The tumour-microenvironment consists of malignant epithelial cells, surrounding cancer associated (myo-)fibroblasts, endothelial cells creating the tumours__ vasculature system and infiltrating... Show moreThe tumour-microenvironment consists of malignant epithelial cells, surrounding cancer associated (myo-)fibroblasts, endothelial cells creating the tumours__ vasculature system and infiltrating inflammatory cells. In this thesis we have studied how interactions between these cell types contribute to the initiation, progression and metastasis formation in gastrointestinal cancers. We have focused on how the availability of two important growth factors (Transforming Growth Factor-_ and Vascular Endothelial Growth Factor) in tumour angiogenesis and myofibroblasts differentiation is regulated by interactions between different cell types. First we revealed that active TGF-_1 levels are strongly increased in gastric and colorectal carcinomas and that they are indicative for the survival of these patients. In premalignant lesions increased activation is not yet observed. In addition we show that active TGF-_ levels are correlated with the number of myofibroblasts in colorectal carcinomas. Furthermore we reveal that interaction between colon cancer cells and cancer associated fibroblasts leads to increased TGF-_ activation, subsequent myofibroblast trans-differentiation accompanied by upregulation of TGF-_ expression and increased matrix metalloproteinase (MMP) secretion. To further evaluate how MMPs regulate tumour progression we have investigated their role in tumour-angiogenesis. We show that MMP-9, derived from tumour-infiltrating neutrophils, contributes to the angiogenic switch, by releasing tumour cell derived VEGF from the extracellular matrix. Finally, we show that tumour-angiogenesis requires endothelial MMP-7 expression and is regulated by MMP-14 dependent cleavage of the TGF-_ co-receptor endoglin on angiogenic endothelial cells. In conclusion, these studies show that interaction between tumour cells, fibroblasts and endothelial cells are important for the generation of myofibroblasts by TGF-_ activation and for the initiation of angiogenesis by regulating VEGF release. These data further validate the tumour-microenvironment as an important therapeutic target. Show less
