Minor Type IV Collagen ?5 Chain Promotes Cancer Progression through Discoidin Domain Receptor-1.

ABSTRACT: Type IV collagens (Col IV), components of basement membrane, are essential in the maintenance of tissue integrity and proper function. Alteration of Col IV is related to developmental defects and diseases, including cancer. Col IV ? chains form ?1?1?2, ?3?4?5 and ?5?5?6 protomers that further form collagen networks. Despite knowledge on the functions of major Col IV (?1?1?2), little is known whether minor Col IV (?3?4?5 and ?5?5?6) plays a role in cancer. It also remains to be elucidated whether major and minor Col IV are functionally redundant. We show that minor Col IV ?5 chain is indispensable in cancer development by using ?5(IV)-deficient mouse model. Ablation of ?5(IV) significantly impeded the development of KrasG12D-driven lung cancer without affecting major Col IV expression. Epithelial ?5(IV) supports cancer cell proliferation, while endothelial ?5(IV) is essential for efficient tumor angiogenesis. ?5(IV), but not ?1(IV), ablation impaired expression of non-integrin collagen receptor discoidin domain receptor-1 (DDR1) and downstream ERK activation in lung cancer cells and endothelial cells. Knockdown of DDR1 in lung cancer cells and endothelial cells phenocopied the cells deficient of ?5(IV). Constitutively active DDR1 or MEK1 rescued the defects of ?5(IV)-ablated cells. Thus, minor Col IV ?5(IV) chain supports lung cancer progression via DDR1-mediated cancer cell autonomous and non-autonomous mechanisms. Minor Col IV can not be functionally compensated by abundant major Col IV.

SUBMITTER: Xiao Q 

PROVIDER: S-EPMC4438069 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature