α11β1 Integrin is Induced in a Subset of Cancer-Associated Fibroblasts in Desmoplastic Tumor Stroma and Mediates In Vitro Cell Migration

Abstract

Integrin α11β1 is a collagen receptor that has been reported to be overexpressed in the stroma of non-small cell lung cancer (NSCLC) and of head and neck squamous cell carcinoma (HNSCC). In the current study, we further analyzed integrin α11 expression in 14 tumor types by screening a tumor tissue array while using mAb 203E3, a newly developed monoclonal antibody to human α11. Different degrees of expression of integrin α11 were observed in the stroma of breast, ovary, skin, lung, uterus, stomach, and pancreatic ductal adenocarcinoma (PDAC) tumors. Co-expression queries with the myofibroblastic cancer-associated fibroblast (myCAF) marker, alpha smooth muscle actin (αSMA), demonstrated a moderate level of α11+ in myCAFs associated with PDAC and HNSCC tumors, and a lack of α11 expression in additional stromal cells (i.e., cells positive for fibroblast-specific protein 1 (FSP1) and NG2). The new function-blocking α11 antibody, mAb 203E1, inhibited cell adhesion to collagen I, partially hindered fibroblast-mediated collagen remodeling and obstructed the three-dimensional (3D) migration rates of PDAC myCAFs. Our data demonstrate that integrin α11 is expressed in a subset of non-pericyte-derived CAFs in a range of cancers and suggest that α11β1 constitutes an important receptor for collagen remodeling and CAF migration in the tumor microenvironment (TME).

Generation of a novel mouse strain with fibroblast-specific expression of Cre recombinase

“…These results suggest that only a subset of wound myofibroblasts has strong ITGA11 promoter activity or that α11-positive wound myofibroblasts display a strictly regulated spatiotemporal distribution, and presumably also function, during the healing process. Recent analysis of cancer associated fibroblasts revealed no or little overlap of α11 and NG2 expression, suggesting that pericytes are not a major source of α11 expressing myofibroblasts [ 16 ]. More recent omic-based studies of aging fibroblast and their role during wound healing show that the ratios of different subpopulations change with aging, and that α11 potentially can be used as a marker for activated fibroblasts in such studies [ 31 ].…”

“…Early studies in human tissues indicated restricted expression of α11 in adult tissues but induction in the stroma of non-small cell lung cancer and head and neck squamous carcinoma [ 13 , 14 ]. More recently the generation of monoclonal antibodies (mAbs) directed against human α11 has increased the specificity and therefore accuracy of detecting α11 expression in human cells and tissues [ 15 , 16 ]. Data using the integrin α11 mAbs so far indicate different degrees of expression of integrin α11 in the stroma of breast, ovary, skin, lung, uterus, stomach and pancreatic ductal adenocarcinoma (PDAC) tumors [ 16 ].…”

The Biological Functions and Clinical Applications of Integrins in Cancers

“…For example, cancer-associated fibroblasts (CAFs), the most abundant tumor stromal cells in TME, mediated matrix remodeling and matrix deposition through integrins, resulting in increased tumor tissue stiffness ( Handorf et al., 2015 ; Attieh et al., 2017 ; Jang and Beningo, 2019 ). CAFs express a variety of integrins, such as integrin αvβ3 ( Attieh et al., 2017 ), α5β1 ( Erdogan et al., 2017 ), and α11 ( Primac et al., 2019 ; Zeltz et al., 2019 ), that participate in the assembly of fibronectin in ECM and facilitate the conversion of fibronectin matrix to fibronectin and the deposition of CAFs on tumor stroma ( Cavaco et al., 2018 ). Studies have shown that platelet-derived growth factor receptor (PDGFR) is an important intermediate mediator of integrin-mediated ECM remodeling ( Erdogan et al., 2017 ).…”

Hold on or Cut? Integrin- and MMP-Mediated Cell–Matrix Interactions in the Tumor Microenvironment

“…Therefore, integrin expression and surface abundance on cancer cells can serve as tumor (suppressor) markers, although this may vary between tumor entities [ 91 , 106 , 107 , 108 ]. For example, the expression of α3β1 and α11β1 integrins changes during CAF differentiation, whereupon CAFs interact via these integrins with ectopically expressed laminin-332 and desmoplastically abundant collagen, respectively, and thus support cancer cells [ 24 , 109 ]. Moreover, integrin expression and function is regulated by the TME characteristic TGF-β, and vice versa [ 110 ].…”