Formyl peptide receptor 1 suppresses gastric cancer angiogenesis and growth by exploiting inflammation resolution pathways

Prevete, Nella; Liotti, Federica; Illiano, Anna; Amoresano, Angela; Pucci, Piero; Paulis, Amato de; Melillo, Rosa Marina

doi:10.1080/2162402x.2017.1293213

Cited by 45 publications

(59 citation statements)

References 50 publications

(69 reference statements)

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“…We further characterized the role of ALX/ FPR2 in aspirin's anticancer activity by systemically treating established tumors (10 6 LLC cells/mouse) in genetically engineered ALX/FPR2 knockout (KO) or wild-type (WT) mice with low-dose aspirin or vehicle. Consistent with the antitumor activity of resolvins (23,(30)(31)(32)(33)(34), LLC tumor growth was accelerated in the ALX/FPR2 KO mice compared with WT mice (Fig. 2C).…”

Section: Resultssupporting

confidence: 74%

Aspirin-triggered proresolving mediators stimulate resolution in cancer

Gilligan

Gartung

Sulciner

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

129

113

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Inflammation in the tumor microenvironment is a strong promoter of tumor growth. Substantial epidemiologic evidence suggests that aspirin, which suppresses inflammation, reduces the risk of cancer. The mechanism by which aspirin inhibits cancer has remained unclear, and toxicity has limited its clinical use. Aspirin not only blocks the biosynthesis of prostaglandins, but also stimulates the endogenous production of anti-inflammatory and proresolving mediators termed aspirin-triggered specialized proresolving mediators (AT-SPMs), such as aspirin-triggered resolvins (AT-RvDs) and lipoxins (AT-LXs). Using genetic and pharmacologic manipulation of a proresolving receptor, we demonstrate that AT-RvDs mediate the antitumor activity of aspirin. Moreover, treatment of mice with AT-RvDs (e.g., AT-RvD1 and AT-RvD3) or AT-LXA 4 inhibited primary tumor growth by enhancing macrophage phagocytosis of tumor cell debris and counter-regulating macrophage-secreted proinflammatory cytokines, including migration inhibitory factor, plasminogen activator inhibitor-1, and C-C motif chemokine ligand 2/monocyte chemoattractant protein 1. Thus, the pro-resolution activity of AT-resolvins and AT-lipoxins may explain some of aspirin's broad anticancer activity. These AT-SPMs are active at considerably lower concentrations than aspirin, and thus may provide a nontoxic approach to harnessing aspirin's anticancer activity. metabolomics | eicosanoids | resolvins | inflammation | metastasis M ore than 80 million aspirin tablets are consumed every year (1). Epidemiologic evidence suggests that the nonsteroidal anti-inflammatory drug (NSAID) aspirin reduces the risk and incidence of cancer and also prolongs survival when administered postdiagnosis (2). While initial studies have focused on colorectal cancers, low-dose aspirin has also demonstrated consistent antitumor activity in other cancers, including lung, breast, prostate, and metastatic cancers (3,4). Studies have also identified survival and chemopreventive benefits of low-dose aspirin following cytotoxic therapy (e.g., radiation, chemotherapy) or surgical tumor resection (5, 6). Compelling evidence of aspirin's anticancer activity stems from patients receiving low-dose aspirin for cardioprevention, in which a substantial fraction (20-30%) benefits from a decrease in cancer incidence (7). In contrast, several studies show that neither nonaspirin NSAIDs nor acetaminophen are associated with a reduced risk of cancer or chemopreventive activity (8,9). While the known anti-inflammatory activity of aspirin offers a generic rationale, the unique antitumor mechanisms of aspirin compared with other NSAIDs remain poorly understood. Importantly, the use of low-dose aspirin in cancer patients is limited by adverse side effects, such as gastrointestinal bleeding and hemorrhagic stroke, that necessitate hospitalization (10).The study of anti-inflammatory mechanisms in cancer has traditionally focused on the suppression of proinflammatory mediators, such as cytokines, eicosanoids, and enzymes (2). Cycloo...

