Abstract
BackgroundPreclinical and clinical studies have shown for decades that tumor cells demonstrate significantly enhanced sensitivity to “fever range” hyperthermia (increasing the intratumoral temperature to 42-45°C) than normal cells, although it is unknown why cancer cells exhibit this distinctive susceptibility.MethodsTo address this issue, mammary epithelial cells and three malignant breast cancer lines were subjected to hyperthermic shock and microarray, bioinformatics, and network analysis of the global transcription changes was subsequently performed.ResultsBioinformatics analysis differentiated the gene expression patterns that distinguish the heat shock response of normal cells from malignant breast cancer cells, revealing that the gene expression profiles of mammary epithelial cells are completely distinct from malignant breast cancer lines following this treatment. Using gene network analysis, we identified altered expression of transcripts involved in mitotic regulators, histones, and non-protein coding RNAs as the significant processes that differed between the hyperthermic response of mammary epithelial cells and breast cancer cells. We confirmed our data via qPCR and flow cytometric analysis to demonstrate that hyperthermia specifically disrupts the expression of key mitotic regulators and G2/M phase progression in the breast cancer cells.ConclusionThese data have identified molecular mechanisms by which breast cancer lines may exhibit enhanced susceptibility to hyperthermic shock.
Highlights
IntroductionPreclinical and clinical studies have shown for decades that tumor cells demonstrate significantly enhanced sensitivity to “fever range” hyperthermia (increasing the intratumoral temperature to 42-45°C) than normal cells, it is unknown why cancer cells exhibit this distinctive susceptibility
Preclinical and clinical studies have shown for decades that tumor cells demonstrate significantly enhanced sensitivity to “fever range” hyperthermia than normal cells, it is unknown why cancer cells exhibit this distinctive susceptibility
To streamline identification of these treatment groups, cells grown at 37°C will be referred to as C and C’, while cells grown at 45°C will be referred to as H and H’
Summary
Preclinical and clinical studies have shown for decades that tumor cells demonstrate significantly enhanced sensitivity to “fever range” hyperthermia (increasing the intratumoral temperature to 42-45°C) than normal cells, it is unknown why cancer cells exhibit this distinctive susceptibility. With the recent and rapid progression of nanobiotechnology applications in medicine, the development of magnetic nanoparticles which can induce tumor hyperthermia through hysteresis loss in an alternating magnetic field has renewed great interest in reexamining this adjuvant therapy in tumor treatments [12] Further development of this technology may have the potential to overcome the previous limitations associated with older modalities of inducing hyperthermia and lead to reduced morbidity and mortality for patients. Several studies have elucidated the heat shock induced changes in global gene expression of tumor cell lines such as squamous cell carcinoma, lymphoma, and glioma and have commonly identified gene networks involved in apoptosis, cell cycle, and cell structure/ maintanence [20,21,22] None of these studies compared the gene expression profiles to that of hyperthermia treated normal cells, it remains unknown how the hyperthermic response of cancer cells differs from that of normal cells. Identification of the unique hyperthermiainduced gene expression changes between normal and cancer cells may shed light on the selective disadvantage of solid tumors in response to mild increases in temperature, but could identify signaling targets and biological processes which potentially could be exploited to sensitize tumors to chemotherapy and radiation
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