Research Grant Report for Endowments sub-committee and BAOMS website
Name:John Collin
Title of project: The innate immune cell response to resection of cancer in zebrafish
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Anticipated date of when paper will be submitted to BJOMS for possible publication:
August 2016
1) The effects of acute surgical inflammation on tumour proliferation
2) The role of the innate immune system and acute inflammation in cancer progression (scientific review paper)
Background
The relationship between inflammation and cancer initiation and progression is complex. The malignant potential of human chronic inflammatory conditions and lesions are increasingly recognised. Both systemic and peri-tumour inflammation are associated with poor outcomes for many cancers. Animal studies have shown that fewer malignant cells are needed to induce tumours within wounds and that injection of inflammatory exudate can increase tumour growth.
The innate immune system has apparently contradictory roles within this story. Macrophages and neutrophils phagocytose oncogene-transformed cells at early stages, yet also appear to be important in facilitating growth and metastasis of established cancers. They have even been shown to be essential for growth of some tumours in vivo.
Clinically, tumour-associated macrophages (TAMs) and neutrophils (TANs) are associated with poor outcomes for a number of cancers. They have roles in almost all aspects of tumour progression, from cancer cell proliferation and survival, to angiogenesis and response to hormones. These effects are thought to be induced via expression of factors by TAMs and TANs, many of which also orchestrate wound healing.
There is increasing clinical evidence that the inflammatory response associated with biopsy and surgery may increase tumour proliferation or recurrence of occult tumour or minimal residual disease. Understanding the roles of individual cell types and the mechanisms involved could have significant implications for the timing of biopsy and definitive surgery and ultimately inform strategies to influence the associated immune-inflammatory response.
Methods
Transgenic zebrafish models of melanoma (adult fish) and squamous cell carcinoma (larval fish) were developed.
Live confocal microscopic imaging of fluorophore expressing melanoma in adultand oncogene-expressing keratinocyte clones in larval fish was performed with and without adjacent wounds. The quantity and timing of neutrophil migration to wounded and unwounded tumours/oncogene expressing cells was determined.
The neutrophil response to surgical wounding in otherwise healthy fish and to cancer cells in unwounded fish was also determined.
Key results to date
Initial experiments in the adult melanoma model suggest an increase in neutrophil numbers within wounded tumours compared with wounds in tissue free of tumour (Antonio et al. 2015).
Neutrophil visits to V12Ras expressing keratinocytes also appears to increase in the presence of an adjacent laser wound in larval fish.
Publications and Presentations
Antonio N, Bønnelykke-Behrndtz ML, Ward LC, Collin J, Christensen IJ,
Steiniche T, Henrik Schmidt H, Feng Y & Martin P. The wound inflammatory
response exacerbates growth of pre-neoplastic cells and progression to
cancer. EMBO J 34, 2219-36
Collin J & Martin P. In Vivo Modelling: Danio rerio. In Basic Science Methods for Clinical Researchers. Ch 14. Ed. Jalali M. Elsevier 2016 (In Press).
The zebrafish as a model of tumour progression. BAOMS Annual Scientific
Meeting, 2015.
The zebrafish as a model organism in research relevant to OMFS. Submitted to BAOMS Scientific Meeting 2016.
Further Study
- Repetition of experiments to provide a quantitative analysis of neutrophil responses.
- Determination of macrophage and eosinophil behaviour using similar zebrafish models.
- Analysis of tumour proliferation with ablation of innate immune cell lines.
- Ethical approval has been granted to analyse the innate immune association and tumour proliferation of human mucocutaneous tumours at the time of diagnostic biopsy and definitive resection to see if observations in the zebrafish models translate to human cancer.