Tumor microenvironment in cancer progression

Keywords: tumor microenvironment; Heat-shock Factor 1 (HSF1) Billions of years of evolution through changing environments led organisms to develop an arsenal of cytoprotec-tive pathways to promote their survival under stressful conditions. We hypothesized that tumors exploit these mechanisms to support their own survival as they rapidly develop and evolve in a hostile and stressful environment. For tumors to form, progress and metastasize, they must recruit and reprogram normal cells in their microenvi-ronment into a protumorigenic stroma. Recently we have shown that Heat-shock Factor 1 (HSF1), master regulator of the heat-shock response, plays a crucial role in this process. Across a broad range of human cancers, HSF1 is activated not only in the malignant cells themselves, but also in cancer-associated fibroblasts (CAFs). In early stage breast and lung cancer, high stromal HSF1 activation is strongly associated with poor patient outcome. HSF1 drives a transcriptional program in CAFs that complements, yet is completely different from, the program it drives in adjacent cancer cells. This CAF program is uniquely struc-tured to support the malignant potential of cancer cells in a non-cell-autonomous way. Here we further explore the HSF1-dependent cross talk between cancer and stroma. We dissect the mechanism of stromal HSF1 activation, identify key components of the HSF1-dependent stromal transcriptional program and highlight the prognostic implications of cell-autonomous and non-cell-autonomous activation of HSF1 in cancer. Vitamin C influences the anticancer activity of several anti-cancer drugs by increasing their toxic activity toward cancer cells and simultaneously decreasing their toxic activity toward normal cells. Our data showed that mitoxantrone encapsulated in anacardic acid (AA) containing liposomes by a vitamin C ion gradient increased the number of surviving normal cells (NHDF-normal human dermal fibroblasts), in comparison to liposomes where mitoxantrone was encapsulated by an ammonium sulfate gradient. The opposite effect was observed in cancer cells (A375, Hs294T-mela-noma cell lines). These results suggest that our liposomes have a dual mechanism of action, depending on the type of cells they interact with. Apoptosis is characterized by cell shrinkage, chromatin condensation, membrane blebbing, protein fragmentation and DNA degradation. Many proteins are involved in this complex process. Caspases, a family of cysteine-dependent aspartatedirected proteases, play a critical role in the initiation and execution of apoptosis. Among this family of caspases, caspases 3 and 7 are believed to be some of the caspases most commonly involved in the execution of ap-optosis in various cell types. The aim of this project was …