Thomas Anita, Slade Kimberly Sue, Blaheta Roman A, Markowitsch Sascha D, Stenzel Philipp, Tagscherer Katrin E, Roth Wilfried, Schindeldecker Mario, Michaelis Martin, Rothweiler Florian, Cinatl Jaroslav, Dotzauer Robert, Vakhrusheva Olesya, Albersen Maarten, Haferkamp Axel, Juengel Eva, Cinatl Jindrich, Tsaur Igor
Department of Urology and Pediatric Urology, University Medicine Mainz, 55131 Mainz, Germany.
Department of Pathology, University Medicine Mainz, 55131 Mainz, Germany.
Cancers (Basel). 2022 Mar 25;14(7):1683. doi: 10.3390/cancers14071683.
Whereas the lack of biomarkers in penile cancer (PeCa) impedes the development of efficacious treatment protocols, preliminary evidence suggests that c-MET and associated signaling elements may be dysregulated in this disorder. In the following study, we investigated whether c-MET and associated key molecular elements may have prognostic and therapeutic utility in PeCa. Formalin-fixed, paraffin-embedded tumor tissue from therapy-naïve patients with invasive PeCa was used for tissue microarray (TMA) analysis. Immunohistochemical staining was performed to determine the expression of the proteins c-MET, PPARg, β-catenin, snail, survivin, and n-MYC. In total, 94 PeCa patients with available tumor tissue were included. The median age was 64.9 years. High-grade tumors were present in 23.4%, and high-risk HPV was detected in 25.5%. The median follow-up was 32.5 months. High expression of snail was associated with HPV-positive tumors. Expression of β-catenin was inversely associated with grading. In both univariate COX regression analysis and the log-rank test, an increased expression of PPARg and c-MET was predictive of inferior disease-specific survival (DSS). Moreover, in multivariate analysis, a higher expression of c-MET was independently associated with worse DSS. Blocking c-MET with cabozantinib and tivantinib induced a significant decrease in viability in the primary PeCa cell line UKF-PeC3 isolated from the tumor tissue as well as in cisplatin- and osimertinib-resistant sublines. Strikingly, a higher sensitivity to tivantinib could be detected in the latter, pointing to the promising option of utilizing this agent in the second-line treatment setting.
阴茎癌（PeCa）中生物标志物的缺乏阻碍了有效治疗方案的开发，而初步证据表明，c-MET及相关信号元件在这种疾病中可能失调。在以下研究中，我们调查了c-MET及相关关键分子元件在PeCa中是否具有预后和治疗价值。来自未经治疗的浸润性PeCa患者的福尔马林固定、石蜡包埋肿瘤组织用于组织芯片（TMA）分析。进行免疫组织化学染色以确定蛋白质c-MET、PPARg、β-连环蛋白、蜗牛蛋白、生存素和n-MYC的表达。总共纳入了94例有可用肿瘤组织的PeCa患者。中位年龄为64.9岁。23.4%为高级别肿瘤，25.5%检测到高危人乳头瘤病毒（HPV）。中位随访时间为32.5个月。蜗牛蛋白的高表达与HPV阳性肿瘤相关。β-连环蛋白的表达与分级呈负相关。在单变量COX回归分析和对数秩检验中，PPARg和c-MET表达增加均预示疾病特异性生存（DSS）较差。此外，在多变量分析中，c-MET的高表达与更差的DSS独立相关。用卡博替尼和替万替尼阻断c-MET可导致从肿瘤组织分离的原发性PeCa细胞系UKF-PeC3以及顺铂和奥希替尼耐药亚系的活力显著下降。引人注目的是，在后者中可检测到对替万替尼更高的敏感性，这表明在二线治疗中使用该药物是一个有前景的选择。
