Kats-Ugurlu Gursah, Oosterwijk Egbert, Muselaers Stijn, Oosterwijk-Wakka Jeannette, Hulsbergen-van de Kaa Christina, de Weijert Mirjam, van Krieken Han, Desar Ingrid, van Herpen Carla, Maass Cathy, de Waal Rob, Mulders Peter, Leenders William
Department of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Neoplasia. 2014 Mar;16(3):221-8. doi: 10.1016/j.neo.2014.03.007. Epub 2014 Apr 13.
Clear cell renal cell carcinoma (ccRCC) is characterized by high constitutive vascular endothelial growth factor A (VEGF-A) production that induces a specific vascular phenotype. We previously reported that this phenotype may allow shedding of multicellular tumor fragments into the circulation, possibly contributing to the development of metastasis. Disruption of this phenotype through inhibition of VEGF signaling may therefore result in reduced shedding of tumor fragments and improved prognosis. To test this hypothesis, we investigated the effect of neoadjuvant sorafenib treatment on tumor cluster shedding.
Patients with renal cancer (n = 10, of which 8 have ccRCC) received sorafenib for 4 weeks before tumor nephrectomy. The resection specimens were perfused, and the perfundate was examined for the presence of tumor clusters. Effects of the treatment on the tumor morphology and overall survival were investigated (follow-up of 2 years) and compared with a carefully matched control group.
Neoadjuvant sorafenib treatment induced extensive ischemic tumor necrosis and, as expected, destroyed the characteristic ccRCC vascular phenotype. In contrast to the expectation, vital groups of tumor cells with high proliferation indices were detected in postsurgical renal venous outflow in 75% of the cases. Overall survival of patients receiving neoadjuvant treatment was reduced compared to a control group, matched with regard to prognostic parameters.
These results suggest that neoadjuvant sorafenib therapy for ccRCC does not prevent shedding of tumor fragments. Although this is a nonrandomized study with a small patient group, our results suggest that neoadjuvant treatment may worsen survival through as yet undefined mechanisms.
透明细胞肾细胞癌（ccRCC）的特征是组成型血管内皮生长因子A（VEGF-A）产生水平高，可诱导特定的血管表型。我们之前报道过，这种表型可能会使多细胞肿瘤碎片脱落进入循环系统，这可能有助于转移的发生。因此，通过抑制VEGF信号传导来破坏这种表型可能会减少肿瘤碎片的脱落并改善预后。为了验证这一假设，我们研究了新辅助索拉非尼治疗对肿瘤团块脱落的影响。
肾癌患者（n = 10，其中8例为ccRCC）在肿瘤肾切除术前接受索拉非尼治疗4周。对切除标本进行灌注，并检查灌注液中是否存在肿瘤团块。研究了该治疗对肿瘤形态和总生存期的影响（随访2年），并与精心匹配的对照组进行比较。
新辅助索拉非尼治疗导致广泛的缺血性肿瘤坏死，并且正如预期的那样，破坏了ccRCC的特征性血管表型。与预期相反，在75%的病例中，术后肾静脉流出物中检测到具有高增殖指数的存活肿瘤细胞群。与对照组相比，接受新辅助治疗的患者的总生存期缩短，对照组在预后参数方面相匹配。
这些结果表明，ccRCC的新辅助索拉非尼治疗不能防止肿瘤碎片的脱落。尽管这是一项针对小患者群体的非随机研究，但我们的结果表明，新辅助治疗可能通过尚未明确的机制使生存期恶化。
