Matrix Crosslinking Forces Tumor Progression by Enhancing Integrin Signaling

Abstract

Summary Tumors are characterized by extracellular matrix (ECM) remodeling and stiffening. The importance of ECM remodeling to cancer is appreciated; the relevance of stiffening is less clear. We found that breast tumorigenesis is accompanied by collagen crosslinking, ECM stiffening and increased focal adhesions. Inducing collagen crosslinking stiffened the ECM, promoted focal adhesions, enhanced PI3 Kinase (PI3K) activity, and induced the invasion of an oncogene-initiated epithelium. Inhibiting integrin signaling repressed the invasion of a premalignant epithelium into a stiffened, crosslinked ECM, and forced integrin clustering promoted focal adhesions, enhanced PI3K signaling and induced the invasion of a premalignant epithelium. Consistently, reducing lysyl oxidase-mediated collagen crosslinking prevented MMTV-Neu-induced fibrosis, decreased focal adhesions and PI3K activity, impeded malignancy and lowered tumor incidence. These data show how collagen crosslinking can modulate tissue fibrosis and stiffness to force focal adhesions, growth factor signaling and breast malignancy.

Role of Helicobacter pylori infection in cancer‐associated fibroblast‐induced epithelial‐mesenchymal transition in vitro

“…HIF‐1α is known to induce transcription of more than 60 genes and to play an important role in CAFs activation and release of a great number of proangiogenic factors including SDF‐1, IL‐8, and VEGF35, 65 also examined in our present study. CAFs produce a variety of ECM proteins such as fibronectin, TNC, and collagens, the structural components that make up connective tissue and contribute to the dense fibrous nature of solid tumors 66, 67, 68, 69, 70, 71. The metabolism of collagen is deregulated in cancer by the increased expression, turnover, elevated deposition, and altered organization with enhanced matrix metalloproteinases (MMPs) activity, all implicated in tumor progression 67, 68.…”

“…CAFs produce a variety of ECM proteins such as fibronectin, TNC, and collagens, the structural components that make up connective tissue and contribute to the dense fibrous nature of solid tumors 66, 67, 68, 69, 70, 71. The metabolism of collagen is deregulated in cancer by the increased expression, turnover, elevated deposition, and altered organization with enhanced matrix metalloproteinases (MMPs) activity, all implicated in tumor progression 67, 68. Furthermore, ECM stiffening was required to corporate with TGFβ to induce EMT in human breast tumor cells, further strengthening the notion that mechanical properties of the tumor microenvironment are key factors regulating EMT and promoting tumor progression 69…”

“…The tumor invasion and metastasis are initiated by EMT program involving cells acquiring mesenchymal phenotype characterized with decreased cell‐to‐cell adhesion, increased motility and invasive properties. Such cells once detached from primary tumor invade surrounding tissues through collective or individual cell migration 3, 20, 21, 22, 23, 24, 25, 26, 67, 68, 69, 70, 71, 73. Therefore, we propose that fibroblasts infected with H. pylori (cagA+vacA+) likely acquired characteristics of CAFs with changes in morphology and elevated HGF, TGFβ, and additionally IL‐6 and SDF‐1 release, which may enhance EMT program in epithelial gastric cells.…”

Periductal stromal collagen topology of pancreatic ductal adenocarcinoma differs from that of normal and chronic pancreatitis

“…Collagen is the preeminent scaffolding element in the human body, and alignment and cross-linking have been shown to increase tumor tissue stiffness levels. 53,54 Cells, in turn, are able to sense changes in the mechanical properties of the local environment and respond to them in ways that deviate from behaviors under normal tissue homeostasis. 55,56 Therapeutic targeting of lysyl oxidase in mouse models has shown promise in reducing collagen cross-linking and tumor stiffness, and ultimately in reversing the malignant phenotypes of cells.…”

The biology of personalized cancer medicine: Facing individual complexities underlying hallmark capabilities

“…In such tumors, CAFs produce copious fibrotic tissue – referred to as “desmoplastic stroma” – particularly at the boundaries between the invasive cancer and the host tissue. The presence of desmoplastic stroma is associated with enhanced tumor cell invasiveness and is a major determinant of tumor cell malignancy (Egeblad et al., 2010; Levental et al., 2009). The high interstitial pressure measured in the desmoplastic stroma limits tumor blood vessel perfusion and the delivery of chemo and other forms of therapy.…”