Department of Surgery I, University of Wuerzburg, Wuerzburg, Germany.
Ann Surg Oncol. 2013 Apr;20(4):1105-13. doi: 10.1245/s10434-012-2784-6. Epub 2013 Mar 2.
In patients with isolated peritoneal carcinomatosis (PC) of gastrointestinal cancer, hyperthermic intraperitoneal chemotherapy (HIPEC) represents a promising treatment option integrated into multimodal concepts. Heat shock proteins (HSP) seem to play a major role in cellular stress during HIPEC therapy. We analyzed differentially hyperthermic conditions and HSPs responsible for cell stress-mediated repair mechanisms in tumor tissues from patients who underwent HIPEC therapy and in an in vitro hyperthermic model.
Tumor tissues from our patient cohort with isolated PC were selected for further analysis when representative material was available before and after HIPEC therapy. To further dissect the role of HSPs under conditions of hyperthermia, gene and protein expression was additionally determined, together with cellular apoptosis and proliferation in human HT-29 colon cancer cells.
Differently up-regulated HSP70/72 and HSP90 gene and protein expression was found in all investigated patient tumors. In vitro studies confirmed observations from clinical tumor analysis as underlying HSP-mediated cell stress mechanisms. Moreover, results from proliferation and apoptosis assays combined with differentiated HSP expression analysis demonstrated the relevance of preselecting specific target temperatures to achieve optimal toxic effects on remaining tumor cells in vivo.
Therapeutic approaches like HIPEC to achieve antiproliferative and apoptosis-inducing cellular effects in patients with PC are negatively influenced by highly conserved HSP mechanisms in tumor cells. This study shows for the first time that specific hyperthermic conditions are necessary to be established to achieve optimal toxic effects on tumor cells during HIPEC therapy, a finding that opens potentially new therapeutic strategies.
在患有胃肠道癌孤立性腹膜癌病（PC）的患者中，腹腔内热灌注化疗（HIPEC）作为一种有前途的治疗选择，与多模式概念相结合。热休克蛋白（HSP）在 HIPEC 治疗期间的细胞应激中似乎起着重要作用。我们分析了不同的高热条件和 HSPs，这些 HSPs 负责在接受 HIPEC 治疗的患者的肿瘤组织中和体外高热模型中与细胞应激介导的修复机制有关。
当有代表性的材料在 HIPEC 治疗前后可用时，我们从患有孤立性 PC 的患者队列中选择肿瘤组织进行进一步分析。为了进一步剖析 HSP 在高热条件下的作用，我们还确定了基因和蛋白质表达，以及人 HT-29 结肠癌细胞的细胞凋亡和增殖。
在所有研究的患者肿瘤中均发现 HSP70/72 和 HSP90 的基因和蛋白质表达不同上调。体外研究证实了临床肿瘤分析中的观察结果，即 HSP 介导的细胞应激机制。此外，增殖和凋亡测定的结果与分化的 HSP 表达分析相结合，表明预先选择特定目标温度对于在体内实现对残留肿瘤细胞的最佳毒性作用具有重要意义。
像 HIPEC 这样的治疗方法旨在在患有 PC 的患者中实现抗增殖和诱导细胞凋亡的细胞效应，但这受到肿瘤细胞中高度保守的 HSP 机制的负面影响。本研究首次表明，需要建立特定的高热条件，以在 HIPEC 治疗期间对肿瘤细胞产生最佳的毒性作用，这一发现为潜在的新治疗策略开辟了可能性。
