Tumormikromilieu-abhängige angiokrine Tumorsuppression im kolorektalen Karzinom (DFG-FOR 2438)

FOR 2438: Cell Plasticity in Colorectal Carcinogenesis

Colorectal cancer (CRC) is among the major death-causing cancers worldwide. Exploiting cellular memory processes of cultivated tumor endothelial cells (TEC), we identified SPARCL1 as a marker of tumor microenvironment (TME)-dependent plasticity of TEC in CRC. In tissues, SPARCL1 was highly expressed in mature, quiescent vessels in normal colon and CRC with a Th1-TME but down-regulated in CRC with non-Th1-TME and worse prognosis. In culture, SPARCL1 expression was induced in endothelial cells after confluence was reached and was positively related with cell quiescence and inversely with cell proliferation. In agreement with the latter ectopically expressed SPARCL1 inhibited endothelial cell proliferation and the purified recombinant protein paracrinely inhibited proliferation, migration and sprouting of endothelial cells and proliferation of CRC tumor cells. These results indicated that SPARCL1 may regulate vessel maturation and in addition may act as an endothelial cell-secreted antagonist of tumor growth in CRC with a Th1-like TME (associated with improved prognosis). This led to the hypothesis that specific TME-induced phenotypes of TEC may actively counteract tumor development. Based on these results the main research questions of the planned project are to investigate the role and underlying mechanisms of SPARCL1 as a regulatory molecule of vessel homeostasis and vascular-derived antagonist of CRC progression. The project will deliver new insights into the role of TME-associated blood vessel plasticity on CRC tumorigenesis with the long-term objective to exploit these mechanisms for the development of a SPARCL1-based treatment approach to suppress development of metastases in CRC patients.