Osteopontin signaling upregulates cyclooxygenase-2 expression in tumor-associated macrophages leading to enhanced angiogenesis and melanoma growth via α9β1 integrin

Abstract

Tumor-associated macrophages (TAMs) have multifaceted roles in tumor development, particularly linked with tumor angiogenesis and invasion, but the molecular mechanism underlying this association remains unclear. In this study, we report that lack of osteopontin (OPN) suppresses melanoma growth in opn(-/-) mice and macrophages are the crucial component responsible for OPN-regulated melanoma growth. In tumor microenvironment, OPN activates macrophages and influences angiogenesis by enhancing cyclooxygenase-2 (COX-2)-dependent prostaglandin E2 (PGE2) production in an autocrine manner. Furthermore, we identify α9β1 integrin as a functional receptor for OPN that mediates its effect and activates ERK and p38 signaling, which ultimately leads to COX-2 expression in macrophages. The major role played by OPN and PGE2 in angiogenesis are further amplified by upregulation of MMP-9. OPN-activated macrophages promote the migration of endothelial and cancer cells via PGE2. These findings provide evidence that TAMs serve as source of key components such as OPN and COX-2-derived PGE2 and MMP-9 in melanoma microenvironment. Clinical specimens analyses revealed that increased infiltration of OPN-positive TAMs correlate with melanoma growth and angiogenesis. These data provide compelling evidence that OPN and COX-2 expressing macrophages are obligatory factors in melanoma growth. We conclude that OPN signaling is involved in macrophage recruitment into tumor, and our results emphasize the potential role of macrophage in modulation of tumor microenvironment via secretion of OPN, PGE2 and MMP-9, which trigger angiogenesis and melanoma growth. Thus, blockade of OPN and its regulated signaling network provides unique strategy to eradicate melanoma by manipulating TAMs.

Macrophages Promote Coal Tar Pitch Extract-induced Tumorigenesis of BEAS-2B Cells and Tumor Metastasis in Nude Mice Mediated by AP-1

“…These results suggested that macrophage-like THP-1 cells facilitate angiogenesis in tumors to provide rapidly proliferating transformed-cells much more oxygen and nutrients. The proangiogenic role of TAMs has been characterized by previous studies that showed the correlation between TAMs infiltration and high number of vascular in many tumors, such as squamous cell carcinoma of the esophagus, prostate cancer and ameloblastoma (Koide et al, 2004;Halin et al, 2009;Guzman-Medrano et al, 2012), the main reason for this may be that TAMs produce many cytokines for angiogenesis: vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), TNF-α, transforming growth factor-β (TGF-β) (Bingle et al, 2006;Araujo et al, 2010;Shu et al, 2012), and several angiogenesis-modulating enzymes, such as matrix metalloproteinases (MMP) (Pollard, 2004;Kale et al, 2014). The fact that the specific proangiogenic program in tumor turns on indicated that tumor is in a condition of hypoxic, rendering tumor cells to angiogenesis.…”

Macrophages in skin melanoma-the key element in melanomagenesis (Review)

“…Osteopontin combined with PGE2 substantially increases the influence on angiogenesis by enhancing the expression of MMP-9 (36). Another study revealed that the increased expression of COX-2 in melanoma tumor types is associated with increased VEGF expression, density of micro vessels and inflammatory infiltration formed of macrophages (37,38).…”

“…Macrophages stimulated by osteopontin from the melanoma microenvironment start to synthesize the COX-2 protein (37). α9β1 integrin on macrophages is the receptor for osteopontin, which stimulates COX-2 expression in macrophages through the ERK and p38 pathways (37). In addition to maintaining inflammation, COX-2 additionally promotes melanoma cell migration and angiogenesis through the COX-2 dependent production of PGE2 (37).…”

“…α9β1 integrin on macrophages is the receptor for osteopontin, which stimulates COX-2 expression in macrophages through the ERK and p38 pathways (37). In addition to maintaining inflammation, COX-2 additionally promotes melanoma cell migration and angiogenesis through the COX-2 dependent production of PGE2 (37). Osteopontin combined with PGE2 substantially increases the influence on angiogenesis by enhancing the expression of MMP-9 (36).…”

Darwinian Principles in Cancer Therapy

“…For example, it has been demonstrated that melanoma cells can recruit macrophages and induce cyclooxygenase-2 expression, which leads to increased angiogenesis and tumour growth. 64 While they are probably not essential for tumour angiogenesis, TAMs certainly contribute to the speed of this process. 65 Several of those secreted factors, growth factors such EGF, VEGF and cytokines such as interleukin (IL)-10 and IL-23, also contribute to tumour growth and metastasis.…”