title: A host deficiency of discoidin domain receptor 2 (DDR2) inhibits both tumour angiogenesis and metastasis.
abstract: Discoidin domain receptor 2 (DDR2) is a unique receptor tyrosine kinase (RTK) that signals in response to collagen binding and is implicated in tumour malignant phenotypes such as invasion and metastasis. Although it has been reported that DDR2 expression is up-regulated in activated endothelial cells (ECs), functional studies are lacking. Herein, we found that enforced expression of DDR2 promoted proliferation, migration and tube formation of primary human umbilical vein endothelial cells (HUVECs). The results of immunohistochemical analysis showed a strikingly high level of DDR2 in human tumour ECs. Most significantly, we discovered that a host deficiency of DDR2 inhibits subcutaneous angiogenesis induced by either VEGF or tumour cells. In addition, the remaining tumour vessels in DDR2-deficient mice exhibit some normalized properties. These vascular phenotypes are accompanied by the up-regulation of anti-angiogenic genes and down-regulation of pro-angiogenic genes, as well as by alleviated tumour hypoxia. By use of a tail vein metastasis model of melanoma, we uncovered that loss of stromal DDR2 also suppresses tumour metastasis to the lung. Hence, our current data disclose a new mechanism by which DDR2 affects tumour progression, and may strengthen the feasibility of targeting DDR2 as an anticancer strategy.
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, People's Republic of China; Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, Department of Biochemistry and Molecular Biology, Ningxia Medical University, Yinchuan, People's Republic of China.
authors.forename: Shuya
authors.initials: S
authors.lastname: Zhang
authors.forename: Xin
authors.initials: X
authors.lastname: Bu
authors.forename: Hu
authors.initials: H
authors.lastname: Zhao
authors.forename: Jiangtian
authors.initials: J
authors.lastname: Yu
authors.forename: Yingmei
authors.initials: Y
authors.lastname: Wang
authors.forename: Di
authors.initials: D
authors.lastname: Li
authors.forename: Chuchao
authors.initials: C
authors.lastname: Zhu
authors.forename: Tong
authors.initials: T
authors.lastname: Zhu
authors.forename: Tingting
authors.initials: T
authors.lastname: Ren
authors.forename: Xinping
authors.initials: X
authors.lastname: Liu
authors.forename: Libo
authors.initials: L
authors.lastname: Yao
authors.forename: Jin
authors.initials: J
authors.lastname: Su
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D000070818:Discoidin Domain Receptors; D042783:Endothelial Cells / Q000201:enzymology* / Q000473:pathology; D005838:Genotype; D061307:Human Umbilical Vein Endothelial Cells / Q000201:enzymology; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000517:prevention & control* / Q000556:secondary; D008546:Melanoma, Experimental / Q000098:blood supply / Q000201:enzymology* / Q000235:genetics / Q000556:secondary; D051379:Mice; D018345:Mice, Knockout; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic; D010641:Phenotype; D020794:Receptor Protein-Tyrosine Kinases / Q000172:deficiency* / Q000235:genetics; D011975:Receptors, Mitogen / Q000172:deficiency* / Q000235:genetics; D012878:Skin Neoplasms / Q000098:blood supply / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden; D059016:Tumor Microenvironment
chemical_list: D011975:Receptors, Mitogen; D000070818:Discoidin Domain Receptors; D020794:Receptor Protein-Tyrosine Kinases
keywords: DDR2; collagen receptor; endothelial cells; tumour angiogenesis