Knapp Deborah W, Dhawan Deepika, Ramos-Vara José A, Ratliff Timothy L, Cresswell Gregory M, Utturkar Sagar, Sommer Breann C, Fulkerson Christopher M, Hahn Noah M
Department of Veterinary Clinical Sciences, Purdue University, West Lafayette, IN, United States.
Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN, United States.
Front Oncol. 2020 Jan 21;9:1493. doi: 10.3389/fonc.2019.01493. eCollection 2019.
There is a great need to improve the outlook for people facing urinary bladder cancer, especially for patients with invasive urothelial carcinoma (InvUC) which is lethal in 50% of cases. Improved outcomes for patients with InvUC could come from advances on several fronts including emerging immunotherapies, targeted therapies, and new drug combinations; selection of patients most likely to respond to a given treatment based on molecular subtypes, immune signatures, and other characteristics; and prevention, early detection, and early intervention. Progress on all of these fronts will require clinically relevant animal models for translational research. The animal model(s) should possess key features that drive success or failure of cancer drugs in humans including tumor heterogeneity, genetic-epigenetic crosstalk, immune cell responsiveness, invasive and metastatic behavior, and molecular subtypes (e.g., luminal, basal). Experimental animal models, while essential in bladder cancer research, do not possess these collective features to accurately predict outcomes in humans. These key features, however, are present in naturally-occurring InvUC in pet dogs. Canine InvUC closely mimics muscle-invasive bladder cancer in humans in cellular and molecular features, molecular subtypes, immune response patterns, biological behavior (sites and frequency of metastasis), and response to therapy. Thus, dogs can offer a highly relevant animal model to complement other models in research for new therapies for bladder cancer. Clinical treatment trials in pet dogs with InvUC are considered a win-win-win scenario; the individual dog benefits from effective treatment, the results are expected to help other dogs, and the findings are expected to translate to better treatment outcomes in humans. In addition, the high breed-associated risk for InvUC in dogs (e.g., 20-fold increased risk in Scottish Terriers) offers an unparalleled opportunity to test new strategies in primary prevention, early detection, and early intervention. This review will provide an overview of canine InvUC, summarize the similarities (and differences) between canine and human InvUC, and provide evidence for the expanding value of this canine model in bladder cancer research.
迫切需要改善膀胱癌患者的预后，尤其是浸润性尿路上皮癌（InvUC）患者，此类患者的致死率达50%。InvUC患者预后的改善可能来自多个方面的进展，包括新兴的免疫疗法、靶向疗法和新的药物组合；根据分子亚型、免疫特征和其他特征选择最有可能对特定治疗产生反应的患者；以及预防、早期检测和早期干预。在所有这些方面取得进展都需要用于转化研究的临床相关动物模型。该动物模型应具备决定癌症药物在人体中成败的关键特征，包括肿瘤异质性、遗传-表观遗传相互作用、免疫细胞反应性、侵袭和转移行为以及分子亚型（如管腔型、基底型）。实验动物模型虽然在膀胱癌研究中必不可少，但并不具备这些共同特征来准确预测人体预后。然而，这些关键特征存在于宠物狗自然发生的InvUC中。犬类InvUC在细胞和分子特征、分子亚型、免疫反应模式、生物学行为（转移部位和频率）以及对治疗的反应方面与人类肌肉浸润性膀胱癌极为相似。因此，在膀胱癌新疗法的研究中，可以用狗提供高度相关的动物模型来补充其他模型。对患有InvUC的宠物狗进行临床治疗试验被认为是一种三赢的局面；每只狗都能从有效治疗中受益，预期结果将有助于其他狗，并且这些发现有望转化为人类更好的治疗效果。此外，狗患InvUC的品种相关风险很高（例如，苏格兰梗的患病风险增加20倍），这为测试一级预防、早期检测和早期干预的新策略提供了无与伦比的机会。本综述将概述犬类InvUC，总结犬类和人类InvUC之间的异同，并为该犬类模型在膀胱癌研究中不断扩大的价值提供证据。
