Abstract
Solid malignant tumors can be regarded as a functional tissue in which architecture and function are maintained by a dynamic interplay between tumor cells and a microenvironment consisting of extracellular matrix (ECM) containing fibroblasts, blood and lymphatic vasculature and infiltrating and resident immune cells (i.e. tumor stroma). In this thesis, we have studied the role of the ECM in growth, progression and metastasis of cutaneous and uveal melanoma, focussing on lymphatics, blood vasculature and specific patterns of ECM formation. Our data showed that lymphatics could reliable be detected, thereby facilitating elucidation of the anatomical relationship between lymphatics and tumor cells. Furthermore, tumor-induced lymphangiogenesis (i.e. the formation of new lymphatics) in uveal melanoma was not present despite expression of the lymphatic growth factor vascular endothelial growth factor-C and its receptor Flt-4 on tumor blood vessels. Moreover, although Flt-4 expression is restricted on the lymphatic vasculature in normal tissues, Flt-4 expression on blood vessels gradually increased as a tumor becomes more malignant in case of melanocytic skin lesions. In addition, we showed that vascular endothelial growth factor-A may be involved in this process. Finally, our data suggested that certain patterns of ECM depositions (i.e. arcs, loops and networks patterns) may accommodate transport of plasma-derived molecules (nutrients) into the tumor lesion and waste products away from the tumor tissue. Furthermore they may serve as an alternative lymphatic system regulating interstitial pressure, they mediate infiltration of tumor tissue by host-derived cells and they provide a gateway for tumor cells to leave the tumor. In conclusion, we provided data suggesting that the ECM compartment is of essential importance for tumor growth and metastasis in cutaneous and uveal melanoma
