Project Details
Projekt
Tumor microenvironment-dependent angiocrine tumor suppression in colorectal cancer
Subject Area
General and Visceral Surgery
Term
from 2016 to 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 280163318
Colorectal cancer (CRC) is among the major death-causing cancers worldwide. Exploiting cellular memory processes of isolated tumor endothelial cells, we found in the past funding period that the matricellular protein SPARCL1 is an angiocrine tumor suppressor in CRC. SPARCL1 expression in CRC tissues was restricted to vascular cells and associated with a Th1 tumor microenvironment (Th1-TME) and improved prognosis of the patients. Functional studies showed that SPARCL1 expression was induced in confluent quiescent endothelial cells and regulated endothelial cell quiescence by inhibiting proliferation, migration and sprouting of these cells. In accord with this SPARCL1 expression in human CRC tissues and mouse models was associated with reduced angiogenic activity and improved vessel maturation. Moreover, SPARCL1 was secreted from quiescent endothelial cells and inhibited mural cell migration and CRC tumor cell proliferation. This indicated that SPARCL1 is an angiocrine tumor suppressor in CRC actively contributing to the favorable prognosis associated with a Th1-TME. Based on these findings, the newly proposed program addresses two major aims: (1) the characterization of the signaling cascade mediating SPARCL1 anti-tumorigenic effects on stromal and tumor cells and (2) the analysis of tumor microenvironment-dependent anti-tumorigenic effects of SPARCL1 in experimental CRC models. It is hoped that the molecular analysis of SPARCL1-regulated tumor and stromal cell plasticity in CRC will provide new insights into host-dependent effects on prognosis, therapy response and resistance in CRC.
DFG Programme
Research Units
Subproject of
FOR 2438:
Cell Plasticity in Colorectal Carcinogenesis
