Our research group is interested in the evolution of calcium regulating hormones and the roles in normal and tumour growth.
Comparative endocrinology allows researchers to find novel roles for known hormones or even discover new hormones. Simpler ancestral animals may have a single hormone that has only one function or task and, as animals have evolved, they now may have several hormones that do that one function. This multiplication of hormones ensures survival of that species.
The hormone that interests us the most is parathyroid hormone-related protein (PTHrP) which we have demonstrated in a range of fish and sharks. PTHrP has been shown to be important in a number of cancers in humans and our group is looking at how the comparative approach can shed more light on PTHrP’s role in cancer, particularly breast and bone cancer.
- Dr Janine Danks, Laboratory Chief
- Kristi Milley, PhD student
- Haley Gunn, PhD student
- Dr Roula Papadopoulos, Pathology consultant
Past laboratory members
- Alex Ibrahim - MSc student- 2007
- Yang Liu - Honours student-2008
- Dr Linda Abrahams, The University of Melbourne, Veterinary Science, Werribee
- Prof Venkatesh Byrappa, Institute of Molecular and Cell Biology, Singapore
- Dr Rachel Davey, The University of Melbourne, Department of Medicine, Austin Health, Heidelberg
- Prof Eleanor Mackie, The University of Melbourne, Veterinary Science, Parkville
- Prof T.J Martin, St Vincent’s Institute of Medical Research, Fitzroy
- Prof Tom Rosol, University of Ohio, Veterinary Biosciences, Columbus, Ohio, USA
- Prof Jane Visvader, Walter and Eliza Hall Institute, Parkville
- Dr Carl Walkley, St Vincent’s Institute of Medical Research, Fitzroy
- Dr Tony Mustaers, St Vincent’s Institute of Medical Research, Fitzroy
- Prof Jeff Zajac, The University of Melbourne, Department of Medicine, Austin Health, Heidelberg
Project Grant APP ID 620203, “Effects of Ephrin/Eph and PTHrP signalling on osteosarcoma“ Prof. T.J. Martin (CIA), Dr C Walkley (CIB), Dr. J.A. Danks (CIC) ($623,500) 1/1/2010-31/12/2012
1. Canine mammary tumours as a model for human breast cancer.
PTHrP has been localized in 60% of primary breast tumours (Southby et al, Cancer Res. 50:7710, 1990) and in 11/13 bony metastases (Powell et al, Cancer Res. 51:3059, 1990). In clinical studies it has been shown that the presence of PTHrP in primary tumours gives a better patient prognosis and a lower rate of metastasis to any site (Henderson et al, Cancer Res. 66:2250, 2006).
Better diagnostic and treatment tools have resulted in limited pathological material available for research and this has resulted in the search for new breast cancer models. Some groups have used transgenic animal models and others have suggested natural models, including canine mammary tumours (Rivera et al, Cancer Res. 69:8770, 2009). Dogs are considered a model of natural occurring breast cancer and they live in the same environment as humans.
In this study we are collecting canine mammary tumours (CMT) have been collected from four specialist veterinary pathology companies and over 100 veterinary surgeons in Victoria and Southern NSW. The large amount of canine mammary tissue is collected as part of normal treatment and this is allowing a direct comparison of full tumour histopathological samples with tissue arrays (TMA). These tumours were classifed pathologically using molecular subtyping,that has been suggested to better reflect patient prognosis (Perou et al, Nature 406:747, 2000) than the current typing by estrogen/progesterone receptor status. Sixty benign and twenty malignant CMTs had both PTHrP and parathyroid hormone receptor 1 (PTH1R) immunohistochemistry (IHC) carried out in both full tumour sections and TMAs. Polyclonal antisera to human PTHrP (1-14) and monoclonal antiserum to PTH1R have been used and there presence in the CMTs indicated that there was a relationship between the presence of PTHrP and the molecular subtypes. This could provide an explanation for the presence of PTHrP in the primary tumours and the association with a better patient prognosis.
2. The evolution of the vertebrate skeleton from cartilage to bone.
A bony skeleton has been considered a feature of highly evolved vertebrates including the most successful group, mammals. However, many vertebrates, including the jawless fish, sharks and rays have a predominantly cartilaginous skeleton.
The dogma is that the development of bone was crucial for the movement of vertebrates onto land. Bone not only provided a physical support but also a readily-accessible reservoir of calcium. Animals living in either a marine or freshwater environment have a constant supply of calcium and other ions. Land-dwelling vertebrates only have episodic access to calcium via their food intake and as calcium is required constantly terrestrial vertebrates have an absolute requirement for readily available calcium. Circulating calcium levels in every vertebrate are maintained at 2.1-2.8 mmol/l ((Dacke, 1979)) and are very tightly regulated. This regulation is one of the features that divide invertebrates from vertebrates. We have shown that the parathyroid hormone gene family, PTHrP and parathyroid hormone (PTH), are present in fish and sharks. The shark we have studied most recently is the elephant shark, Callorinchus milii. This species is found off the Victorian coast and recently its own genome has been sequenced (ESHark website). We are now looking at other genes in the pathways known to be important in bone formation, including the Wnt pathway.
3. Canine osteosarcoma: Is histological subtype is linked to patient outcome?
Osteosarcoma (OS) is the most common primary bone tumour, occurring predominantly in adolescents. OS has a rare presentation in humans accounting for only 2.4% of all childhood tumours. OS is naturally occurring in dogs, although it is 20 times more prevalent in dogs than humans. We will use canine OS as a model for the human disease. In this project we are currently vaildating the canine model using immunohistochemistry and whole genome screening. Next, the canine OS model will be used to investigate the controversial topic of the prognostic value of the histological classification of OS. Currently it is not known if the seven different histological subtypes have differing prognostic outcomes and so we hope to determine the patient outcome for each of the subtypes. This would allow the development of new targeted therapy based on histological subtype in the future, improving patient outcome.
Why not join us?
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