All ETDs from UAB

Advisory Committee Chair

Boris Pasche

Advisory Committee Members

Susan Bellis

Ivan Brezovich

Xiangqin Cui

Paul Goepfert

Lisa Guay-Woodford

Document Type

Dissertation

Date of Award

2012

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Hepatocellular carcinoma (HCC) incidence in the US is dramatically increasing. Five-year survival has remained 3-5% for the past several decades, demonstrating urgent need for additional therapies. Intrabuccal administration of amplitude-modulated radiofrequency electromagnetic fields (RF EMF) is a novel, minimally invasive treatment modality. Clinical evidence demonstrates this treatment approach elicits therapeutic responses in cancer patients. In vitro we have described a phenotype in HCC cells following RF EMF exposure that included proliferative inhibition, modulation of gene expression, and disruption of the mitotic spindle. This phenotype was specific for HCC cells exposed to HCC-specific RF EMF. We have demonstrated similar efficacy in an in vivo model of HCC. Global gene expression data and subsequent validation suggest that modulation frequencies affect intracellular calcium release in cancer cells, resulting in our in vitro phenotype and in vivo efficacy. HCC cells were exposed to RF EMF modulated at specific frequencies previously identified in HCC patients. Cell death mechanisms were evaluated using fluorescence microscopy, flow cytometry, immunohistochemistry, and Western blot. MicroRNA arrays compared exposed and control groups of HCC cells, with validation followed by Western blot. NOD SCID mice received HCC subcutaneous cellular xenografts. Following palpable tumor establishment, mice were exposed to HCC-specific RF EMF, euthanized following excessive tumor burden, and evaluated by immunohistochemistry. We identified increased levels of miRNAs that target mRNAs used to synthesize proteins important in the PI3K pathway, specifically IP3/DAG signaling and intracellular calcium release. This pathway is frequently disrupted in HCC, making it an excellent candidate for modulation by RF EMF; furthermore, downstream effects include: cell cycle progression, proliferation, inhibition of apoptosis, and cell migration, each of which were implicated in our in vitro phenotype. In vivo, normal tissue architecture was preserved and xenograft tumors were seen infiltrated with fibrous tissue. Xenograft tumors in RF EMF treated mice also showed significantly decreased growth rate as compared to controls. These findings uncover a novel mechanism that controls cancer cell growth at specific modulation frequencies, with evidence of modulation of intracellular calcium levels. The optimization of this therapeutic approach may significantly alter the treatment algorithm for patients with HCC.

Share

COinS