CCB seminar Wednesday 13th of June at 10.30 hrs Professor Lena Claesson-Welsh

Abstract:

Tumor vessels as targets for therapy; histidine-rich glycoprotein (HRG) in regulation of tumor vascularization and anti-tumor immune response

Histidine-rich glycoprotein (HRG) is a 75 KDa heparin-binding plasma protein exclusively synthesized by hepatocytes. We have shown potent inhibition of tumor angiogenesis by HRG and peptides derived from its central His/Pro-rich domain, leading to reduced growth of different syngeneic tumor models (1).
In a recent study, we reported that HRG inhibits tumor growth and metastasis by polarizing tumor-associated macrophages (TAMs) to the M1 phenotype, leading to anti-tumor immunity and vessel normalization (2). Infiltration of TAMs into the tumor tissue is associated with an unfavorable prognosis. However, not only the number of infiltrating TAMs but also their phenotype regulates tumorigenesis (3). In nonprogressing or regressing tumors, TAMs are biased to a classic macrophage activation M1-like program, characterized by pro-inflammatory activity, antigen presentation and tumor lysis. In malignant tumors, TAMs resemble alternatively activated macrophages (M2-type), which increase angiogenesis and tumor cell intra/extra-vasation and growth; they suppress anti-tumor immunity by preventing activation of dendritic cells, cytotoxic T lymphocytes and natural killer cells.
Using an hrg gene-inactivated mouse model, we furthermore provided genetic evidence for HRGs effect on macrophage polarization (4). HRG ablation leads to increased tumor growth rate and metastatic dissemination, enhanced tumor vessel abnormalization, and to M2 polarization of macrophages, favoring a suppressed anti-tumor immune response.
Combined, our data show that HRG regulates M1 TAM polarization in tumors, promoting reduced angiogenesis and induction of anti-tumor immunity, whereas, constitutive loss of HRG is associated with M2 TAM polarization, increased tumor angiogenesis and growth. Macrophage polarization by HRG offers new therapeutic opportunities for anti-cancer and anti-angiogenic treatment.

References
1. Lee, C., Bongcam-Rudloff, E., Sollner, C., Jahnen-Dechent, W., and Claesson-Welsh, L. (2009) Type 3 cystatins; fetuins, kininogen and histidine-rich glycoprotein. Front Biosci 14, 2911-2922
2. Rolny, C., Mazzone, M., Tugues, S., et al. (2011) HRG inhibits tumor growth and metastasis by inducing macrophage polarization and vessel normalization through downregulation of PlGF. Cancer Cell 19, 31-44
3. Mantovani, A., and Sica, A. (2010) Macrophages, innate immunity and cancer: balance, tolerance, and diversity. Curr Opin Immunol 22, 231-237
4. Tugues, S., Honjo, S., Konig, C., et al. (2012) Genetic Deficiency in Plasma Protein HRG Enhances Tumor Growth and Metastasis by Exacerbating
Immune Escape and Vessel Abnormalization. Cancer Res 72, 1953-1963

Links:

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