Abstract

Purpose

While systemic tumor-stimulating effects can occur following ablation of normal liver linked to the IL-6/HGF/VEGF cytokinetic pathway, the potential for tumor cells themselves to produce these unwanted effects is currently unknown. Here, we study whether partially treated tumors induce increased tumor growth post-radiofrequency thermal ablation (RFA).

Methods

Tumor growth was measured in three immunocompetent, syngeneic tumor models following partial RFA of the target tumor (in subcutaneous CT26 and MC38 mouse colorectal adenocarcinoma, N = 14 each); and in a distant untreated tumor following partial RFA of target subcutaneous R3230 rat breast adenocarcinoma (N = 12). Tumor cell proliferation (ki-67) and microvascular density (CD34) was assessed. In R3230 tumors, in vivo mechanism of action was assessed following partial RFA by measuring IL-6, HGF, and VEGF expression (ELISA) and c-Met protein (Western blot). Finally, RFA was performed in R3230 tumors with adjuvant c-Met kinase inhibitor or VEGF receptor inhibitor (at 3 days post-RFA, N = 3/arm, total N = 12).

Results

RFA stimulated tumor growth in vivo in residual, incompletely treated surrounding CT26 and MC38 tumor at 3–6 days (p < 0.01). In R3230, RFA increased tumor growth in distant tumor 7 days post treatment compared to controls (p < 0.001). For all models, Ki-67 and CD34 were elevated (p < 0.01, all comparisons). IL-6, HGF, and VEGF were also upregulated post incomplete tumor RFA (p < 0.01). These markers were suppressed to baseline levels with adjuvant c-MET kinase or VEGF receptor inhibition.

Conclusion

Incomplete RFA of a target tumor can sufficiently stimulate residual tumor cells to induce accelerated growth of distant tumors via the IL-6/c-Met/HGF pathway and VEGF production.

中文翻译：

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肿瘤的不完全热消融可促进肿瘤发生

摘要

目的

尽管在消融与IL-6 / HGF / VEGF细胞动力学途径相关的正常肝脏后会发生全身性肿瘤刺激作用，但目前尚不清楚肿瘤细胞自身产生这些不良作用的可能性。在这里，我们研究是否部分治疗的肿瘤诱导射频热消融（RFA）后增加的肿瘤生长。

方法

在靶肿瘤部分RFA后，在三种具有免疫功能的同基因肿瘤模型中测量肿瘤的生长（在皮下CT26和MC38小鼠结直肠腺癌中，N  = 14）；在目标皮下R3230大鼠乳腺腺癌的部分RFA后发生的远处未治疗肿瘤中（N  = 12）。评估肿瘤细胞增殖（ki-67）和微血管密度（CD34）。在R3230肿瘤中，通过测量IL-6，HGF和VEGF表达（ELISA）和c-Met蛋白（Western blot），在部分RFA后评估了体内作用机制。最后，在R3230肿瘤中用辅助c-Met激酶抑制剂或VEGF受体抑制剂进行RFA（RFA后3天，N  = 3 /臂，总N  = 12）。

结果

RFA在3–6天时在残留的，未完全治疗的CT26和MC38肿瘤周围刺激体内肿瘤生长（p  <0.01）。在R3230中，与对照组相比，RFA在治疗7天后增加了远处肿瘤的肿瘤生长（p  <0.001）。对于所有模型，Ki-67和CD34均升高（p  <0.01，所有比较）。IL-6，HGF和VEGF在不完全的肿瘤RFA后也上调（p  <0.01）。这些标志物通过辅助c-MET激酶或VEGF受体抑制被抑制到基线水平。

结论

目标肿瘤的不完全RFA可以充分刺激残留的肿瘤细胞，从而通过IL-6 / c-Met / HGF途径和VEGF产生来诱导远处肿瘤的加速生长。