ArticleThe American journal of pathology2010
COX-2 and prostaglandin EP3/EP4 signaling regulate the tumor stromal proangiogenic microenvironment via CXCL12-CXCR4 chemokine systems.
Article in The American journal of pathology, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 60 papers, 1 of them a synthesis that pooled it.
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Who cites it
60 citing papers in PubMed, 1 synthesis or guideline pooled it, 109 citations in OpenAlex.
- Abnormal COX2 protein expression may be correlated with poor prognosis in oral cancer: a meta-analysis.BioMed research international · 2014Pooled it
- Cyclooxygenases in pancreatic ductal adenocarcinoma: are they inflammatory catalysts for tumor growth.Frontiers in oncology · 2026Review
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- Epigenetic regulation of the tumor microenvironment in lung cancer: mechanism insights and therapeutic prospects.Frontiers in immunology · 2025Review
- Repurposing celecoxib for colorectal cancer targeting via pH-triggered ultra-elastic nanovesicles: Pronounced efficacy through up-regulation of Wnt/β-catenin pathway in DMH-induced tumorigenesis.International journal of pharmaceutics: X · 2024Article
- Claudin-18.2 mediated interaction of gastric Cancer cells and Cancer-associated fibroblasts drives tumor progression.Cell communication and signaling : CCS · 2024Article
- Correlation and significance of COX-2, Ki67, VEGF and other immune indexes with the growth of malignant pulmonary nodules.Journal of cardiothoracic surgery · 2022Article
- Article
- Stromal disruption facilitating invasion of a 'nano-arsenal' into the solid tumor.Drug discovery today · 2022Review
- Cyclooxygenase inhibition attenuates brain angiogenesis and independently decreases mouse survival under hypoxia.Journal of neurochemistry · 2021Article
- Review
- International Union of Basic and Clinical Pharmacology. CIX. Differences and Similarities between Human and Rodent Prostaglandin EPharmacological reviews · 2020Article
- Cancer-associated fibroblasts: key determinants of tumor immunity and immunotherapy.Current opinion in immunology · 2020Review
- The Role of the CXCL12/CXCR4/CXCR7 Chemokine Axis in Cancer.Frontiers in pharmacology · 2020Review
- Prostaglandin E2/EP Signaling in the Tumor Microenvironment of Colorectal Cancer.International journal of molecular sciences · 2019Review
- Targeting CXCR4 potentiates anti-PD-1 efficacy modifying the tumor microenvironment and inhibiting neoplastic PD-1.Journal of experimental & clinical cancer research : CR · 2019Article
- VEGF Receptor 1-Expressing Macrophages Recruited from Bone Marrow Enhances Angiogenesis in Endometrial Tissues.Scientific reports · 2019Article
- Cancer-associated fibroblast regulation of tumor neo-angiogenesis as a therapeutic target in cancer.Oncology letters · 2019Review
- Prolonged activation of cAMP signaling leads to endothelial barrier disruption via transcriptional repression of RRAS.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2018Article
- Prostaglandin E2 involvement in mammalian female fertility: ovulation, fertilization, embryo development and early implantation.Reproductive biology and endocrinology : RB&E · 2018Review
Corrections and comments
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Authors and funding
14 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Bone marrow (BM)-derived hematopoietic cells, which are major components of tumor stroma, determine the tumor microenvironment and regulate tumor phenotypes. Cyclooxygenase (COX)-2 and endogenous prostaglandins are important determinants for tumor growth and tumor-associated angiogenesis; however, their contributions to stromal formation and angiogenesis remain unclear. In this study, we observed that Lewis lung carcinoma cells implanted in wild-type mice formed a tumor mass with extensive stromal formation that was markedly suppressed by COX-2 inhibition, which reduced the recruitment of BM cells. Notably, COX-2 inhibition attenuated CXCL12/CXCR4 expression as well as expression of several other chemokines. Indeed, in a Matrigel model, prostaglandin (PG) E2 enhanced stromal formation and CXCL12/CXCR4 expression. In addition, a COX-2 inhibitor suppressed stromal formation and reduced expression of CXCL12/CXCR4 and a fibroblast marker (S100A4) in a micropore chamber model. Moreover, stromal formation after tumor implantation was suppressed in EP3-/- mice and EP4-/- mice, in which stromal expression of CXCL12/CXCR4 and S100A4 was reduced. The EP3 or EP4 knockout suppressed S100A4+ fibroblasts, CXCL12+, and/or CXCR4+ stromal cells as well. Immunofluorescent analyses revealed that CXCL12+CXCR4+S100A4+ fibroblasts mainly comprised stromal cells and most of these were recruited from the BM. Additionally, either EP3- or EP4-specific agonists stimulated CXCL12 expression by fibroblasts in vitro. The present results address the novel activities of COX-2/PGE2-EP3/EP4 signaling that modulate tumor biology and show that CXCL12/CXCR4 axis may play a crucial role in tumor stromal formation and angiogenesis under the control of prostaglandins.
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