Prostaglandin E2/EP Signaling in the Tumor Microenvironment of Colorectal Cancer

Mizuno, Rei; Kawada, Kenji; Sakai, Yoshiharu

doi:10.3390/ijms20246254

Cited by 131 publications

(106 citation statements)

References 105 publications

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“…In support of future combination clinical trials, Albu et al showed that EP4 antagonism combined with either Treg depletion or with an antibody to CTLA-4 provided superior tumor control to either monotherapy (Albu et al, 2017). Cancer clinical trials to evaluate EP4 inhibitors are recruiting in trials of Grapiprant (ARY-007) in combination with pembrolizumab in subjects with either advanced MSS colorectal cancers (NCT03658772) or, in a separate trial in advanced NSCLC (NCT03696212) (Mizuno et al, 2019;Take et al, 2020). E7046 is being examined in a rectal cancer trial (NCT03152370) and BMS 986310 plus nivolumab is being investigated in a phase 1 trial in advanced solid tumors (NCT03661632).…”

Section: Future Directionsmentioning

confidence: 99%

Eicosanoids in Cancer: Prostaglandin E2 Receptor 4 in Cancer Therapeutics and Immunotherapy

2020

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The cyclooxygenase-2 (COX-2) enzyme is frequently overexpressed in epithelial malignancies including those of the breast, prostate, lung, kidney, ovary, and liver and elevated expression is associated with worse outcomes. COX-2 catalyzes the metabolism of arachidonic acid to prostaglandins. The COX-2 product prostaglandin E 2 (PGE 2) binds to four G-protein-coupled EP receptors designated EP1-EP4. EP4 is commonly upregulated in cancer and supports cell proliferation, migration, invasion, and metastasis through activation of multiple signaling pathways including ERK, cAMP/PKA, PI3K/AKT, and NF-kB. EP4 antagonists inhibit metastasis in preclinical models. Cancer stem cells, that underlie therapy resistance and disease relapse, are driven by the expression of EP4. Resistance to several chemotherapies is reversed in the presence of EP4 antagonists. In addition to tumor cell-autonomous roles of EP4, many EP4-positive host cells play a role in tumor behavior. Endothelial cell-EP4 supports tumor angiogenesis and lymphangiogenesis. Natural Killer (NK) cells are critical to the mechanism by which systemically administered EP4 antagonists inhibit metastasis. PGE 2 acts on EP4 expressed on the NK cell to inhibit tumor target cell killing, cytokine production, and chemotactic activity. Myeloid-derived suppressor cells (MDSCs), that inhibit the development of cytotoxic T cells, are induced by PGE 2 acting on myeloid-expressed EP2 and EP4 receptors. Inhibition of MDSC-EP4 leads to maturation of effector T cells and suppresses the induction of T regulatory cells. A number of EP4 antagonists have proven useful in dissecting these mechanisms. There is growing evidence that EP4 antagonism, particularly in combination with either chemotherapy, endocrine therapy, or immunebased therapies, should be investigated further as a promising novel approach to cancer therapy. Several EP4 antagonists have now progressed to early phase clinical trials and we eagerly await the results of those studies.

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Section: Future Directionsmentioning

confidence: 99%

Eicosanoids in Cancer: Prostaglandin E2 Receptor 4 in Cancer Therapeutics and Immunotherapy

2020

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“…However, phospholipases A 2 (PLA 2 ) are the main cellular regulators of PUFA release, maintaining the homeostatic levels of several free PUFAs, and in particular of those that are precursors of mediators with pro-inflammatory properties, such as arachidonic acid (AA, 20:4 n-6). In the inflammation process, AA is released by PLA 2 activity, and prostaglandin E 2 (PGE 2 ) is subsequently generated from arachidonic acid by the enzyme cyclooxygenase-2 (COX-2) [ 34 , 35 ]. One of the mechanisms that Tregs uses to suppress T cell activity is PGE 2 production, which can be reversed by COX-2 inhibitors [ 36 ].…”

Section: Lipid Metabolism Impacts Immune Activation Against Tumor mentioning

confidence: 99%

Lipidomic-Based Advances in Diagnosis and Modulation of Immune Response to Cancer

Balgoma

Montero

2020

Metabolites

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While immunotherapies for diverse types of cancer are effective in many cases, relapse is still a lingering problem. Like tumor cells, activated immune cells have an anabolic metabolic profile, relying on glycolysis and the increased uptake and synthesis of fatty acids. In contrast, immature antigen-presenting cells, as well as anergic and exhausted T-cells have a catabolic metabolic profile that uses oxidative phosphorylation to provide energy for cellular processes. One goal for enhancing current immunotherapies is to identify metabolic pathways supporting the immune response to tumor antigens. A robust cell expansion and an active modulation via immune checkpoints and cytokine release are required for effective immunity. Lipids, as one of the main components of the cell membrane, are the key regulators of cell signaling and proliferation. Therefore, lipid metabolism reprogramming may impact proliferation and generate dysfunctional immune cells promoting tumor growth. Based on lipid-driven signatures, the discrimination between responsiveness and tolerance to tumor cells will support the development of accurate biomarkers and the identification of potential therapeutic targets. These findings may improve existing immunotherapies and ultimately prevent immune escape in patients for whom existing treatments have failed.

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“…These M2 macrophages secrete anti-inflammatory IL-10, and PGE2 supporting the migration of endothelial cells and angiogenesis [218]. In addition to promoting angiogenesis, PGE2 released from dying cells also provokes the recruitment of macrophages, CAFs, and neutrophils into TME and suppresses the antitumor functions of T cells and natural killer cells [219].…”

Section: Communication Between Cancer Cells and Surrounding Stromal Cmentioning

confidence: 99%

New Insights into Therapy-Induced Progression of Cancer

Shnaider

Ivanova

Malyants

et al. 2020

IJMS

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The malignant tumor is a complex heterogeneous set of cells functioning in a no less heterogeneous microenvironment. Like any dynamic system, cancerous tumors evolve and undergo changes in response to external influences, including therapy. Initially, most tumors are susceptible to treatment. However, remaining cancer cells may rapidly reestablish the tumor after a temporary remission. These new populations of malignant cells usually have increased resistance not only to the first-line agent, but also to the second- and third-line drugs, leading to a significant decrease in patient survival. Multiple studies describe the mechanism of acquired therapy resistance. In past decades, it became clear that, in addition to the simple selection of pre-existing resistant clones, therapy induces a highly complicated and tightly regulated molecular response that allows tumors to adapt to current and even subsequent therapeutic interventions. This review summarizes mechanisms of acquired resistance, such as secondary genetic alterations, impaired function of drug transporters, and autophagy. Moreover, we describe less obvious molecular aspects of therapy resistance in cancers, including epithelial-to-mesenchymal transition, cell cycle alterations, and the role of intercellular communication. Understanding these molecular mechanisms will be beneficial in finding novel therapeutic approaches for cancer therapy.

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Prostaglandin E2/EP Signaling in the Tumor Microenvironment of Colorectal Cancer

Cited by 131 publications

References 105 publications

Eicosanoids in Cancer: Prostaglandin E2 Receptor 4 in Cancer Therapeutics and Immunotherapy

Eicosanoids in Cancer: Prostaglandin E2 Receptor 4 in Cancer Therapeutics and Immunotherapy

Lipidomic-Based Advances in Diagnosis and Modulation of Immune Response to Cancer

New Insights into Therapy-Induced Progression of Cancer

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