title: Vascular endothelial growth factor plays a critical role in the formation of the pre-metastatic niche via prostaglandin E2.
abstract: Factors secreted by primary tumors can alter the microenvironment at distant organ sites, generating pre-metastatic niches for subsequent metastatic cancer cell colonization. Breast cancer cells have a propensity to home preferentially to the lung, but the underlying molecular mechanisms whereby primary breast carcinoma-derived factors affect the pre-metastatic lung environment before the arrival of the tumor cells are poorly understood. In this study, 4T1 mammary carcinoma cells were subcutaneously injected into the mammary glands of mice, resulting in the induction of inflammation, increased total vessel density and recruitment of bone marrow-derived cells (BMDCs) in pre-metastatic lungs. Subsequent examination revealed that the sites of inflammatory cell clusters in the lungs were tumor metastasis sites. Moreover, vascular endothelial growth factor (VEGF) induced prostaglandin E2 (PGE2) production in mouse pulmonary microvascular endothelial cells (MPVECs) and enhanced the adhesion of 4T1 cells. Treatment with the cyclooxygenase-2 inhibitor celecoxib significantly reduced 4T1 cell adhesion to MPVECs, and also reduced cancer metastasis and the inflammatory response. These results suggest that VEGF may be an underlying carcinoma-derived factor responsible for formation of the pre-metastatic niche in the lung of 4T1 cell-bearing mice. This study, therefore, demonstrated that primary tumors can alter the lung microenvironment during the pre-metastatic phase by triggering an inﬂammatory response and PGE2 production. Primary tumor-derived VEGF might thus be a crucial factor responsible for the formation of the pre-metastatic niche by inducing PGE2 production.
authors.affiliation: Department of Medical Microbiology, School of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China.
authors.forename: Shili
authors.initials: S
authors.lastname: Liu
authors.affiliation: Cancer Therapy and Research Center, Shandong Provincial Hospital, Shandong University, Jinan, Shandong 250021, P.R. China.
authors.forename: Man
authors.initials: M
authors.lastname: Jiang
authors.affiliation: Department of Medical Microbiology, School of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: Cancer Therapy and Research Center, Shandong Provincial Hospital, Shandong University, Jinan, Shandong 250021, P.R. China.
authors.forename: Shancheng
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Medical Microbiology, School of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Peng
authors.affiliation: Cancer Therapy and Research Center, Shandong Provincial Hospital, Shandong University, Jinan, Shandong 250021, P.R. China.
authors.forename: Pengfei
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Cancer Therapy and Research Center, Shandong Provincial Hospital, Shandong University, Jinan, Shandong 250021, P.R. China.
authors.forename: Mingyong
authors.initials: M
authors.lastname: Han
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D000068579:Celecoxib; D002465:Cell Movement; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000502:physiology*; D005260:Female; D006801:Humans; D008168:Lung / Q000473:pathology; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D011720:Pyrazoles / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068579:Celecoxib; D015232:Dinoprostone