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

Cédric Zeltz,Pugazendhi M Erusappan,Edna Cukierman,Anders Molven,Heinz Hoschuetzky,Hengshuo Liu,Jahedul Alam,Daniela-Elena Costea,Donald Gullberg,Ning Lu,Himalaya Parajuli

doi:10.3390/cancers11060765

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).

Highlights

The importance of the tumor microenvironment (TME) for the growth and spread of tumors is being increasingly recognized
We found here that cancer-associated fibroblasts (CAFs) expressing integrin α11 do not systematically co-express αSMA, since we noted a strong co-expression of integrin α11 and αSMA in CAFS around the tumor cells of the pancreatic ductal adenocarcinoma (PDAC) and head and neck squamous cell carcinoma (HNSCC) sections, which suggested that these α11+ -CAFs could have a role in collagen remodeling at the border of the tumor in order to facilitate tumor cell invasion
Immunostaining was performed on fresh-frozen tumor tissue sections from patients that were diagnosed with pancreatic ductal adenocarcinoma (PDAC) or head and neck squamous carcinoma (HNSCC), which were both obtained from Haukeland University Hospital and subject to ethical approval from the Committee for Ethics in Health Research of West Norway

Summary

Introduction

The importance of the tumor microenvironment (TME) for the growth and spread of tumors is being increasingly recognized. Cancers 2019, 11, 765 matrix (ECM) serves as a reservoir of growth factors and cytokines that take part in the bidirectional communication between the stroma and the tumor cells [1,2]. The major cell types in the tumor stroma of solid tumors include cancer-associated fibroblasts (CAFs) of varying origin, endothelial cells, pericytes, mesenchymal stem cells, and immune cells [3,4]. CAFs represent a major cell type within the stroma contributing to ECM synthesis and ECM remodeling, and they take part in the paracrine signaling, which affects the growth and invasive properties of the tumor cells, in chemoresistance and in the establishment of metastatic niches [3,4,5]. Fibroblastic cells constitute a group of mesenchymal cells of varying origins, some of which (i.e., myCAFs) share characteristics with the myofibroblasts that are found in granulation tissue during wound healing and tissue fibrosis [9]

Methods

Results

Discussion

Conclusion