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Section: Resultssupporting

confidence: 74%

Aspirin-triggered proresolving mediators stimulate resolution in cancer

Gilligan

Gartung

Sulciner

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

129

113

View full text Add to dashboard Cite

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“…The participation of FPR1 on angiogenesis has been preferentially shown in cancer conditions, and depends on a complex scenario in the tumor microenvironment. Activation of FPR1 on cancer gastric cells reduced the local angiogenesis and cancer growth, depending on pro-resolving mediators of inflammation, such as metabolic activity of lipoxygenases (ALOX5/15) ( Prevete et al, 2015 , 2017 ). Differently, the D1 and D2 linear sequences of uroquinase-type plasminogen activator (uPAR) induced angiogenesis by binding to FPR1 on endothelial cells ( Prevete et al, 2015 ), and the blockage of the interaction of uPAR with the receptor that prevents capillary-like tubes formation in co-culture with chondrosarcoma cells ( Ingangi et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Annexin A12–26 Treatment Improves Skin Heterologous Transplantation by Modulating Inflammation and Angiogenesis Processes

et al. 2018

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Skin graft successful depends on reduction of local inflammation evoked by the surgical lesion and efficient neovascularization to nutrition the graft. It has been shown that N-terminal portion of the Annexin A1 protein (AnxA1) with its anti-inflammatory properties induces epithelial mucosa repair and presents potential therapeutic approaches. The role of AnxA1 on wound healing has not been explored and we investigated in this study the effect of the peptide Ac2–26 (N-terminal AnxA1 peptide Ac2–26; AnxA12–26) on heterologous skin scaffolds transplantation in BALB/c mice, focusing on inflammation and angiogenesis. Treatment with AnxA12–26, once a day, from day 3–60 after scaffold implantation improved the take of the implant, induced vessels formation, enhanced gene and protein levels of the vascular growth factor-A (VEGF-A) and fibroblast influx into allograft tissue. It also decreased pro- while increasing anti-inflammatory cytokines. The pro-angiogenic activity of AnxA12–26 was corroborated by topical application of AnxA12–26 on the subcutaneous tissue of mice. Moreover, treatment of human umbilical endothelial cells (HUVECs) with AnxA12–26 improved proliferation, shortened cycle, increased migration and actin polymerization similarly to those evoked by VEGF-A. The peptide treatment instead only potentiated the tube formation induced by VEGF-A. Collectively, our data showed that AnxA12–26 treatment favors the tissue regeneration after skin grafting by avoiding exacerbated inflammation and improving the angiogenesis process.

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“…Cells were analyzed with a FACS Calibur cytofluorimeter using CellQuest software (BD Biosciences). 10 4 events for each sample were acquired in all analyses [ 44 ].…”

Section: Methodsmentioning

confidence: 99%

Glucose impairs tamoxifen responsiveness modulating connective tissue growth factor in breast cancer cells

et al. 2017

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Type 2 diabetes and obesity are negative prognostic factors in patients with breast cancer (BC). We found that sensitivity to tamoxifen was reduced by 2-fold by 25 mM glucose (High Glucose; HG) compared to 5.5 mM glucose (Low Glucose; LG) in MCF7 BC cells. Shifting from HG to LG ameliorated MCF7 cell responsiveness to tamoxifen. RNA-Sequencing of MCF7 BC cells revealed that cell cycle-related genes were mainly affected by glucose. Connective Tissue Growth Factor (CTGF) was identified as a glucose-induced modulator of cell sensitivity to tamoxifen. Co-culturing MCF7 cells with human adipocytes exposed to HG, enhanced CTGF mRNA levels and reduced tamoxifen responsiveness of BC cells. Inhibition of adipocyte-released IL8 reverted these effects. Interestingly, CTGF immuno-detection in bioptic specimens from women with estrogen receptor positive (ER+) BC correlated with hormone therapy resistance, distant metastases, reduced overall and disease-free survival. Thus, glucose affects tamoxifen responsiveness directly modulating CTGF in BC cells, and indirectly promoting IL8 release by adipocytes.

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Formyl peptide receptor 1 suppresses gastric cancer angiogenesis and growth by exploiting inflammation resolution pathways

Cited by 45 publications

References 50 publications

Aspirin-triggered proresolving mediators stimulate resolution in cancer

Aspirin-triggered proresolving mediators stimulate resolution in cancer

Annexin A12–26 Treatment Improves Skin Heterologous Transplantation by Modulating Inflammation and Angiogenesis Processes

Glucose impairs tamoxifen responsiveness modulating connective tissue growth factor in breast cancer cells

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