Host responses to therapy and the tumour microenvironment contribute to the development of tumour resistance

• 
  Professor
  Christopher Christophi

  c.christophi@unimelb.edu.au

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Project Details

In almost all metastatic cancer treatments including colorectal cancer (CRC) a small fraction of tumour cells survive invariably giving rise to recurrence. Thus highlights the need to understand the mechanisms of tumour resistance to treatment.

Antitumor therapies, in addition to direct cytotoxic effects on tumour cells, also provoke a host response which plays a role in therapy resistance. We have shown drug treatments induce tumour promoting host responses even in the absence of tumour. In addition, tumours surviving cytotoxic treatments undergo a rapid but transient change known as epithelial to mesenchymal transition (EMT).We hypothesize that EMT bestows surviving tumour cells with transient drug resistance. In the clinic tumours are responsive to several rounds of drug treatment before permanent resistance develops. Interestingly we found tumours survive and undergo EMT only when they reside in close proximity to host immune cells known to secrete tumour protective factors. The results suggest a significant role for the immune system and the tumour microenvironment in the development of tumour resistance.

We are investigating the tumour microenvironment and the host response contributions to resistance development, with specific emphasis on the contribution of immune cells including macrophages/neutrophils and their secreted molecules.

Researchers

• Professor Christopher Christophi, Head of department
• Dr Linh Nguyen, Postdoctoral Research Fellow
• Dr Theodora Fifis, Postdoctoral Research Fellow
• Dr Edith Gomez, Research Assistant

Collaborators

• Professor Eric Thompson, School - Biomedical Sciences,
• Research - Biomedical Sciences, Queensland University of Technology
• Dr Mark Waltham, Breast Cancer Invassion Metastasis Unit, St Vincent's Intistute of Medical Research
• Professor Mauro Sandrin, Transplantation Immunology Research group
• Dr Ben Lang, Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University
• Professor Elizabeth Vincan, Head, Cancer Biology Lab Anatomy and Neuroscience, University of Melbourne

Funding

Austin Medical Research Foundation

Research Outcomes

1. Nguyen, L., Fifis T,  and C. Chrisophi,  Vascular Disruptive Agent OXi4503 and anti-Angiogenic Agent Sunitinib combination treatment prolong survival of mice with CRC liver metastasis. BMC Cancer. 2016 in Press.
2. Ager, E.I., Christophi, C et al., Regulation of colorectal cancer cell epithelial to mesenchymal transition by the renin angiotensin system. J Gastroenterol Hepatol, 2016 Feb 6. doi: 10.1111/jgh.13307. [Epub ahead of print]
3. Wen, S.W., E.I. Ager, and C. Christophi, Bimodal role of Kupffer cells during colorectal cancer liver metastasis. Cancer Biol Ther, 2013. 14(7): 606-13.
4. Wen, S.W., E.I. Ager, J. Neo, C, Christophi et al., The renin angiotensin system regulates Kupffer cells in colorectal liver metastases. Cancer Biol Ther, 2013. 14(8): 720-7.
5. Fifis T, Nguyen, L., Malcontenti-Wilson, C., Chan, LS., Luiza Nunes Costa, P., Daruwalla, J., Nikfarjam, M., Muralidharan, V., Waltham, M., Thompson, EW., Chrisophi,C. Treatment with the vascular disruptive agent OXi4503 induces an immediate and widespread epithelial to mesenchymal transition in the surviving tumor. Cancer medicine. 2013 2(5):595-610.
6. Nguyen L, Fifis T, Malcontenti-Wilson C, Chan LS, Costa PN, Nikfarjam M, et al. Spatial morphological and molecular differences within solid tumors may contribute to the failure of vascular disruptive agent treatments. BMC Cancer. 2012 12:522.
7. Lin WX, Fifis T, Malcontenti-Wilson C, Nikfarjam M, Muralidharan V, Nguyen L, et al. Induction of Th1Immune responses following laser ablation in a murine model of colorectal liver metastases. J Transl Med. 2011 9:83.