Targeting the tumour stroma to increase efficacy of chemo- and radiotherapy.

The impact of a favourable microenvironment on tumour progression is a limiting factor for current tumour therapy protocols, as it contributes to the selection of resistant tumour cells. Apart from immune and inflammatory cells, the extracellular matrix, cancer-associated fibroblasts and vascular endothelial cells are crucial mediators of protective signals. An important research effort exposes potential environmental targets that may define new therapeutic strategies for solid tumours.

Targeting the tumour stroma to increase efficacy of chemo- and radiotherapy

The impact of a favourable microenvironment on tumour progression is a limiting factor for current tumour therapy protocols, as it contributes to the selection of resistant tumour cells. Apart from immune and inflammatory cells, the extracellular matrix, cancer-associated fibroblasts and vascular endothelial cells are crucial mediators of protective signals. An important research effort exposes potential environmental targets that may define new therapeutic strategies for solid tumours (AU)

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Establishment of stable human fibroblast cell lines constitutively expressing active Rho-GTPases.

Small GTP-binding proteins of the Rho family (RhoA, Cdc42, Rac1) regulate the organisation and the turnover of the cell's cytoskeleton and adhesion structures. A significant function of these cellular structures is to translate and counterbalance forces applied to, or generated by, cells in order to maintain homeostasis and control cell movement. We therefore hypothesised that Rho-GTPases are directly involved in cellular gravity perception and may participate in the alterations induced in microgravity. To define an adequate cellular model allowing to investigate this issue, we have established stable cell lines constitutively expressing active forms of either RhoA, Cdc42, or Rac1. The three cell lines differ by morphology and by their ability to form filopodia, lamellipodia, and bundles of actin stress fibers. Overexpression of the active form of either RhoA, Cdc42, or Rac1 is compatible with cell viability and does not affect cell population doubling time. Thus, our series of mutant cells appear well suited to gain further knowledge on the molecular mechanisms of cellular gravity perception.

Effects of constitutively active GTPases on fibroblast behavior.

The GTP-binding proteins RhoA, Cdc42 and Rac1 regulate the organization and turnover of the cytoskeleton and cell-matrix adhesions, structures bridging cells to their support, and translating forces, external or generated within the cell. To investigate the specific requirements of Rho GTPases for biomechanical activities of clonal cell populations, we compared side-by-side stable lines of human fibroblasts expressing constitutively active (CA) RhoA, Cdc42 or Rac1. There was no marked effect of any CA GTPase on cell adhesion to different extracellular matrix proteins. Cell spreading was CA Rho GTPase specific and independent of the extracellular matrix proteins allowing adhesion. Mechanical properties were dramatically restricted by CA RhoA on bi- and in tri-dimensional surroundings, were boosted by CA Rac1 on bi-dimensional surroundings only, and were not or marginally affected by CA Cdc42. In conclusion, the action of Rho GTPases appears to depend on the task cells are performing.