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Updated: May 11, 2026
07:41
Three-dimensional Cell Culture Model for Measuring the Effects of Interstitial Fluid Flow on Tumor Cell Invasion
Published on: July 25, 2012
Matrix crosslinking forces tumor progression by enhancing integrin signaling.
Kandice R Levental1, Hongmei Yu, Laura Kass
1Department of Bioengineering and Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA 19104, USA.
Cell
|November 26, 2009
Summary
Tumor stiffness, driven by collagen crosslinking, promotes cancer by increasing focal adhesions and PI3 kinase activity. Reducing this crosslinking impedes malignancy and lowers tumor incidence in breast cancer.
Area of Science:
- Oncology
- Biochemistry
- Biophysics
Background:
- Tumors exhibit extracellular matrix (ECM) remodeling and stiffening, but the role of stiffening in cancer progression is not fully understood.
- While ECM remodeling is recognized in cancer, the specific contribution of ECM stiffening to tumorigenesis requires further elucidation.
Purpose of the Study:
- To investigate the role of collagen crosslinking and ECM stiffening in breast cancer progression.
- To determine the mechanistic link between ECM stiffness, focal adhesions, PI3 kinase signaling, and breast malignancy.
Main Methods:
- Induction and inhibition of collagen crosslinking using lysyl oxidase.
- Assessment of ECM stiffness, focal adhesions, and PI3 kinase (PI3K) activity.
- In vivo studies using MMTV-Neu mouse models to evaluate tumor incidence and fibrosis.
Main Results:
- Collagen crosslinking led to ECM stiffening, increased focal adhesions, enhanced PI3K activity, and promoted epithelial invasion.
- Inhibition of integrin signaling reduced invasion into stiffened ECM, while integrin clustering promoted focal adhesions and PI3K signaling.
- Reduced lysyl oxidase-mediated collagen crosslinking prevented fibrosis, decreased focal adhesions and PI3K activity, and impeded breast malignancy.
Conclusions:
- Collagen crosslinking is a key driver of ECM stiffening and fibrosis in breast tumorigenesis.
- ECM stiffening, mediated by collagen crosslinking, promotes focal adhesions and PI3K signaling, thereby driving breast cancer progression.
- Targeting lysyl oxidase-mediated collagen crosslinking represents a potential therapeutic strategy to impede breast malignancy.
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