Abstract
Stroma mediated wound healing signals may share similarities with the ones produced by tumor’s microenvironment and their modulation may impact tumor response to the various anti-cancer treatments including radiation therapy. Therefore we conducted this study, to assess the crosstalk between stromal and carcinoma cells in response to radiotherapy by genetic modulation of the stroma and irradiation. We found that fibroblasts irrespective of their RhoB status do not modulate intrinsic radiosensitivity of TC-1 but produce diffusible factors able to modify tumor cell fate. Then we found that Wt and RhoB deficient fibroblasts stimulated TC-1 migration through distinct mechanisms which are TGF-β1 and MMP-mediated respectively. Lastly, we found that simultaneous irradiation of fibroblasts and TC-1 abrogated the pro-migratory phenotype by repression of TGF-β and MMP secretion. This last result is highly relevant to the clinical situation and suggests that conversely to, the current view; irradiated stroma would not enhance carcinoma migration and could be manipulated to promote anti-tumor immune response.
Highlights
Wound healing and carcinogenesis are defined as complex, adaptive processes which are controlled by intricate communications between the host and the tissue microenvironment
We showed that conditioned medium (CM) produced by non-irradiated Wild type (Wt) fibroblasts had no effect on TC-1 cell migration, whereas CM produced by 10 Gy irradiated fibroblasts significantly stimulated TC-1 cells migratory capability (Fig. 3A)
Alongside we showed that CM produced by non-irradiated RhoB-/- fibroblasts increased TC-1 cell migration more significantly than Wt fibroblasts, suggesting that RhoB deficiency promote the production of pro-migratory signals
Summary
Wound healing and carcinogenesis are defined as complex, adaptive processes which are controlled by intricate communications between the host and the tissue microenvironment. During a normal wound healing process, regeneration and repair of a wound, depends on a variety of signals which coordinate the response to injury. These processes entail cell proliferation, survival, and migration which are controlled by growth factors, cytokines as well as inflammatory and angiogenic signals. These signals are derived from multiple intra and extracellular components embedded in the microenvironment of wounds and are involved in cancer. A number of phenotypic similarities are shared by wounds and cancers in cellular
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