Oral Presentation 2014 Cutaneous Biology Meeting

Flightless neutralising antibody reduces tumour cell invasion and decreases squamous cell carcinomas in mice (#43)

Zlatko Kopecki 1 2 , Gink N Yang 1 , Jessica E Jackson 1 , Elizabeth L Melville 1 , Vera Martins 3 , Matthew Caley 3 , Charlotte Proby 4 , Dodiee Pouniotis 5 , Dedee F Murrell 6 , Ian Darby 5 , Edel O'Toole 3 , Allison J Cowin 1 2
  1. Regenerative Medicine, Mawson Institute, University of South Australia, Adelaide, South Australia
  2. Discipline of Paediatrics, University of Adelaide, Adelaide, South Australia
  3. Centre for Cutaneous Research, Barts and the London School of Medicine and Dentistry, University of London, London, UK
  4. School of Medicine, University of Dundee, Dundee, Scotland
  5. School of Medical Sciences, RMIT University, Melbourne, Australia
  6. Derpatment of Dermatology, St George Hospital and University of New South Wales, Sydney, Australia

Cutaneous Squamous Cell Carcinomas (cSCC) are highly invasive and often fatal in the elderly and immunocompromised patients. The cytoskeleton and members of the gelsolin family of actin remodelling proteins are known to mediate cellular processes important in tumorigenesis. The aim of this study was to determine if Flightless I (Flii), an actin remodelling protein could modulate cSCC formation. Flii was found to be highly elevated in human cSCC tissues and serum samples. A 3D organotypic SCC skin model using sporadic cSCC cell lines showed that Flii is specifically expressed by invading cells penetrating the dermis and addition of Flii neutralising antibodies (FnAb) (50µg/ml) to sporadic cSCC cells altered cell proliferation and migration while blocking cellular invasion. cSCCs were therefore induced in Flii heterozygous (Flii+/-), wild-type (Flii+/+) and Flii transgenic mice (FliiTg/Tg) mice following a single intradermal injection of 3-Methylcholanthrene (MCA) (n=12). A higher incidence, quicker onset, and more acute development of necrotic, ulcerated tumours with larger macroscopic and microscopic areas and significantly increased tumour volume and cross sectional tumour width were observed in FliiTg/Tg animals compared to wild-type mice. In contrast, mice with reduced Flii (Flii+/-) exhibited fewer, smaller and less invasive tumours. To determine if reducing the level of Flii in the SCC mouse model could reduce the size and severity of tumours, intradermal injections of 100µl FnAb (50µg/ml) were administered during SCC initiation and development in both Flii transgenic (FliiTg/Tg) and wild-type mice. Tumour growth and invasion were significantly reduced following FnAb treatment compared to IgG controls in both wild-type and FliiTg/Tg mice. These results suggest that elevated Flii in SCCs may contribute to tumour formation and invasion and that lowering the level of Flii may reduce the incidence and severity of these skin cancers.

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  2. Jackson, J.E., et al., Flii neutralizing antibodies improve wound healing in porcine preclinical studies. Wound Repair Regen, 2012. 20(4): p. 523-36.
  3. Wakita, D., et al., IFN-gamma-dependent type 1 immunity is crucial for immunosurveillance against squamous cell carcinoma in a novel mouse carcinogenesis model. Carcinogenesis, 2009. 30(8): p. 1408-15.