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Living cells sense and respond to their microenvironment through chemical and physical signals. In vivo, their interactions are determined both by the adjacent cells and by the surrounding extracellular matrix (ECM) network. Tumor development is regulated by complex interactions of both normal and cancerous cells with their ECM. Such interactions are not well understood due mainly to the lack of appropriate characterization techniques covering length scales ranging from the molecular to the matrix/cellular level. Our goal is to study the optical/structural and mechanical properties of ECM fibrillar structures in physiological and tumor environments, from the single protein to the cellular/tissue level and to investigate tumor vascularization mechanisms.
Combining fluorescence resonance energy transfer and multiple beam interferometry through surface forces apparatus characterization, we measured the molecular conformation, Young’s modulus and viscosity of the ECM deposited by cancer-associated fibroblasts preconditioned with tumor soluble factors derived from an aggressive breast cancer cells line. Our results reveal that tumor factors promote (i) single ECM protein unfolding, (ii) overall ECM stiffening, and (iii) increased ECM viscosity with respect to control. We next quantified the effect of this altered tumor-associated ECM on cell proangiogenic capability. Our findings indicate that the unfolded and stiff tumor-associated ECM significantly enhances the secretion of vascular growth factors by surrounding stromal cells. Collectively, our multi-scale analysis suggests that conformation and mechanics of ECM proteins at both the molecular and the matrix/tissue levels significantly dysregulate the downstream proangiogenic behavior of surrounding cells, which likely contributes to tumor vascularization and development.
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