Alday-Parejo Begoña, Stupp Roger, Rüegg Curzio
Pathology Unit, Department of Oncology, Microbiology and Immunology, Faculty of Science and Medicine, University of Fribourg, Chemin du Musée 18, Per 17, CH-1700 Fribourg, Switzerland.
Departments of Neurological Surgery, Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Neurology and Medicine, Feinberg School of Medicine, Northwestern University, 676 N St Clair St, Suite 2210, Chicago, IL 60611, USA.
Cancers (Basel). 2019 Jul 12;11(7):978. doi: 10.3390/cancers11070978.
Correlative clinical evidence and experimental observations indicate that integrin adhesion receptors, in particular those of the αV family, are relevant to cancer cell features, including proliferation, survival, migration, invasion, and metastasis. In addition, integrins promote events in the tumor microenvironment that are critical for tumor progression and metastasis, including tumor angiogenesis, matrix remodeling, and the recruitment of immune and inflammatory cells. In spite of compelling preclinical results demonstrating that the inhibition of integrin αVβ3/αVβ5 and α5β1 has therapeutic potential, clinical trials with integrin inhibitors targeting those integrins have repeatedly failed to demonstrate therapeutic benefits in cancer patients. Here, we review emerging integrin functions and their proposed contribution to tumor progression, discuss preclinical evidence of therapeutic significance, revisit clinical trial results, and consider alternative approaches for their therapeutic targeting in oncology, including targeting integrins in the other cells of the tumor microenvironment, e.g., cancer-associated fibroblasts and immune/inflammatory cells. We conclude that integrins remain a valid target for cancer therapy; however, agents with better pharmacological properties, alternative models for their preclinical evaluation, and innovative combination strategies for clinical testing (e.g., together with immuno-oncology agents) are needed.
相关临床证据和实验观察表明，整合素黏附受体，尤其是αV家族的那些受体，与癌细胞的特征相关，包括增殖、存活、迁移、侵袭和转移。此外，整合素促进肿瘤微环境中对肿瘤进展和转移至关重要的事件，包括肿瘤血管生成、基质重塑以及免疫和炎症细胞的募集。尽管有令人信服的临床前结果表明抑制整合素αVβ3/αVβ5和α5β1具有治疗潜力，但针对这些整合素的整合素抑制剂的临床试验一再未能在癌症患者中证明有治疗益处。在此，我们综述整合素的新功能及其对肿瘤进展的潜在作用，讨论治疗意义的临床前证据，回顾临床试验结果，并考虑在肿瘤学中针对它们进行治疗靶向的替代方法，包括靶向肿瘤微环境中的其他细胞，如癌症相关成纤维细胞和免疫/炎症细胞中的整合素。我们得出结论，整合素仍然是癌症治疗的有效靶点；然而，需要具有更好药理学特性的药物、用于临床前评估的替代模型以及用于临床试验的创新联合策略（例如与免疫肿瘤学药物联合使用）。
