Host prostaglandin EP3 receptor signaling relevant to tumor-associated lymphangiogenesis

Kubo, Hidefumi; Hosono, Kanako; Suzuki, Tatsunori; Ogawa, Yoshitsugu; Katô, Hiroshi; Kamata, Hiroki; Yoshiya, Ikuto; Aoki, Hideki; Kato, Tetsuki; Sakagami, Hiroyuki; Hayashi, Izumi; Sugimoto, Yukihiko; Narumiya, Shuh; Watanabe, Masahiko; Murakami, Masataka

doi:10.1016/j.biopha.2009.04.039

Cited by 37 publications

(32 citation statements)

References 33 publications

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“…[27][28][29] However, the roles of PGs in lymphangiogenesis remain not fully clarified. 30 In the present study, we used Matrigel plugs to evaluate lymphangiogenesis during development of proliferative granulation tissues around the gels, although this Matrigel model was used for the evaluation of angiogenesis and cell migration assays. We have a strong interest in lymphangiogenesis during development of chronic inflammation, and we repeatedly used the surgical sponge implantation models that allow us to analyze the pro-and antiangiogenic activities.…”

Section: Discussionmentioning

confidence: 99%

Roles of Prostaglandin E ₂ –EP3/EP4 Receptor Signaling in the Enhancement of Lymphangiogenesis During Fibroblast Growth Factor-2–Induced Granulation Formation

Hosono

Suzuki

Tamaki

et al. 2011

ATVB

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Objective— One of the hallmarks of inflammation is lymphangiogesis that drains the interstitial fluids. During chronic inflammation, angiogenesis is induced by a variety of inflammatory mediators, such as prostaglandins (PGs). However, it remains unknown whether they enhance lymphangiogenesis. We examined the roles of cyclooxygenase-2 (COX-2) and PGE 2 receptor signaling in enhancement of lymphangiogenesis during proliferative inflammation. Methods and Results— Lymphangiogenesis estimated by podoplanin/vascular endothelial growth factor (VEGF) receptor-3/LYVE-1 expression was upregulated during proliferative inflammation seen around and into subcutaneous Matrigel plugs containing fibroblast growth factor-2 (125 ng/site). A COX-2 inhibitor (celecoxib) significantly reduced lymphangiogenesis in a dose-dependent manner, whereas topical PGE 2 enhanced lymphangiogenesis. Topical injection of fluorescein isothiocyanate–dextran into the Matrigel revealed that lymphatic flow from the Matrigels was COX-2 dependent. Lymphangiogenesis was suppressed in the granulation tissues of mice lacking either EP3 or EP4, suggesting that these molecules are receptors in response to endogenous PGE 2 . An EP3-selective agonist (ONO-AE-248) increased the expression of VEGF-C and VEGF-D in cultured macrophages, whereas an EP4-selective agonist (ONO-AE1-329) increased VEGF-C expression in cultured macrophages and increased VEGF-D expression in cultured fibroblasts. Conclusion— Our findings suggest that COX-2 and EP3/EP4 signaling contributes to lymphangiogenesis in proliferative inflammation, possibly via induction of VEGF-C and VEGF-D, and may become a therapeutic target for controlling lymphangiogenesis.

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Section: Discussionmentioning

confidence: 99%

Roles of Prostaglandin E ₂ –EP3/EP4 Receptor Signaling in the Enhancement of Lymphangiogenesis During Fibroblast Growth Factor-2–Induced Granulation Formation

Hosono

Suzuki

Tamaki

et al. 2011

ATVB

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“…12,13 However, little is known about the direct contribution of COX-2 to lymphedema-associated lymphangiogenesis, although positive correlations between COX-2 expression in tumor tissues and lymphangiogenesis and lymph node metastasis have been reported for several human cancers, [28][29][30] as well as the effect of COX-2 inhibition on lymphangiogenesis in a tumor implantation model. 14 In a study utilizing a nonselective COX inhibitor in a mouse tail lymphedema model, ketoprofen treatment normalized the histopathology with increased TNF-a expression and VEGF-C expression. 31 The surprising difference between the effect of COX-2 inhibition on VEGF-C expression in that study and ours suggests that the selectivity of COX inhibitors is important.…”

Section: Discussionmentioning

confidence: 99%

“…We further clarified that tumor-associated lymphangiogenesis was upregulated by endogenous PGs derived from COX-2. 14 In addition, upregulation of VEGFR-3 was observed in response to host PG signaling, and this was accompanied by a COX-2-dependent increase in VEGF-C expression. These data suggested that PGs are endogenous regulators of lymphangiogenesis in some pathological conditions, although it remains unknown whether endogenous PGE 2 enhances lymphangiogenesis during secondary lymphedema.…”

mentioning

confidence: 99%

Role of COX-2 in lymphangiogenesis and restoration of lymphatic flow in secondary lymphedema

Kashiwagi

Hosono

Suzuki

et al. 2011

Laboratory Investigation

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“…In this issue, Lyons et al report that expression of PGE 2 by postpartum tumor cells stimulates LECs directly in an EP2-dependent manner (10), although other studies of tumor-associated stroma implicate EP3 (11,12). In human prostate cancer, EP3 protein levels were positively correlated with lymphatic vessel density (11), and COX-2-overexpressing Lewis lung carcinomas drove stromal cell secretion of VEGF-C via EP3 activation (12). Therefore, PGE 2 -mediated tumor lymphangiogenesis is complex (13), involving many cell types and EP receptors that likely participate in much cross-talk (Figure 1).…”

