Hhip regulates tumor-stroma-mediated upregulation of tumor angiogenesis

Tumor growth is governed by the coordinated action of various types of cells that are present in the tumor environment. Fibroblasts, which constitute a major fraction of the stroma, participate actively in various signaling events and regulate tumor development and metastasis. The Hedgehog (Hh) pathway plays an important role in promoting tumor malignancy via fibroblasts; however, the role of hedgehog interacting protein (hhip; inhibitor of Hh pathway) in tumor growth is poorly understood. Here we implanted B16F10 tumors in hhip+/− mice to study the tumor growth characteristics and the vascular phenotype. Furthermore, the mechanism involved in the observed phenomena was explored to reveal the role of hhip in tumor growth. The tumors that were implanted in hhip+/− mice exhibited accelerated growth and increased tumor angiogenesis. Although we observed a decrease in hypoxia, blood vessels still had abnormal phenotype. We found that increased Hh signaling in tumor fibroblasts induced a high expression of vascular endothelial growth factor (VEGF), which subsequently resulted in an increased proliferation of endothelial cells. Thus, the heterozygous knockdown of hhip in mice could affect Hh signaling in tumor fibroblasts, which could cause the increased production of the growth factor VEGF. This signaling, via a paracrine effect on endothelial cells, increased tumor vascular density. The deletion of a protein that regulates a key signalling pathway speeds up tumor growth according to scientists in Korea. Young-Guen Kwon and co-workers at Yonsei University in Seoul sought to determine the role of the 'hhip' protein during the development of cancerous tumors. Hhip is thought to regulate the Hedgehog (Hh) signalling pathway, which, in addition to playing a role in normal development, promotes cancer blood vessels proliferation via fibroblasts (common cells found in many tissues). Kwon's team experimented on mice lacking hhip and tracked how their bodies responded to tumors compared to normal mice. The mice without hhip showed increased Hh signalling in fibroblasts, leading to accelerated tumor growth through the development of new blood vessels and denser tumor structures. Therapies targeting tumor fibroblasts and associated signalling pathways may help inhibit tumor growth.