Antitumor effects of heating on human renal cancer cells in vivo

Objective: Reported to be a useful and minimally invasive treatment for small renal cancers, radiofrequency ablation (RFA) typically induces tissue necrosis via heat coagulation at 100°C. Some reports, however, indicate that the propagation of heat to surrounding organs generates complications. With this in mind, we examined the antitumor effects of heat treatment in vivo at temperatures below those typically used in RFA. Materials and Methods: We injected Caki-1 (human renal cell carcinoma cell line) subcutaneously into the backs of 3-week-old female BALB/c-nu nude mice. The resulting tumors were heated at 45°C, 55°C, or 65°C for 5 or 10 minutes with heat therapeutic equipment designed for research use and heat needles. We subsequently measured tumor volumes at 1, 2, 4, 7, 14, 21, and 28 days after heat treatment. Additionally, the resected tumor was histologically evaluated. Results: Tumor volumes in the nonheated group (tumors subjected only to needle-puncture) gradually increased, reaching approximately 3.5 times the baseline volume on day 28 after heat treatment. In the groups subjected to heat treatment at 45°C for 5 and 10 minutes, the treatment inhibited tumor volume by day 7, but tumors increased rapidly thereafter. In contrast, tumors shrank in the groups subjected to heat treatment at 55°C and 65°C. In the group subjected to heat treatment at 65°C for 10 minutes, maximum reductions in tumor volume—to approximately 15% of the volume observed immediately after the puncture—were obtained on day 28. We examined the constitutive expression of nicotinamide adenine dinucleotide phosphate (NADPH) to evaluate cell function. Heat treatment at 45°C had minimal effect on the constitutive expression of NADPH in cells. While the area of the site exhibiting diminished cell function after heat treatment at 55°C or 65°C increased on day 1, this function was subsequently restored. Heat treatment resulted in a slight increase in apoptosis in the focal area surrounding the tumor compared to the control group. In the groups subjected to heat treatment at 45°C, hematoxylin and eosin (H&E) staining showed inflammatory cell infiltration on day 4 and subsequent narrow range of necrosis. In the groups subjected to heat treatment at 55°C and 65°C, inflammatory cell infiltration occurred earlier and necrosis was more extensive than in the 45°C-heated group. Conclusion: Heat treatment at temperatures below those used in RFA as currently implemented in clinical settings has antitumor effects on renal cancer cells. In addition to direct coagulation necrosis induced by heat treatment, secondary inflammatory cell infiltration may be involved in the enhancement of these antitumor effects. Our results should lead to the development of local treatments that feature minimal complications.