Abstract
Simple SummaryThe 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.
Highlights
Physiological Roles of Angiogenesis and LymphangiogenesisAngiogenesis and lymphangiogenesis are normal physiological processes, important in fetal and post-natal development, tissue homeostasis, and wound repair
As reviewed by Nyberg et al, there exist a large number of endogenous inhibitors of angiogenesis [4]. They include matrix-derived molecules such as Arrestin and Canstatin, Endorepellin, Endostatin and Anastellin, Fibulin, Thrombospondin (TSP-1 and TSP-2) and Tumstatin; certain growth factors and cytokines such as IFNα, IFNβ, IL-1β, IL-4, IL-12, IL-18, Pigment Epithelium-Derived Factor (PEDF) and Platelet factor (PF)4; and other molecules such as Angiostatin, Vasostatin, Cleaved antithrombin III, Chondromodulin-1, 2-Methoxyestradiol, Plasminogen Kringle 5, Prothrombin Kringle 2, Prolactin (PRL) fragments, Tissue Inhibitors of Metalloproteases (TIMPs), Troponin-1 and s-Flt-1
The following reasons suggest that EP4 is a suitable target: (i) as listed above, EP4 expressed by cancer cells and multiple host cells plays a key role in COX-2-mediated breast cancer progression; (ii) many physiological functions of EP4 shared by EP2 via protein kinase A (PKA) stimulation [91,122] suggest the relative redundancy of EP4; (iii) non-conical signaling by EP4, not shared by EP2, involves PI3k/Akt pathway promoting cancer cell survival including the survival of stem-like cells, induced by EP4 activity (Figure 5d); (iv) targeting EP4 spares EP3-mediated vasoprotection by prostaglandin E2 (PGE2) and PGI2 receptor (IP)-mediated vasoprotection by PGI2, as suggested by findings in a variety of animal models of cardiac ischemia
Summary
Angiogenesis and lymphangiogenesis are normal physiological processes, important in fetal and post-natal development, tissue homeostasis, and wound repair. Lymphatic capillaries are nearly three times larger than blood capillaries (10–60 μm in diameter), lined with a single layer of LECs. Unlike blood capillaries, the basal lamina of lymphatic vessels is incomplete, discontinuous, or even absent and lack surrounding pericytes and smooth muscle cells (Figure 1). The majority of inter-endothelial cell interactions are maintained by “button-like” junctions The nature of these junctions renders lymphatic capillaries highly permeable to interstitial fluids and proteins and allows them to facilitate the migration of immune cells. LECs are bound by anchoring filaments, such as reticular, elastic and collagen fibers, in the extracellular matrix (ECM), allowing for proper lymph flow These anchoring filaments can stretch to open the lymphatic lumen when the volume of interstitial fluid increases, leading to increased hydrostatic pressure, facilitating the absorption of fluid from surrounding tissue. Lymphatic collector vessels propel lymphatic fluid by the rhythmic contraction of surrounding smooth muscle cells, which are absent around lymphatic capillaries
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