 and differentiated C4 subtypes, characterized by their high infiltration of immune cells and better prognosis, have the highest expression of cytoplasmic caspase-8 and NF-κB [7]. The current therapies are not sufficient to overcome advanced ovarian cancer and most of the patients experience disease recurrence (25% of early-stage and 80% of advancedstage patients), chemoresistance (90% of the patients in advanced stage), or high toxicity. The microenvironment in ovarian cancer has been shown to alter the protein expression and cell signaling in the tumor cells, supporting their invasiveness and suppressing apoptosis and immune response [9]. Caspase-8 may be the link in the crosstalk between the tumor and the TME
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