The University of Melbourne
	Department of Surgery
	Royal Melbourne Hospital and Western Hospital

Department of Surgery Western Hospital

Research

Head of unit Professor Steven Chan
Senior Research Fellow Dr Paul Senior

Introduction
Surgical treatment of cancer of the colon and rectum and other tumours of the gut are a major clinical focus of this department. Cancers of the colon and rectum are the second most common type of tumour occurring in the Victorian population and surgical treatment is very successful provided the tumour is localised. Unfortunately in many cases the tumour has already commenced spreading by the time it is diagnosed and many patients die due to growth of the tumour in the liver. Understanding the mechanisms by which cancer cells are able to spread through the body to organs such as the liver (metastasis) is an important area of research which will ultimately lead to improved treatment and survival.
To successfully spread the tumour cell must be able to invade surrounding tissue, enter the blood, survive in harsh foreign environment of a distant organ, divide, cause the formation of new blood vessels to supply the growing tumour and it must also evade growth control mechanisms such a programmed cell death (apoptosis) which regulate normal tissues. Over the last few years studies have identified a number of genes which are expressed at high levels in tumour cells but whose expression is low or absent in normal cells. This raises the possibility that these genes may confer on the tumour cell the abilities needed to spread successfully. Testing whether these candidate genes contribute to tumour spread is an important area of cancer research also these genes are proving to be useful targets for novel therapies.

Tissue Banking

Human tumour tissue represents a valuable resource for research in a collaboration between Western Health and the Ludwig Institute for Cancer Research we have established tissue banking facilities within the department which are an extension of the existing Tissue Bank at the Royal Melbourne Hospital This will allow colorectal and other tumours from consenting patients treated at the Western Hospital to be preserved and made available to scientists all over the country.

Projects
Research in this Department commenced in June 2003 We are initiating a research program aimed at understanding aspects of the metastatic process.

We are currently investigating four genes

1. Survivin: Over expression of this gene makes cells resistant to stimuli which result in programmed cell death (apoptosis) of normal cells.

2. VEGF: This gene stimulates the formation of new blood vessels and is thought to play a role in the establishment of metastases.

3. C-Met: Cell lines over-expressing C-Met have been shown to have increased adhesiveness and migration ability

4. Eph-B2 is involved in modulating cell adhesion it has an important role in the regulation of the normal colon.We are using Tissue Bank material to determine the proportion of colon tumours in the local population which over-express the genes we re interested in utilising tissue sections and immunohistochemistry. This technique allows not only the determination of whether the gene of interest is over expressed in the tumour, but also whether all tumour cells express equally and whether specific areas of the tumour (e.g. regions of active tissue invasion) show differential expression. In addition tumours will be stained for cells which are proliferating or undergoing apoptosis. This data will be put together with clinical and pathological information to determine any anatomic correlation of expression with areas of invasion, proliferation or apoptosis within the tumour and determine any correlation with tumour type, location, stage, patient gender or age of onset.

We are creating colon tumour cell lines in which the level of expression of the genes we
are interested in can be modulated from very low to very high levels. The effect of modulating expression levels in these cells will be tested in vitro in standard assays for invasion migration and survival. In vivo experiments will focus on the effects of modulating expression levels in models of cancer growth and metastasis using well established models. We will assess the effects of changing gene expression levels at various times during the establishment of the tumours these models.