Moderate hyperthermic heating encountered during thermal ablation increases tumor cell activity

Abstract

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 °C or 43 ± 1 °C in vitro for 5-10 min and incubated thereafter at 37 °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, TNFα, 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, naïve cancer cells were incubated with medium from R3230 and human cancer cells that were subjected to 43–45 °C for 5 or 10 min and incubated for 3 or 8 h at 37 °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, TNFα, 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.

Keywords:

• Radiofrequency ablation
• interventional oncology
• tumorigenesis
• moderate hyperthermia
• tumor growth

Disclosure statement

S. Nahum Goldberg has unrelated sponsored research and consulting from Angiodynamics and Cosman Company. All other authors have no conflicting interests to report.

Additional information

Funding

This work was supported by National Cancer Institute [grant number 1R01CA197081-01A1]; Israel Ministry of Science and Technology [grant number 3-12063]; and Israel Science Foundation [grant number 1277/15].