Matrix stiffness: a key feature in cancer progression

Increased ExtraCellular Matrix (ECM) stiffness is a common process in many cancers (Pickup et al, 2014). This process influences the behaviour of cancer cells in the tumour microenvironment. The accumulation of ECM in the stroma is mainly due to a high production of ECM molecules by TGF-β(Transforming Growth Factor-beta) -stimulated CAFs (cancer-associated fibroblasts) during fibrosis.

Moreover, tumour cells can also participate in the accumulation of ECM. For example, in the development of pancreatic ductal adenocarcinoma (PDAC), cancer cells stimulate the proliferation of pancreatic stellate cells via platelet-derived growth factor (PDGF), as well as the synthesis of ECM via fibroblast growth factor 2 (FGF-2) and TGF-β1. This process results in an accumulation of collagen I and III and fibronectin around the cancer cells, leading to a desmoplastic reaction (Bachem et al., 2005).

The increase ECM rigidity in the microenvironment stimulates the proliferation of cancer cells, like in hepatocellular cancer (HCC) cells through integrin β1, focal adhesion kinase (FAK) and the ERK signalling pathway (Schrader et al., 2011).

In addition to its contribution to the stimulation of lung cancer cell proliferation, a stiff ECM can also induce resistance to drugs used in chemotherapies targeting epithelial growth factor receptors (EGFR) and hepatocyte growth factor receptors (HGFR) for the treatment of adenocarcinoma (Chang et al., 2015). Indeed, by creating a physical barrier, the ECM prevents the diffusion of therapeutic molecules into the tumour microenvironment. One of the major processes leading to the stiffening of the ECM in cancers is the cross-linking of collagen molecules by lysyl oxidase (LOX) which is highly expressed in tumours, leading for example to the progression of breast cancer (Levental et al., 2009).

In the aim to take into account the matrix stiffness impact in in vitro models, HCS Pharma has developed BIOMIMESYS® Oncology, a hyaluronic acid-based hydrascaffold with adaptable stiffness, which mimics the ECM and allows to culture cancerous cells in 3 dimensions in a relevant microenvironment. Fell free to contact us if you want more information about BIOMIMESYS®!

Pickup, M.W., Mouw, J.K., Weaver, V.M. (2014). The extracellular matrix modulates the hallmarks of cancer. EMBO reports 15: 1243–1253 ; Bachem, M.G., Schünemann, M., Ramadani, M., Siech, M., Beger, H., Buck, A., Zhou, S., Schmid-Kotsas, A., Adler, G. (2005). Pancreatic carcinoma cells induce fibrosis by stimulating proliferation and matrix synthesis of stellate cells. Gastroenterology 128: 907–921 ; Schrader, J., Gordon-Walker, T.T., Aucott, R.L., van Deemter, M., Quaas, A., Walsh, S., Benten, D., Forbes, S.J., Wells, R.G., Iredale, J.P. (2011). Matrix stiffness modulates proliferation, chemotherapeutic response, and dormancy in hepatocellular carcinoma cells. Hepatology (Baltimore, Md.) 53: 1192–1205 ; Levental, K.R., Yu, H., Kass, L., Lakins, J.N., Egeblad, M., Erler, J.T., Fong, S.F.T., Csiszar, K., Giaccia, A., Weninger, W., Yamauchi, M., Gasser, D.L., Weaver, V.M. (2009). Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 139: 891–906