Histidine-rich glycoprotein in tumour vessel normalization and anti-tumour immune responsiveness


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Lena Claesson-Welsh
Uppsala University, Sweden

Abstract

Histidine-rich glycoprotein (HRG) is a 75 kDa heparin-binding plasma protein produced by hepatocytes. HRG negatively regulates tumour 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 &alpha2 integrin-dependent manner. Recent data indicate that the effect of HRG in vivo to a large extent is dependent on infiltrating tumour macrophages. In mice with fibrosarcoma, breast cancer or pancreas cancer over expressing HRG, tumour vessels are normalized, displaying several signs of a mature vessel morphology and better capacity to lead blood. This is accompanied by reduced primary tumour growth rate and reduced metastatic spread. In agreement, hrg knockout mice grow larger primary tumours that metastasize more. The pattern of gene regulation in HRG-treated macrophages ex vivo and in macrophages purified from HRG-expressing tumours, show a consistent pattern with reduced proangiogenic stimulators and increased anti-tumour immune response, leading to tumour-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.