Loss of Integrin α1β1 Ameliorates Kras-Induced Lung Cancer

Abstract

The collagen IV binding receptor integrin A1B1 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 A1-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/A1-null mice have a decreased incidence of primary lung tumors and longer survival compared with KrasLA2/A1 wild-type controls. Tumors from KrasLA2/A1-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/A1-null mice showed diminished extracellular signal-regulated kinase (ERK) but enhanced p38 mitogenactivated protein kinase activation. Primary lung tumor epithelial cells isolated from KrasLA2/A1-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/A1 wild-type tumor cells. These results indicate that loss of the integrin A1 subunit decreases the incidence and growth of lung epithelial tumors initiated by oncogenic Kras, suggesting that both Kras and integrin A1B1 cooperate to drive the growth of non-small cell lung cancer in vivo. [Cancer Res 2008;68(15):6127-9]

The integrin–collagen connection – a glue for tissue repair?

“…Reduced experimental tumorigenesis in lung cancer models (Chen et al, 2005;Macias-Perez et al, 2008).…”

“…2). Furthermore, the absence of α1 has been found to ameliorate or reduce tumor growth and metastasis in a number of lung cancer models (Chen et al, 2005;Macias-Perez et al, 2008). Careful investigation of the role of α1 in the colon has revealed that it is expressed on both epithelial cells and submucosal myofibroblasts (Boudjadi et al, , 2015.…”

APE1/Ref‐1 knockdown in pancreatic ductal adenocarcinoma – characterizing gene expression changes and identifying novel pathways using single‐cell RNA sequencing

“…ITGA1, part of the integrin signaling and virus entry via endocytic pathways as identified by IPA, is involved in cell proliferation (Macias‐Perez et al ., 2008) and invasion (Yang et al ., 2015), as well as inflammation (Becker et al ., 2013) and fibrosis (Ramos et al ., 2012), which have all been previously linked to APE1 (Aamann et al ., 2016; Shah et al ., 2017). …”

ITGA1 (integrin, alpha 1)

“…Note In mouse models, the α1β1 integrin mediates cell invasion through the regulation of stromelysin-1 expression (Lochter et al, 1999) and, together with the Kras oncogenic factor, potentiates tumour growth and cell motility (Macias-Perez et al, 2008).…”