Poster Presentation 25th Lorne Cancer Conference 2013

Targeting a Novel MicroRNA Angiogenesis Pathway as a Next Generation Cancer Therapy (#315)

Prue N Plummer 1 , Vivek Mittal 2 , Albert S Mellick 1
  1. Host Response to Cancer Laboratory, Griffith University, Southport, QLD, Australia
  2. Neuberger Berman Lung Cancer Centre, Weill Cornell University Medical College, New York, United States

Tumour angiogenesis is essential for malignant growth and metastasis. Bone marrow (BM)-derived endothelial progenitor cells (EPCs) contribute to angiogenesis-mediated tumour growth. In previous studies1-4 we have shown that EPCs can be tracked form the BM to sites throughout the body including the BM compartment of the tumour-stroma. We have also demonstrated that the Inhibitor of DNA binding 1 (ID1) proximal promoter can be used to silence genes in EPCs, through directed delivery of short hairpin RNA inhibition resulting in a decrease in tumour growth and angiogenesis2. Here we report through the use of microRNA deep sequencing, transgenic mouse models and lentiviral delivery of transgenes in vivo, a novel small RNA pathway required for regulation of EPC function and tumour angiogenesis. In this pathway, the microRNA 10b is up-regulated in the tumour vasculature (compared to normal vasculature) and in EPCs in response to tumour challenge. Western blot analysis demonstrates that this microRNA is working via regulating the HOXD10 signalling pathway. Through the use of fluorescent in situ hybridization on human breast cancer biopsies we also show that microRNA 10b is expressed in the vasculature of aggressive late stage invasive ductal carcinoma but not in the more contained ductal carcinoma in situ. Directed delivery of an anti-miRNA encapsulated in a liposome to tumour vasculature targeting the microRNA 10b in vivo demonstrated decreased tumour growth, vasculature development and EPC mobilization1. This result indicates that the targeting of microRNA 10b may have clinical implications. We are currently creating a liposome conjugated to a novel EPC peptide for directed delivery of the anti-miRNA targeting microRNA 10b. As this approach would target tumour vasculature and not normal vasculature, due to microRNA 10b expression patterns, we believe this approach may lead to a novel anti-cancer therapy without side-effects associated with current therapies.

  1. Plummer PN, Freeman R, Taft R et al. MicroRNAs Regulate Tumor Angiogenesis Modulated by Endothelial Progenitor Cells. Cancer Res. Online First doi: 10.1158/0008-5472, 2012.
  2. Mellick AS, Plummer PN, Nolan D, et al. Using Transcription Factor Id1 to Selectively Target Endothelial Progenitor Cells Offers Novel Strategies to Inhibit Tumour Angiogenesis and Growth. Cancer Res. 70:7273-82, 2010.
  3. Nolan DJ, Ciarrocchi A, Mellick AS, et al. Bone marrow-derived endothelial progenitor cells are a major determinant of nascent tumour neovascularization. Genes & Dev. 21:1546-58, 2007.
  4. Gao D, Nolan DJ, Mellick AS, et al. EPCs control the angiogenic switch in mouse lung metastasis. Science. 319:195-8, 2008.