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.