Gastrointestinal Cancer

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The gastrointestinal cancer lab. is situated in the Department of Medicine at the University of Melbourne campus, Western Hospital in beautiful downtown Footscray. Current staff and students at the gastrointestinal cancer lab:

• Louise Judd, PhD: CR Roper Fellow
• Trevelyan Menheniott, PhD: NHMRC Research Officer
• Meegan Howlett, BSc (Hons): PhD student
• Cameron Jackson, BSc (Hons): PhD student
• Anthony Peterson, BSc (Hons): PhD student
• Helen Lescensen: BSc Honours student
• Anastasia Kalantzis, BSc (Hons): Research Assistant
• Biba Horvatic, BSc (Hons): Research assistant
• Shelly Delaland: Biology Technician
• David Ong, MB BS: Visiting Research Fellow (Singapore)
• Maha Chaer: Visiting MSc student (Sweden)
• Anna-Karin Orbjorn: Visiting MSc student (Sweden)

Research Interests

The gastrointestinal cancer lab has major research interests in:

• Identifying factors which influence initiation, progression and submucosal invasion of gastric cancer. Currently we are focusing on the IL-6/IL-11 cytokines and their target genes.
• The role of tumour-associated macrophages in gastric cancer progression.
• Molecular mechanisms by which Helicobacter pylori induces neoplasia.
• The role of the trefoil peptides and their binding proteins as tumour suppressor genes and epithelial cell repair mediators in the gastrointestinal tract.
• The role of the bombesin/GRP family of growth factors in colon cancer development and uterine renewal.

See also our translational research in gastrointestinal cancer led by Dr Alex Boussioutas.

Projects

Gastric Cancer

We have recently described a new mouse model (gp130 757F/F or F/F ) of gastric cancer in collaboration with the Ernst laboratory at the Ludwig Institute of Cancer Research in Melbourne.

The F/F mouse has defective IL-6 signaling in its MAP kinase activating arm, resulting in loss of expression of the Erk-activated tumour suppressor (TFF1) and compensatory over-expression of oncogenic phospho-STAT3.The result is rapid gastric tumour growth leading to tumour cell invasion of blood vessels in the underlying submucosa. This model recapitulates many of the precancerous events that lead to neoplasia in the most common form of human gastric cancer, and therefore the model may facilitate the recognition of genes important for tumour development.

Work is ongoing on the following projects:

1. Establishing the F/F mouse model as a paradigm for human intestinal type gastric cancer: The gastric cancer phenotype develops in the F/F mouse in part as a result of constitutive phospho-STAT3 and reduced TFF1 tumour suppressor activity. Recent data suggest that activated STAT3 plays a role in inducing epithelial proliferation, promoting inflammation, and in inhibiting immunocyte apoptosis and the actions of cytostatic genes. Work is ongoing to establish which genes are disregulated downstream of gp130, how these are driven, and how they might contribute to gastric cancer progression. (see refs 4, 6, 7, 9)

2. Tumour-associated macrophages in gastric neoplasia: Like other epithelial cancers, we have established that tissue macrophages may play an important role in tumour growth. This project will focus on the outcome of depleting macrophages in F/F mice and in assessing the role of important signalling molecules in macrophage action.

3. Translational research on human pre-neoplastic lesions of the gastric mucosa: We believe that the dysregulated signaling and consequently the functional outcome of the engineered mutation in the F/F mouse, also occurs in certain forms of human gastric cancer induced by the bacterium Helicobacter pylori . Using both gastric cancer cell lines and human gastric biposies, we are testing the validity of this paradigm and will utilise these systems to better understand how the human disease is initiated and progresses. (See translational research in gastrointestinal cancer.)

4. Factors that regulate submucosal invasion of gastric tumour: We have observed that as F/F mice age, they progressively develop invasive tumours which penetrate the epithelium and the submucosal vascular system, but do not metastasise to other organs. This phenotype is about 10-fold more prevalent in gp130 757F/F mice that also lack IL-6 which may normally restrict tumour spread by augmenting local tumour surveillance functions or inhibiting the factors tumours need to spread. Current investigations are centred on determining how this occurs. (see ref. 2)

5. Inhibition of tumour progression and induction of regression. We are currently testing several drugs and processes in the F/F mouse model, which appear to inhibit tumour progression and may also cause regression. These drugs/processes target luminal bacteria/inflammation, as well as angiogenesis and motility pathways, and current experiments are aimed at determining their mode, range of actions, efficacy and specificity.

