BBB Seminar: Lena Claesson-Welsh
Histidine-rich glycoprotein in tumor vessel normalization and anti-tumor immune responsiveness
Department of Immunology, Genetics and Pathology, Uppsala University, Sweden
Histidine-rich glycoprotein (HRG) is a 75 kDa heparin-binding plasma protein produced by hepatocytes. HRG negatively regulates tumor angiogenesis and arrests endothelial cell migration in a matrix-dependent manner. Thus, endothelial cell migration on collagen towards heparin-binding forms of VEGF is inhibited by HRG in an a2 integrin-dependent manner. Recent data indicate that the effect of HRG in vivo to a large extent is dependent on infiltrating tumor macrophages. In mice with fibrosarcoma, breast cancer or pancreas cancer overexpressing HRG, tumor vessels are normalized, displaying several signs of a mature vessel morphology and better capacity to lead blood. This is accompanied by reduced primary tumor growth rate and reduced metastatic spread. In agreement with this, hrg knockout mice grow larger primary tumors that metastasize more. The pattern of gene regulation in HRG-treated macrophages ex vivo and in macrophages purified from HRG-expressing tumors, show a consistent pattern with reduced proangiogenic stimulators and increased anti-tumor immune response, leading to tumor-infiltration of cytotoxic T cells, NK cells and dendritic cells by HRG. Identification of a putative HRG receptor is pursued using U937 monoblasts, which respond to HRG during early stage differentiation to monocytes, and which display high affinity cell surface binding of HRG. Development of receptor agonists as an alternative to HRG delivery is a very attractive goal to complement immune- and chemotherapy for cancer treatment.
Host: Helge Wiig , Department of Biomedicine