Department of Urology, Ludwig-Maximilians-Universität, Munich, Germany.
Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Pathology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Cancer Sci. 2021 May;112(5):1987-1996. doi: 10.1111/cas.14878. Epub 2021 Mar 31.
Signaling pathways that drive bladder cancer (BC) progression may be promising and specific targets for systemic therapy. Here, we investigated the clinical significance and targetability of NOTCH and mitogen-activated protein kinase (MAPK) signaling for this aggressive malignancy. We assessed NOTCH1 and MAPK activity in 222 stage III and IV BC specimens of patients that had undergone radical cystectomy, and tested for clinical associations including cancer-specific and overall survival. We examined therapeutic effects of NOTCH and MAPK repression in a murine xenograft model of human bladder cancer cells and evaluated tumor growth and tumor cell plasticity. In BC, NOTCH1 and MAPK signaling marked two distinct tumor cell subpopulations. The combination of high NOTCH1 and high MAPK activity indicated poor cancer-specific and overall survival in univariate and multivariate analyses. Inhibition of NOTCH and MAPK in BC xenografts in vivo depleted targeted tumor cell subpopulations and revealed strong plasticity in signaling pathway activity. Combinatorial inhibition of NOTCH and MAPK signaling most strongly suppressed tumor growth. Our findings indicate that tumor cell subpopulations with high NOTCH and MAPK activity both contribute to tumor progression. Furthermore, we propose a new concept for BC therapy, which advocates specific and simultaneous targeting of these different tumor cell subpopulations through combined NOTCH and MAPK inhibition.
驱动膀胱癌（BC）进展的信号通路可能是有前途的和特定的系统治疗靶点。在这里，我们研究了 NOTCH 和丝裂原活化蛋白激酶（MAPK）信号在这种侵袭性恶性肿瘤中的临床意义和靶向性。我们评估了 222 例接受根治性膀胱切除术的 III 期和 IV 期 BC 标本中的 NOTCH1 和 MAPK 活性，并测试了包括癌症特异性和总体生存率在内的临床相关性。我们在人类膀胱癌细胞的小鼠异种移植模型中研究了 NOTCH 和 MAPK 抑制的治疗效果，并评估了肿瘤生长和肿瘤细胞可塑性。在 BC 中，NOTCH1 和 MAPK 信号标记了两个不同的肿瘤细胞亚群。在单因素和多因素分析中，高 NOTCH1 和高 MAPK 活性的组合表明癌症特异性和总体生存率较差。在体内 BC 异种移植中抑制 NOTCH 和 MAPK 耗尽了靶向肿瘤细胞亚群，并显示出信号通路活性的强烈可塑性。NOTCH 和 MAPK 信号的联合抑制最强烈地抑制了肿瘤生长。我们的研究结果表明，具有高 NOTCH 和 MAPK 活性的肿瘤细胞亚群均有助于肿瘤进展。此外，我们提出了一种新的 BC 治疗概念，即通过联合 NOTCH 和 MAPK 抑制特异性和同时靶向这些不同的肿瘤细胞亚群。