Cholangiocarcinoma

7. The role of trefoil peptides in the development of cholangiocarcinoma. We were among the first to show that the trefoil peptides (TFF1 and 3) are present in the biliary tree where they are over-expressed in particular populations of epithelial ducts and diseases. The present work focuses on the role of trefoil peptides in the development of cholangiocarcinoma. (see refs 5, 8)

Colon Cancer

8. Identifying a new GRP gene product thought to be important in pregnancy and cancer. We have previously shown that the pregnant ovine endometrium generates very large amounts of a protein product of the GRP (bombesin) gene which is different from the known bioactive GRP products of mammals. This protein may also be important in colon cancer development as we have shown that GRP peptides regulate colonic growth and the development of pre-malignant lesions. We have recently isolated and identified this protein and when it is synthesized it will be used in functional studies using a mainly in vitro approach. This project is part of a long-standing collaboration between our group and that of Professor Arthur Shulkes of the University of Melbourne, Department of Surgery at the Austin and Repatriation Medical Centre. (see ref. 10)

Grant Support

Our research is support by;

• National Health and Medical Research Council
• Australian Research Council
• Western Hospital
• Cancer bequests

Facilities

In 2006 the lab. will consist of 14 members, including seven students, the C.R. Roper Senior Research Fellow, Senior Research Officer, and 4 technical staff. We have spacious laboratories, well equipped to carry out a full range of protein and molecular (DNA/RNA) analysis. In addition, we have two tissue culture suites and a histology/microscopy laboratory.

There are shared office facilities for all staff and students (2/office) and a computer lab. with a number of networked terminals, scanner and printers. The hospital library has numerous online journals and computer facilities.

All staff have access to the nearby hospital carpark for secure off-street parking at reasonable rates. There are banking and coffee-shop/kiosk facilities close by on the hospital campus.

Key Publications (last 5 years)

1. Loncar MB & Giraud AS (2005). Multiple regulatory pathways for trefoil factor (TFF) genes. Cell.Mol. Life Sci., 62:2921–31 (-/4.8).
2. Howlett M, Judd L, Jenkins B, Ernst M, Giraud AS (2005). Differential regulation of gastric tumor growth and submucosal invasion by cytokines that signal exclusively through the co-receptor gp130. Gastroenterology, 129:1005–18 (-/13.1).
3. Franic T, Giraud AS, Gleeson P, van Driel I & Judd LM (2005). Trefoil peptides 1 and 2 are differentially and reciprocally regulated by gastrin i mouse models of gastric hypertrophy and metaplasia. J. Pathol, 207:43–52 (-/5.3).
4. Jenkins BJ, Grail D, Nheu T, Naidovska M, Wang B, Waring P, Inglese M, McLoughlin RM, Jones SA, Topley N, Baumann H, Judd LM, Giraud AS, Zhu HJ & Ernst M (2005). Exaggerated STAT3-activity promotes gastric hyper-proliferation in gp130 mutant mice due to desensitized TGF? signaling. Nature Medicine, 11:845–52 (-/31.2).
5. Nozaki L, Lund JG, Specht S, Park JI, Giraud AS, Murase N, Demetris AJ (2004). Regulation and function of trefoil factor family 3 expression in the biliary tree. Am.J.Pathol., 165:1907–20 (-/6).
6. Franic T, Judd LM, Giraud AS, Samuelson LC, Gleeson P & van Driel I (2004). Growth factors associated with gastric mucosal hypertrophy in autoimmune gastritis. Am.J.Physiol. (Gastro), 287:G910–18 (-/3.5).
7. Judd LM*, Alderman BM*, Howlett M, Shulkes A, Dow C, Moverley J, Grail D, Jenkins BJ, Ernst M & Giraud AS (2004). Gastric cancer development in mice lacking the SHP2 binding site on the IL-6 family co-receptor gp130. Gastroenterology, 126:196–207 (9/13.4). (* Joint first authors)
8. Kimura Y, Leung PSC, Kenny TP, van de Water J, Nishioka M, Giraud AS, Neuberger J, Ansari AA, Coppel RL & Gershwin ME (2002). Differential expression of intestinal trefoil factor (ITF) in biliary epithelial cells of primary biliary cirrhosis. Hepatology, 36:1227–35 (5/9).
9. Tebbutt NC, Giraud AS, Inglese M., Waring P, Jenkins B, Clay FJ, Malki S, Grail D, Hollande F, Heath JK &Ernst M (2002). Reciprocal regulation of gastrointestinal homeostasis by SHP2 and STAT-mediated trefoil gene activation in gp130 mutant mice.  Nature Medicine, 8:1089–97 (41/31.2). (* Joint first authors)
10. Houli N, Loh SW, Giraud AS, Baldwin GS & Shulkes A (in press 2006). Mitogenic effects of both amidated and glycine-extended gastrin-releasing peptide in de-functioned and azoxymethane treated rat colon. Regulatory Peptides (-/2.5).