The role of activated stromal fibroblasts in regulation of progression of human hematopoietic malignancies

Project leader: Jozef Bizik
Project duration: 2006 - 2008

The aim of the proposed project is to characterize mesenchymal cells activation, specifically stromal fibroblasts, leading to inflammatory response and to study the possible influence of this process on progression of human haematopoietic malignant compartment. The rationale for choosing stromal fibroblasts was that they are active participants in translating specific physiological signals and are the key sentinel cells to first recruit specific immune cells to sites of inflammation. During the early stages of local inflammatory response, leukocytes move from peripheral blood into inflamed tissue where they are exposed to various pro-inflammatory cytokines. As the results of such stimuli certain subpopulations of blood-derived cells are expanded but at the end of active phase of inflammation must be removed. These physiological processes become disordered in leukemia patients since inflammatory infiltrate persists and tissue hyperplasia appears. We have demonstrated recently that mesenchymal fibroblasts can be activated by clustering a process that mimics tissue hyperplasia and wound healing. Activated fibroblasts produce various chemokines and cytokines which are characteristic for inflammation, a critical component also in tumour progression as many tumours arise at sites of chronic inflammation. Therefore, we plan to analyse at molecular level process of an inflammatory reaction, which ensues within the foci of activated and consequently necrotizing stromal fibroblasts. We will also test effect of nonsteroidal anti-inflammatory drugs (NSAIDs) on progression of the leukemia cell cultures in proposed experimental setting. The cellular system employed here is likely to contribute to more precise identification of gene pattern involved in inflammation and human leukemia progression.

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