Angiogenesis and untying tumours

Associate Professor Ruth Ganss is head of the angiogenesis unit in the Laboratory for Cancer Medicine at the Western Australian Institute for Medical Research (WAIMR) and an invited speaker at this year's Lorne Cancer conference.

Ganss joined the growing number of talented researchers at the WAIMR in January last year, following eight years as group leader in the Department of Molecular Immunology at the German Cancer Research Centre in Heidelberg.

Prior to that she worked as a postdoctoral fellow at the University of California in San Francisco with Doug Hanahan, a keynote plenary speaker at Lorne.

Ganss will speak at one of the sessions on angiogenesis, a major topic of the 2007 Lorne agenda. Angiogenesis is the formation of a new vascular network that comes with tumour development and is the thing that enables small tumours to develop into hypervascular, rapidly growing cancers. Ganss is intrigued by how tumours create this new microenvironment and how it appears to prevent immune cells from carrying out their job to destroy the cancer.

An immunologist by trade, Ganss' work in this area was stimulated by observations made by many in the field of tumour immunology that activating T-cells (mainly CD8+ and CD4+ T cells) to become effector cells against tumour antigens, and knowing a whole lot about tumour antigens, had limited success in getting remission of tumours.

Even persistently high levels of activated killer T cells failed to eradicate the tumours in the cancer model that Ganss studies. The problem seems to involve both the cells not being able to access or 'extravasate' the tumour mass as well as not functioning effectively if they are able to penetrate.

In pre-clinical mouse models, Ganss and others have observed that adoptive transfer of activated T cells had some success with clearing small nodules, but as the size of the tumour increased it became more refractory to effector cell infiltration, indicating that tumours develop intrinsic mechanisms to escape immune destruction as they themselves develop.

Ganss wanted to know what was going on with these tumours and became interested in the link between these findings on immune cell anti-tumour activity and angiogenesis, which is crucial to the manifestation of a tumour micro-environment.

Clinical course of tumour development

Ganss' team uses a transgenic mouse model originally developed by Doug Hanahan to track angiogenesis during the stepwise growth of a spontaneously occurring tumour of the pancreas. This model is a closer representation of the clinical course of tumour development than in vitro cell lines or transplantation models where mice are injected under the skin with tumour cells.

These tumours arise spontaneously in their tissue of origin, allowing examination of the morphological and functional status of the vasculature at all stages of carcinogenesis.

The new vasculature induced by tumour growth develops characteristic and stage-specific morphological features compared with normal vessels. The phenotype is quite "chaotic and aberrant", Ganss says. Using their mouse models of multistage carcinogenesis, Ganss and colleagues initially showed that the chaotic vascular phenotype appeared in the early stages of tumour progression. They went on to find that the anti-tumour effect of T cells was actually enhanced when instead of killing vessels, they were 'normalised'. That is, the phenotype was returned to resemble that of the non-tumour-associated vasculature.

Ganss achieved this 'normalisation' of the vessels by introducing intra-tumoral inflammation. Research she published in 2002 showed that inducing inflammation via irradiation in the stepwise carcinogenesis model rendered the mice more susceptible to the action of activated effector T cells and subsequent clearing of the tumour.

The later findings on reversing the vascular phenotype therefore introduces an additional and intriguing aspect linking the activity of anti-tumour immune cells to the tumour microenvironment - for the tumour cells to do their job requires an inflammation-induced change in the neovasculature back to a more normal phenotype.

"Basically it seems that angiogenesis is a highly dynamic process, which can be reversed in the 'right' inflammatory context," Ganss says. "This in turn facilitates immune effector cell entry and tumour rejection."

The molecular mechanisms underlying these observations remain a mystery and Ganss is now trying to unravel the differences between the chaotic and normalised vessels that might affect tumour accessibility in mouse models, and she will discuss this at more length at Lorne.

Molecular changes in vasculature

She will also present some new findings following work published in the journal Blood in 2005. While still in Heidelberg, Ganss's group identified a gene that is upregulated in the chaotic and abnormal tumour vessels and becomes downregulated on normalising of the vasculature.

This gene encodes the regulator of G-protein signaling-5 (RGS-5) protein and is specifically induced early on during angiogenesis and then further elevated in tumour vessels. Intra-tumoral RGS-5 appears to be specific for immature pericytes, stromal cells that underlie the endothelial cells of the vessels, indicating that these cells are also involved in the molecular changes happening during neovascularisation and making them a potential novel therapeutic target.

In fact, Ganss proposes that changes in the pericyte compartment might be a key factor in the difference between angiogenic and normal vessels.

In the latter half of 2006, Ganss received significant local and international recognition of her research, boosting her career move to Australia. Together with a successful application for NHMRC project funding to the tune of $528 000, she was also awarded one of eight New Independent Researcher Infrastructure Support (NIRIS) Awards from the West Australian state government, recognising new medical and health researchers, and the George Koehler Prize for Immunology, an international award given to one young investigator for their outstanding contribution to the understanding of our immune system.

When asked about the long-term goals of her research, Ganss did not hesitate in expressing the wish to see her work translated into new anti-tumour therapies in clinical trials that will ultimately help cancer patients. "For me, this work is both exciting and important as it has the potential to help so many people, and that is what it is all about."