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.

Highlights

  • Image-guided percutaneous minimally-invasive thermal ablation using various energy sources (predominantly radiofrequency (RF) and microwave (MW) energies) is commonly used to successfully treat a wide range of focal primary and metastatic tumors in the liver, lung, kidney, and other sites due to their high efficiency, and low risks of complication [1,2,3,4,5]

  • Cell line specific dose and time dependent elevations of at least a doubling in Heat shock protein 70 (HSP70), IL-6, TNFα, STAT3, and HGF gene expression were observed in R3230 and human cancer cells subjected to moderate hyperthermia

  • Where it has been previously shown that partial injury of normal liver or kidney from nonlethal heating, as routinely seen following complete thermal ablation, can cause accelerated growth in distant tumor, more recently it has been demonstrated that even partial ablation of R3230 mammary tumors in rats and subcutaneous CT26 and MC38 mouse colorectal adenocarcinoma tumors can cause similar accelerated tumor growth and increased intratumoral angiogenesis of local or distant tumors [8]

Read more

Summary

Introduction

Image-guided percutaneous minimally-invasive thermal ablation using various energy sources (predominantly radiofrequency (RF) and microwave (MW) energies) is commonly used to successfully treat a wide range of focal primary and metastatic tumors in the liver, lung, kidney, and other sites due to their high efficiency, and low risks of complication [1,2,3,4,5]. Multiple cytokine, growth factor, and transcription factor mediators, including IL-6, STAT3, HGF/c-Met, and VEGF/VEGFR, that contribute to downstream ablation-induced tumor growth stimulation are upregulated in the periablational rim surrounding the ablation zone and in the serum after complete and partial RFA of normal and tumor tissues [6, 7, 9,10,11,12]. Within the periablational zone of normal tissue, multiple cell populations, including native hepatocytes and infiltrating myofibroblasts and macrophages, contribute to increased expression of factors that contribute to off-target distant tumor stimulation post-ablation [14]. Residual viable tumor cells have been identified in up to 20% of clinical cases following ablation [15, 16], confirming the need to further study the potential influence of heated tumor cells on production of pro-oncogenic factors following ablation

Methods
Results
Conclusion
Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call