Therapeutic potential of an anti-angiogenic multimodal biomimetic peptide in hepatocellular carcinoma
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Mustafa A. Barbhuiya1,*, Adam C. Mirando2,*, Brian W. Simons3, Ghali Lemtiri-Chlieh1, Jordan J. Green2, Aleksander S. Popel2, Niranjan B. Pandey2 and Phuoc T. Tran1,3
1Department of Radiation Oncology and Molecular and Radiation Sciences, Sidney Kimmel Comprehensive Cancer Centre, Johns Hopkins School of Medicine, Baltimore, MD, USA
2Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA
3Department of Medical Oncology, Sidney Kimmel Comprehensive Cancer Centre and Department of Urology, The Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA
*These authors have contributed equally to this work
Aleksander S. Popel, email: [email protected]
Keywords: hepatocellular carcinoma; angiogenesis; c-Met; HGF; IGF1R
Received: April 07, 2017 Accepted: August 26, 2017 Published: September 21, 2017
Hepatocellular carcinoma (HCC) is a major cause of cancer-related death worldwide. Due to inadequate screening methods and the common coexistence of limited functional liver reserves, curative treatment options are limited. Liver transplantation is the only curative treatment modality for early HCC. There are multidisciplinary treatment options like ablative treatments, radiation and systemic therapy available for more advanced patients or those that are inoperable. Treatment resistance and progression is inevitable for these HCC patients. Newer therapeutics need to be explored for better management of HCC. HCC is a hypervascular tumor and many pro-angiogenic proteins are found significantly overexpressed in HCC. Here we explored the therapeutic potential of the anti-angiogenic, anti-lymphangiogenic, and directly anti-tumorigenic biomimetic collagen IV-derived peptide developed by our group. Human HCC cell lines HuH7, Hep3b and HepG2 showed significant disruption of cell adhesion and migration upon treatment with the peptide. Consistent with previously described multimodal inhibitory properties, the peptide was found to inhibit both c-Met and IGF1R signaling in HepG2 cells and blocked HepG2 conditioned media stimulation of microvascular endothelial cell (MEC) tube formation. Furthermore, the peptide treatment of mouse HepG2 tumor xenografts significantly inhibited growth relative to untreated controls. The peptide was also found to improve the survival of autochthonous Myc-induced HCC in a transgenic mouse model. Mechanistically, we found that the peptide treatment reduced microvascular density in the autochthonous liver tumors with increased apoptosis. This study shows the promising therapeutic potential of our biomimetic peptide in the treatment of HCC.
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