Integrin α11β1 regulates cancer stromal stiffness and promotes tumorigenicity and metastasis in non-small cell lung cancer

Abstract

Integrin α11β1 is a stromal cell-specific receptor for fibrillar collagens and is overexpressed in carcinoma-associated fibroblasts (CAFs). We have investigated its direct role in cancer progression by generating severe combined immune deficient (SCID) mice deficient in integrin α11 (α11) expression. The growth of A549 lung adenocarcinoma cells and two patient-derived non-small cell lung carcinoma (NSCLC) xenografts in these α11 knockout (α11−/−) mice was significantly impeded, as compared with wild-type (α11+/+) SCID mice. Orthotopic implantation of a spontaneously metastatic NCI-H460SM cell line into the lungs of α11−/− and α11+/+ mice showed significant reduction in the metastatic potential of these cells in the α11−/− mice. We identified that collagen cross-linking is associated with stromal α11 expression, and the loss of tumor stromal α11 expression was correlated with decreased collagen reorganization and stiffness. This study shows the role of integrin α11β1, a receptor for fibrillar collagen in differentiation of fibroblasts into CAFs. Furthermore, our data support an important role for α11 signaling pathway in CAFs, promoting tumor growth and metastatic potential of NSCLC cells and being closely associated with collagen cross-linking and the organization and stiffness of fibrillar collagen matrices.

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

“…The picture of collagen-binding integrins playing a relatively minor role in normal physiology contrasts with the severe phenotypes that have been documented when the ligands of these integrins -members of the collagen family -are defective . Recent data, however, have highlighted the contribution of the collagen-binding integrins to fibroblast function in wounds (Schulz et al, 2015), in fibrotic tissue (TaliorVolodarsky et al, 2015) and tumor models (Lu et al, 2014;Navab et al, 2015). These findings, which establish important roles for collagen-binding integrins in relation to fibroblasts, are timely and fit well into the recent awareness that wound healing, fibrosis and tumor-stroma interactions share key mechanisms at the molecular level (Rybinski et al, 2014).…”

“…This reorganization of the matrix resulted in an increase in interstitial fluid pressure (Lu et al, 2014), forming a barrier to drug delivery. In another recent study, a NSCLC xenograft model has been described, in which α11β1-promoted collagen remodeling, and a correlation between tumor tissue stiffness and α11 expression was observed (Navab et al, 2015). Here, a reduced activation of FAK and ERK in tumors grown with in α11-deficient mice was also noted.…”

“…Here, a reduced activation of FAK and ERK in tumors grown with in α11-deficient mice was also noted. An analysis of possible genes involved in regulating tissue stiffness directly or indirectly revealed a correlation between stromal α11 expression and LOXL1, an elastin and collagen cross-linking enzyme (Navab et al, 2015). As α11 is selectively expressed on fibroblasts, it is not surprising that its mRNA is up-regulated by EMT-like events in various tumor models (Fernando et al, 2010;Ke et al, 2008).…”

“…Its role in the tumor stroma has not been explored in detail but α2β1 on fibroblasts could potentially act in order to reorganize the collagen matrix and alter its stiffness -as has been observed for lysyl oxidase (LOX) (Levental et al, 2009) and α11β1 (Navab et al, 2015) in experimental tumor models. To clarify the role of α2 in the tumor microenvironment it will be necessary to conditionally delete α2 on various cell populations within the tumor stroma.…”

Identification of curcumin-inhibited extracellular matrix receptors in non–small cell lung cancer A549 cells by RNA sequencing

“…35 In NSCLC, integrin regulated cancer cell invasion, metastasis, and chemoresistance. [36][37][38][39][40] Integrin inhibitors have been developed to reverse malignant phenotype of human cancers. Some of the inhibitors have entered into clinical trials, which can significantly improve cancer patients' survival rate.…”