Moderate Hyperthermic Heating Encountered During Thermal Ablation Increases Tumor Cell Activity

Purpose: The aim of this study was to determine whether moderate hyperthermic doses, routinely encountered in the periablational zone during thermal ablation, activate tumor cells sufficiently to secrete pro-tumorigenic factors that can induce increased proliferation. Material and methods: R3230 rat mammary tumor cells and human cancer cell lines, MCF7 breast adenocarcinoma, HepG2 and Huh7 HCC, and HT-29 and SW480 colon adenocarcinoma, were heated in to 45 +/- 1 degrees C or 43 +/- 1 degrees C in vitro for 5-10 min and incubated thereafter at 37 degrees C for 1.5, 3 or 8 hr (n = 3 trials each; total N = 135). mRNA expression profiles of cytokines implicated in RF-induced tumorigenesis including IL-6, TNF alpha, STAT3, HGF, and VEGF, were evaluated by relative quantitative real-time PCR. HSP70 was used as control. c-Met and STAT3 levels were assessed by Western blot. Finally, naive cancer cells were incubated with medium from R3230 and human cancer cells that were subjected to 43-45 degrees C for 5 or 10 min and incubated for 3 or 8 h at 37 degrees C in an xCELLigence or incuCyte detection system. Results: Cell-line-specific dose and time-dependent elevations of at least a doubling in HSP70, IL-6, TNF alpha, STAT3, and HGF gene expression were observed in R3230 and human cancer cells subjected to moderate hyperthermia. R3230 and several human cell lines showed increased phosphorylation of STAT3 3 h post-heating and increased c-Met following heating. Medium of cancer cells subject to moderate hyperthermia induced statistically significant accelerated cell growth of all cell lines compared to non-heated media (p < 0.01, all comparisons). Conclusion: Heat-damaged human tumor cells by themselves can induce proliferation of tumor by releasing pro-tumorigenic factors.