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Review

Prostaglandin E2 Receptor 4 (EP4) as a Therapeutic Target to Impede Breast Cancer-Associated Angiogenesis and Lymphangiogenesis

1
Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON N6A5C1, Canada
2
Department of Biology, Brandon University, Brandon, MB R7A6A9, Canada
*
Author to whom correspondence should be addressed.
Authors contributed equally.
Academic Editors: Kairbaan Hodivala-Dilke and Jose M. Munoz-Felix
Cancers 2021, 13(5), 942; https://doi.org/10.3390/cancers13050942
Received: 15 January 2021 / Revised: 18 February 2021 / Accepted: 19 February 2021 / Published: 24 February 2021
(This article belongs to the Special Issue Targeting Blood Vessel Components to Treat Cancer)
The formation of new blood (angiogenesis) and lymphatic (lymphangiogenesis) vessels are major events associated with most epithelial malignancies, including breast cancer. Inflammation is a key mediator of both processes, hijacked by many cancers by the aberrant expression of the inflammation-associated enzyme cyclo-oxygenase (COX)-2. In this review, we focus on breast cancer and show that COX-2 is a major promoter of both events, primarily resulting from the activation of prostaglandin (PG) E receptor EP4 on tumor cells, tumor-infiltrating immune cells, and endothelial cells; and induction of oncogenic microRNAs. The COX-2/EP4 pathway also promotes additional events in breast cancer progression, such as cancer cell migration, invasion, and the stimulation of stem-like cells. Based on a combination of studies using multiple breast cancer models, we show that EP4 antagonists hold a major promise in breast cancer therapy in combination with other modalities including immune check-point inhibitors.
The formation of new blood (angiogenesis) and lymphatic (lymphangiogenesis) vessels are major events associated with most epithelial malignancies, including breast cancer. Angiogenesis is essential for cancer cell survival. Lymphangiogenesis is critical in maintaining tumoral interstitial fluid balance and importing tumor-facilitatory immune cells. Both vascular routes also serve as conduits for cancer metastasis. Intratumoral hypoxia promotes both events by stimulating multiple angiogenic/lymphangiogenic growth factors. Studies on tumor-associated lymphangiogenesis and its exploitation for therapy have received less attention from the research community than those on angiogenesis. Inflammation is a key mediator of both processes, hijacked by many cancers by the aberrant expression of the inflammation-associated enzyme cyclo-oxygenase (COX)-2. In this review, we focus on breast cancer and showed that COX-2 is a major promoter of both events, primarily resulting from the activation of prostaglandin (PG) E receptor EP4 on tumor cells, tumor-infiltrating immune cells, and endothelial cells; and the induction of oncogenic microRNAs. The COX-2/EP4 pathway also promotes additional events in breast cancer progression, such as cancer cell migration, invasion, and the stimulation of stem-like cells. Based on a combination of studies using multiple breast cancer models, we show that EP4 antagonists hold a major promise in breast cancer therapy in combination with other modalities including immune check-point inhibitors. View Full-Text
Keywords: breast cancer; triple-negative breast cancer; metastasis; angiogenesis; lymphangiogenesis; COX-2; PGE2; EP receptors; EP4; chemokines; cancer stem cells; EMT; microRNAs; patient-derived xenograft (PDX); inflammation; immune checkpoint inhibitors (ICI)s; combination therapy breast cancer; triple-negative breast cancer; metastasis; angiogenesis; lymphangiogenesis; COX-2; PGE2; EP receptors; EP4; chemokines; cancer stem cells; EMT; microRNAs; patient-derived xenograft (PDX); inflammation; immune checkpoint inhibitors (ICI)s; combination therapy
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MDPI and ACS Style

De Paz Linares, G.A.; Opperman, R.M.; Majumder, M.; Lala, P.K. Prostaglandin E2 Receptor 4 (EP4) as a Therapeutic Target to Impede Breast Cancer-Associated Angiogenesis and Lymphangiogenesis. Cancers 2021, 13, 942. https://doi.org/10.3390/cancers13050942

AMA Style

De Paz Linares GA, Opperman RM, Majumder M, Lala PK. Prostaglandin E2 Receptor 4 (EP4) as a Therapeutic Target to Impede Breast Cancer-Associated Angiogenesis and Lymphangiogenesis. Cancers. 2021; 13(5):942. https://doi.org/10.3390/cancers13050942

Chicago/Turabian Style

De Paz Linares, Guillermo Antonio, Reid Morgan Opperman, Mousumi Majumder, and Peeyush K. Lala. 2021. "Prostaglandin E2 Receptor 4 (EP4) as a Therapeutic Target to Impede Breast Cancer-Associated Angiogenesis and Lymphangiogenesis" Cancers 13, no. 5: 942. https://doi.org/10.3390/cancers13050942

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