Physics of Life Processes, Huygens-Kamerlingh Onnes Laboratory, Leiden University, Leiden, The Netherlands.
Department of Medical Oncology, VU University Medical Center Amsterdam, Amsterdam, The Netherlands; Cancer Pharmacology Lab, AIRC Start-Up Unit, University Hospital of Pisa, Pisa, Italy.
Drug Resist Updat. 2017 Mar;31:43-51. doi: 10.1016/j.drup.2017.07.001. Epub 2017 Jul 24.
Pancreatic ductal adenocarcinoma (PDAC) is a highly chemoresistant malignancy. This chemoresistant phenotype has been historically associated with genetic factors. Major biomedical research efforts were concentrated that resulted in the identification of subtypes characterized by specific genetic lesions and gene expression signatures that suggest important biological differences. However, to date, these distinct differences could not be exploited for therapeutic interventions. Apart from these genetic factors, desmoplasia and tumor microenvironment have been recognized as key contributors to PDAC chemoresistance. However, while several strategies targeting tumor-stroma have been explored including drugs against members of the Hedgehog family, they failed to meet the expectations in the clinical setting. These unsatisfactory clinical results suggest that, an important link between genetics and the influence of tumor microenvironment on PDAC chemoresistance remains to be elucidated. In this respect, mechanobiology is an emerging multidisciplinary field that encompasses cell and developmental biology as well as biophysics and bioengineering. Herein we provide a comprehensive overview of the key players in pancreatic cancer chemoresistance from the perspective of mechanobiology, and discuss novel experimental avenues such as elastic micropillar arrays that could provide fresh insights for the development of mechanobiology-targeted therapeutic approaches (know as mechanopharmacology) to overcome anticancer drug resistance in pancreatic cancer.
胰腺导管腺癌 (PDAC) 是一种高度耐药的恶性肿瘤。这种耐药表型在历史上与遗传因素有关。主要的生物医学研究集中在确定具有特定遗传病变和基因表达特征的亚型上，这些特征表明存在重要的生物学差异。然而，迄今为止，这些明显的差异还不能用于治疗干预。除了这些遗传因素外，细胞外基质和肿瘤微环境也被认为是 PDAC 耐药的关键因素。然而，尽管已经探索了几种针对肿瘤-基质的策略，包括针对 Hedgehog 家族成员的药物，但它们在临床环境中的效果并不理想。这些令人不满意的临床结果表明，遗传因素与肿瘤微环境对 PDAC 耐药性的影响之间的重要联系仍有待阐明。在这方面，机械生物学是一个新兴的多学科领域，涵盖了细胞和发育生物学以及生物物理学和生物工程。本文从机械生物学的角度全面概述了胰腺癌细胞耐药性的关键因素，并讨论了新的实验途径，如弹性微柱阵列，这可能为开发针对机械生物学的治疗方法（称为机械药理学）提供新的见解，以克服胰腺癌中的抗癌药物耐药性。
