Mechanotransduction in cancer

Abstract

Tissue stiffness is tightly controlled under normal conditions, but changes with disease. In cancer, tumors often tend to be stiffer than the surrounding uninvolved tissue, yet the cells themselves soften. Within the past decade, and particularly in the last few years, there is increasing evidence that the stiffness of the extracellular matrix modulates cancer and stromal cell mechanics and function, influencing such disease hallmarks as angiogenesis, migration, and metastasis. This review briefly summarizes recent studies that investigate how cancer cells and fibrosis-relevant stromal cells respond to ECM stiffness, the possible sensing appendages and signaling mechanisms involved, and the emergence of novel substrates - including substrates with scar-like fractal heterogeneity - that mimic the in vivo mechanical environment of the cancer cell.

Figure 1

(a) Modifications of hyaluronic acid (HA) can affect its activity. Thiol-modified HA (HA-S) is not biologically active compared to native HA [64]. Bar graph shows extent of binding of fluorescently labeled HA (Fl-HA) to human MSCs, which is significantly reduced by adding HA as a competing partner, but not upon adding HA-S with its chemical modification. (b) Fibronectin (FN) streaks seen on soft HA substrates. Myocytes were cultured on (1000 μm²) square FN micro-patterned 300 Pa HA and 30 kPa PAA substrates for a period of 72 hours. Myocytes were unable to migrate out of the micropatterns even after attachment to HA substrates for a 3 day period. Arrowheads indicate formation of integrin α5 clusters. FN streaks seen on soft HA substrates are due to micro-contact printing on soft substrates and existed before cell plating [49]. (c) Mesenchymal stem cells (MSCs) are perivascular cells in nearly all tissues and have a major role in fibrosis. Ablation of Gli1+ MSCs by diphtheria toxin, DTX, reduced severity of kidney fibrosis as demonstrated by trichrome staining and immunostaining for α-SMA and quantification of interstitial fibrosis. Scale bars, left two panels, 500 μm; others, 50 μm [58]. (d) Scar in a dish reveals key role of matrix rigidity, even if heterogeneous. Scar-like islands of collagen-I are heterogeneously entrapped at the subsurface of the soft hydrogel. The heterogeneity of the MMMS was confirmed by both immunofluorescence and staining with the histochemical dye, Sirius Red. Human MSCs cultured on conventional homogeneous gels and separately on MMMS [57].