Radiofrequency ablation (RFA)-induced systemic tumor growth can be reduced by suppression of resultant heat shock proteins

Muneeb Ahmed*, Gaurav Kumar, Svetlana Gourevitch, Tatyana Levchenko, Eithan Galun, Vladimir Torchilin, S. Nahum Goldberg

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

Purpose: To determine the role of hepatic radiofrequency ablation (RFA) heating parameters and their activation of heat shock proteins (HSPs) in modulating distant tumor growth. Methods and materials: First, to study the effects of RFA dose on distant tumor growth, rats with subcutaneous R3230 adenocarcinoma (10 ± 1 mm) were assigned to 3 different hepatic RF doses (60 °C × 10 min, 70 °C × 5 min or 90 °C × 2 min) that induced identical sized ablation or sham (n = 6/arm). Post-RFA tumor growth rates, cellular proliferation (Ki-67) and microvascular density (MVD) were compared at 7d. Next, the effect of low and high power doses on local HSP70 expression and cellular infiltration (α-SMA + myofibroblasts and CD68 + macrophages), cytokine (IL-6) and growth factor (HGF and VEGF) expression was assessed. Finally, 60 °C × 10 min and 90 °C × 2 min RFA were combined with anti-HSP micellar quercetin (MicQ, 2 mg/ml). A total of 150 animals were used. Results: Lower RF heating (70 °C × 5 min and 60 °C × 10 min) resulted in larger distant tumors at 7d (19.2 ± 0.8 mm for both) while higher RF heating (90 °C × 2) led to less distant tumor growth (16.7 ± 1.5 mm, p <.01 for both), though increased over sham (13.5 ± 0.5 mm, p <.01). Ki-67 and MVD correlated with tumor growth (p <.01 for all). Additionally, lower dose 60 °C × 10 min hepatic RFA had more periablational HSP70 compared to 90 °C × 2 min (rim: 1.106 ± 163 µm vs. 360 ± 18 µm, p <.001), with similar trends for periablational α-SMA, CD68 and CDC47 (p <.01 for all). Anti-HSP70 MicQ blocked distant tumor growth for lower dose (60 °C × 10: RF/MicQ 14.6 ± 0.4 mm vs. RF alone: 18.1 ± 0.4 mm, p <.01) and higher dose RFA (90 °C × 2 min: RF/MicQ 14.6 ± 0.5 mm vs. RF alone: 16.4 ± 0.7 mm, p <.01). Conclusion: Hepatic RF heating parameters alter periablational HSP70, which can influence and stimulate distant tumor growth. Modulation of RF heating parameters alone or in combination with adjuvant HSP inhibition can reduce unwanted, off-target systemic tumorigenic effects.

Original languageAmerican English
Pages (from-to)934-942
Number of pages9
JournalInternational Journal of Hyperthermia
Volume34
Issue number7
DOIs
StatePublished - 3 Oct 2018

Bibliographical note

Funding Information:
This work was supported by the National Institutes of Health/National Cancer Institute [grant number 5R01CA197081], the Israel Science Foundation [grant number ISF1277/15], and the Israel Ministry of Science and Technology [grant number 48204]. SN Goldberg has unrelated sponsored research and consulting from Angiodynamics (Marlborough, MA) and Cosman Instruments (Cambridge, MA).

Publisher Copyright:
© 2018, © 2018 Informa UK Limited, trading as Taylor & Francis Group.

Keywords

  • Heat shock response (i.e., HSP, chaperones, thermotolerance)
  • heat targeted drug delivery (i.e., nanoparticles, liposomes, monoclonal antibodies)
  • radiofrequency/microwave
  • thermal ablation

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