Stroma-targeting: a directed approached aimed at tumor stroma fibroblasts

In recent years the awareness about the importance of the stroma for normal tissue homeostasis and tumor growth has increased. Much of this progress has been in the field of angiogenesis and anti-angiogenesis approaches are currently receiving considerabl e attention. In contrast to the recent focus on endothelial cells, much less is known about the major cell type in the stroma, the fibroblast. These cells produce an extracellular network containing fibrillar proteins in a process named fibrilloogenesis. Pathological fibrrillogenesis results in a fibrotic dysfunctional tissue in a variety of fibrotic disorders and in tumorogenesis the extent of fibrillogenesis by tumor associated fibroblasts affects tumor growth. Given the central role of the activated tu mor associated fibroblasts in tumor growth it is of interest to target the tumor fibroblast in an anti-fibrillogenesis approach. In analogy with the anti-angiogenesis approach termed angio-targeting, we collectively name these approaches stroma-targeting. In an attempt towards reachign a better un derstanding of the bi-directional signalling between tumor and stroma cells we will: - establish in vitro systems in a 3-D setting (spheroids) for carcinoma cells and tissue specific fibroblasts of different in tegrin genotypes but also generate spheroids from human colon cancers, - establish xenograft models of spheroids in different types of SCID mice, - identify stroma specific markers, - analyze integrins, metalloproteases and cytokines, with the aim of crea ting tissue-specific tumor stroma fibroblast "interactomes". Central in this work will be the access to the different FUGE-supported platforms in the Bergen area. We are hopeful that our studies will give new insight into the influence of microenvironment on carcinoma growth and metastasis.