MYO-DESMOPLASIA · Modulating the behaviour of cancer myofibroblasts to control tumour desmoplasia

Modulating the behaviour of cancer myofibroblasts to control tumour desmoplasia

The tumor micro-environment consists of stromal cells (including fibroblasts and myofibroblasts, also known as cancer associated fibroblasts (CAFs)), the extracellular matrix (ECM) and myriad soluble factors in the extracellular milieu whose importance in cancer progression and metastasis is indisputable. In many types of tumors (e.g., pancreatic and breast cancers), the complex interplay among tumor micro-environment components leads to remodeling and overproduction of the tumor ECM, resulting in a desmoplastic reaction. Desmoplasia is a cancer-specific type of fibrosis, characterized by the presence of CAFs and overproduction of ECM proteins, such as collagen type I. Desmoplasia stiffens the tumor tissue, and as a result, it increases the compressive mechanical forces in the interior of the tumor. Among the wide range of physical alterations that occur during cancer and the many TME constituents that are present, the CAFs, the transforming growth factor beta (TGFβ) and the matrix stiffness stand out as key players, responsible for tumor desmoplasia. One pathway through which extensive ECM synthesis and remodeling occur is the activation of TGFβ along with the mechanical forces exerted on fibroblasts from the ECM and other structural components of the tumor. Specifically, it is known that TGFβ activation and stiffening of the ECM contribute to the conversion of fibroblasts to contractile CAFs. Subsequently, CAFs increase the synthesis of ECM proteins, such as collagens, while TGFβ down-regulates the expression of matrix-depleting metalloproteinases. Furthermore, TGFβ regulates the production of matrix-modifying enzymes, which increase the degree of collagen crosslinking. This mechanism results in desmoplasia and further stiffening of the matrix. Matrix stiffening, in turn, will cause an increase in TGFβ expression and will further fibroblasts conversion. Therefore, it appears to be a positive feedback loop, which gives rise to continuous activation of TGFβ and formation of CAFs that exacerbate tumor desmoplasia. However, the underlying mechanisms, leading to the desmoplastic reaction of solid tumors are not yet fully understood. Elucidation of the role of matrix stiffness and TGFβ in controlling tumor desmoplasia can lead to new approaches for treating cancer. Specifically, it has been shown that targeting tumor desmoplasia can improve the systemic delivery of drugs and hinder metastasis. The specific research objectives of the project were: Research Objective 1: Development of a collagen based ECM model, with pre-determined topography and tunable stiffness. Research Objective 2: Characterization of the mechanical properties and behaviour of fibroblasts and myofibroblasts cultured in the ECM models as a function of TGFβ. Research Objective 3: gene expression analysis of fibroblasts and CAFs in the matrix models to identify genes responsible for ECM production as a function of TGFβ and correlate to cell mechanical properties.

Data: CORDIS, © European Union