Section: Lactation Involution and Breast Cancermentioning

confidence: 98%

“…The diversity of identified EP receptors is not surprising given the host of cell types in the tumor microenvironment (including tumor cells themselves) that can express prostaglandin receptors as well as secrete VEGF-C and VEGF-D. For example, in human lung and breast cancer cell lines, COX-2 overexpression has been shown to stimulate endogenous PGE 2 -mediated EP1 and EP4 signaling to drive upregulation of VEGF-C and VEGF-D directly by the tumor cells (7,9). In this issue, Lyons et al report that expression of PGE 2 by postpartum tumor cells stimulates LECs directly in an EP2-dependent manner (10), although other studies of tumor-associated stroma implicate EP3 (11,12). In human prostate cancer, EP3 protein levels were positively correlated with lymphatic vessel density (11), and COX-2-overexpressing Lewis lung carcinomas drove stromal cell secretion of VEGF-C via EP3 activation (12).…”

Section: Lactation Involution and Breast Cancermentioning

confidence: 99%

Inflammatory lymphangiogenesis in postpartum breast tissue remodeling

Swartz

2014

J. Clin. Invest.

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C o m m e n t a r y3 7 0 Lymphangiogenesis in cancer, inflammation, and tissue remodelingLymphatic vessels are common routes for tumor cell metastasis, and sentinel lymph node metastasis is a major prognostic indicator of breast cancer outcome. Since the identification of lymphatic-specific growth factors VEGF-C and VEGF-D and their receptor VEGFR-3, numerous studies have demonstrated striking correlations between tumor-associated lymphangiogenesis, or peritumoral lymphatic expansion, and metastasis (1). Originally the correlation between lymphangiogenesis and tumor metastasis was attributed to increased accessibility for tumor cell dissemination, but recent studies have shown that tumor-associated lymphangiogenesis provides many immune-suppressive features to the tumor microenvironment and can pacify tumor-specific cytotoxic T lymphocytes as well as drive deletional tolerance of naive T cells (2, 3). On the other hand, lymphangiogenesis is not specific to the tumor microenvironment and generally accompanies all types of inflammation, particularly in late or chronic stages, including chronic infections, wound healing and tissue remodeling, autoimmune diseases like Crohn's disease, and the resolution phase of acute inflammation (3, 4). Lymphangiogenesis is driven by a host of inflammatory cells that secrete VEGF-C, including mast cells, neutrophils, macrophages, activated stromal cells, angiogenic blood endothelium, and B cells (3). These cells can upregulate their production of VEGF-C or VEGF-D upon exposure to prostaglandin E2 (PGE 2 ), which plays many important and complex roles in the tumor microenvironment.Overall, cyclooxygenase-2-driven (COX-2-driven) PGE 2 upregulation is thought to help control cytotoxic immune responses in later stages of inflammation; as such, it is also expressed in chronic infection and autoimmunity (5). The major actions of COX-2-dependent PGE 2 expression on leukocytes and stromal cells tend to be suppressive, and in the tumor microenvironment, this pathway drives development of myeloid-derived suppressor cells, regulatory T cells, and alternatively activated macrophages. In dendritic cells, PGE 2 upregulates suppressive factors, like IL-10 and indoleamine 2,3-dioxygenase (IDO), leading to dysfunctional T cell activation. Therefore, since these inflammatory events in the tumor microenvironment are coincident with lymphangiogenesis, teasing out the mechanisms by which lymphangiogenesis specifically contributes to cancer metastasis is inherently difficult. Function and consequences of inflammatory lymphangiogenesisDuring inflammation, lymphangiogenesis often involves hyperplasia of preexisting lymphatic vessels, increased vessel diameters, and decreased organization and patterning. The expanded lymphatic network in inflamed tissues often resembles the vascular plexus of the liver sinusoids or bone marrow vasculature. It remains controversial whether these altered vessels have increased transport functionsdraining fluid or carrying cells to the lymph node -but several recent studies ...

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Host prostaglandin EP3 receptor signaling relevant to tumor-associated lymphangiogenesis

Cited by 37 publications

References 33 publications

Roles of Prostaglandin E ₂ –EP3/EP4 Receptor Signaling in the Enhancement of Lymphangiogenesis During Fibroblast Growth Factor-2–Induced Granulation Formation

Roles of Prostaglandin E ₂ –EP3/EP4 Receptor Signaling in the Enhancement of Lymphangiogenesis During Fibroblast Growth Factor-2–Induced Granulation Formation

Role of COX-2 in lymphangiogenesis and restoration of lymphatic flow in secondary lymphedema

Inflammatory lymphangiogenesis in postpartum breast tissue remodeling

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Host prostaglandin EP3 receptor signaling relevant to tumor-associated lymphangiogenesis

Cited by 37 publications

References 33 publications

Roles of Prostaglandin E 2 –EP3/EP4 Receptor Signaling in the Enhancement of Lymphangiogenesis During Fibroblast Growth Factor-2–Induced Granulation Formation

Roles of Prostaglandin E 2 –EP3/EP4 Receptor Signaling in the Enhancement of Lymphangiogenesis During Fibroblast Growth Factor-2–Induced Granulation Formation

Role of COX-2 in lymphangiogenesis and restoration of lymphatic flow in secondary lymphedema

Inflammatory lymphangiogenesis in postpartum breast tissue remodeling

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Roles of Prostaglandin E ₂ –EP3/EP4 Receptor Signaling in the Enhancement of Lymphangiogenesis During Fibroblast Growth Factor-2–Induced Granulation Formation

Roles of Prostaglandin E ₂ –EP3/EP4 Receptor Signaling in the Enhancement of Lymphangiogenesis During Fibroblast Growth Factor-2–Induced Granulation Formation