Angiogenesis and Tumour Immunology

Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Angiogenesis is a normal process in growth and development, as well as in wound healing. However, this is also a fundamental step in the transition of tumors from a dormant state to a malignant state.

Cancer is one of the major causes of mortality and its incidence continues to increase. Although tumours are 'seen' by the immune system, clinical success with immune-based anti-tumour therapies remains rare. Our previous work has shown that the unique conditions inside solid tumours control the effectiveness of anti-cancer immune cells. In particular, remodelling of blood vessels during tumour growth, a process termed angiogenesis, appears to control the movement of immune cells into solid tumours.

We have previously shown that inflammatory factors can overcome the 'blood-tumour' barrier and open solid tumours for effector cell influx and destruction. Our research program aims to identify mechanisms which control neovascularization, to develop "angio-immuno" therapies which alter the tumour vasculature and promote immune cell entry and to study the role of vessel-specific genes which may control the barrier function of solid tumours. We expect that our findings will lead to highly specific, targeted and effective anti-tumour therapies which can be readily translated into clinical trials with potentially huge benefits for cancer patients.

Senior Research Staff

Professor Ruth Ganss Head, Angiogenesis and Tumour Immunology Research: angiogenesis; multistage tumorigenesis; tumour immunology

Research Details

Currently, our research program has attracted funding for two major research areas which centre around transgenic mouse models for multistep tumour formation (RIPTag, insulinoma, and AlbTag, hepatocellular carcinoma).

1. The 'blood-tumour' barrier: overcoming tumour-intrinsic resistance to immune effector function

Solid tumours create their own microenvironment by inducing aberrant stromal components and sprouting of new blood vessels (angiogenesis). Strikingly, the effectiveness of anti-tumour strategies declines with increasing tumour size demonstrating that tumours develop intrinsic mechanisms to escape immune destruction. To study the complex interrelationship between immune cells and tumour stroma, we use a transgenic mouse model of de novo carcinogenesis where highly vascularized tumours develop through temporally and histologically specific stages. We previously demonstrated that angiogenesis is reversible in the right inflammatory context. Triggering of inflammation overcomes the endothelial 'barrier' and opens solid tumours for effector cell infiltration and destruction.

Recently, a peptide has been identified (RGR peptide, CRGRRST), which specifically homes to neoplastic, but not normal vessels in our mouse model. Using this tool, we will target inflammatory mediators into tumours that dually modulate stroma and attract/activate leukocytes (eg. IFNγ, IL-2, CpG-ODN, anti-CD40 antibodies). We expect that the consequent local inflammation in the tumour bed will overcome its intrinsic resistance to leukocyte infiltration.

This project involves a broad spectrum of techniques such as cloning of fusion constructs, protein purification, intravenous injections into mice, adoptive transfers of immune cells, histology and immunohistochemistry, FACS analyses and long-term survival studies on transgenic mice.

2. The role of Regulator of G protein signalling-5 during vascular maturation and as a regulator of the 'blood-tumour' barrier

Recently, we have described Regulator of G protein signaling-5 (RGS-5) as the first marker for angiogenic pericytes. We have also demonstrated that RGS-5 is upregulated during physiological neovascularization such as wound healing and ovulation. Biochemically, RGS-5 is well characterized and known to inactivate G protein-coupled receptors. However, its receptor specificity and physiologic role in vivo are unknown. To address these questions we will (i) identify binding partners for RGS-5 and (ii) study mice deficient in RGS-5.

My laboratory has established the first RGS-5 knock-out mice (unpublished). Preliminary data show placental defects in RGS-5 deficient mice. We will use RGS-5 -/- embryos to further study vascular processes during placental development. Moreover, tumours which develop in the RGS-5-deficient background show a vascular network which resembles normal vessels. This is in clear contrast to tumours in non-RGS-5 deficient mice, which display a heterogeneous vasculature with large vessel calibres.

This finding confirms our previous observation of RGS-5 being downregulated during vessel 'normalization' and tumour regression. We will now investigate the implications of the different tumour vasculature between RGS-5 deficient and non-deficient mice, especially in relation to tumour sensitivity to chemotherapeutic drugs, and for effector cell infiltration. We will purify normal and tumour vascular cells from RGS-5 knock-out and non-deficient mice in order to generate a molecular profile using gene chip technology. This will provide insights into the regulatory molecules and pathways which interact with RGS-5. Moreover, RGS-5-deficient mice are an excellent tool to study molecular pathophysiology of the vasculature in cardiac hypertrophy, hypertension and atherosclerosis, all of which are major clinical entities contributing substantially to human morbidity and mortality.

This project involves a wide range of techniques including DNA cloning, RT-PCR, protein interaction and mRNA expression studies, array analysis, tissue culture, histology and immunohistochemistry.

Major Grants Awarded

• Ada Bartholomew Medical Research Trust Grant, 2006
• New Independent Researcher Infrastructure Award, from the Department of Health, 2006
• Medical Research Foundation Grant, 2007
• NHMRC project grant: Regulator of G-protein Signalling-5: a key modulator of vascular maturation and the "blood-tumour" barrier, 2007-2009
• The Cancer Council Western Australia: Enhancing anti-tumour immunity by targeting tumour vasculature, 2007-2008

Major Collaborators

• Prof Guenter Haemmerling, Dr Bernd Arnold, Dr Gerd Moldenhauer - German Cancer Research Center, Heidelberg, Germany
• Dr Fabian Kiessling - German Cancer Research Center, Heidelberg, Germany
• Prof Stefan Offermanns, Dr Nina Wettschureck, Dr Angela Wirth - University of Heidelberg, Heidelberg, Germany
• A/Prof Gabriele Bergers - University of California San Francisco, San Francisco, USA
• Dr Joe Altin - Australian National University, Canberra, ACT, Australia
• Dr Delia Nelson - School of Biomedical Sciences, Curtin University, WA, Australia
• A/Prof Karin Eidne - Western Australian Institute for Medical Research, Centre for Medical Research, WA, Australia