title: Loss of integrin alpha1beta1 ameliorates Kras-induced lung cancer.
abstract: The collagen IV binding receptor integrin alpha1beta1 has been shown to regulate lung cancer due to its proangiogenic properties; however, it is unclear whether this receptor also plays a direct role in promoting primary lung tumors. To investigate this possibility, integrin alpha1-null mice were crossed with KrasLA2 mice that carry an oncogenic mutation of the Kras gene (G12D) and develop spontaneous primary tumors with features of non-small cell lung cancer. We provide evidence that KrasLA2/alpha1-null mice have a decreased incidence of primary lung tumors and longer survival compared with KrasLA2/alpha1 wild-type controls. Tumors from KrasLA2/alpha1-null mice were also smaller, less vascularized, and exhibited reduced cell proliferation and increased apoptosis, as determined by proliferating cell nuclear antigen and terminal deoxynucleotidyl-transferase-mediated dUTP nick-end staining, respectively. Moreover, tumors from the KrasLA2/alpha1-null mice showed diminished extracellular signal-regulated kinase (ERK) but enhanced p38 mitogen-activated protein kinase activation. Primary lung tumor epithelial cells isolated from KrasLA2/alpha1-null mice showed a significant decrease in anchorage-independent colony formation, collagen-mediated cell proliferation, ERK activation, and, most importantly, tumorigenicity when injected into nude mice compared with KrasLA2/alpha1 wild-type tumor cells. These results indicate that loss of the integrin alpha1 subunit decreases the incidence and growth of lung epithelial tumors initiated by oncogenic Kras, suggesting that both Kras and integrin alpha1beta1 cooperate to drive the growth of non-small cell lung cancer in vivo.
authors.affiliation: Department of Medicine, Division of Nephrology, Vanderbilt University Medical Center, Veterans Affairs Hospital, Nashville, Tennessee 37232, USA.
authors.forename: Ines
authors.initials: I
authors.lastname: Macias-Perez
authors.forename: Corina
authors.initials: C
authors.lastname: Borza
authors.forename: Xiwu
authors.initials: X
authors.lastname: Chen
authors.forename: Xuexian
authors.initials: X
authors.lastname: Yan
authors.forename: Raquel
authors.initials: R
authors.lastname: Ibanez
authors.forename: Glenda
authors.initials: G
authors.lastname: Mernaugh
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Matrisian
authors.forename: Roy
authors.initials: R
authors.lastname: Zent
authors.forename: Ambra
authors.initials: A
authors.lastname: Pozzi
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D049109:Cell Proliferation; D024141:Collagen Type IV / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D011905:Genes, ras; D007150:Immunohistochemistry; D039222:Integrin alpha1beta1 / Q000235:genetics / Q000502:physiology*; D008175:Lung Neoplasms / Q000098:blood supply / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D016019:Survival Analysis
chemical_list: D024141:Collagen Type IV; D039222:Integrin alpha1beta1; D048049:Extracellular Signal-Regulated MAP Kinases