Loss of integrin alpha1beta1 ameliorates Kras-induced lung cancer.
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.
Macias-Perez
Ines
I
Department of Medicine, Division of Nephrology, Vanderbilt University Medical Center, Veterans Affairs Hospital, Nashville, Tennessee 37232, USA.
Borza
Corina
C
Chen
Xiwu
X
Yan
Xuexian
X
Ibanez
Raquel
R
Mernaugh
Glenda
G
Matrisian
Lynn M
LM
Zent
Roy
R
Pozzi
Ambra
A
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
D024141:Collagen Type IV; D039222:Integrin alpha1beta1; D048049:Extracellular Signal-Regulated MAP Kinases