Truong Linh-Huyen, Pauklin Siim
Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Old Road, University of Oxford, Oxford OX3 7LD, UK.
Cancers (Basel). 2021 Oct 8;13(19):5028. doi: 10.3390/cancers13195028.
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal human solid tumors, despite great efforts in improving therapeutics over the past few decades. In PDAC, the distinct characteristic of the tumor microenvironment (TME) is the main barrier for developing effective treatments. PDAC TME is characterized by a dense stroma, cancer-associated fibroblasts, and immune cells populations that crosstalk to the subpopulations of neoplastic cells that include cancer stem cells (CSCs). The heterogeneity in TME is also exhibited in the diversity and dynamics of acellular components, including the Extracellular matrix (ECM), cytokines, growth factors, and secreted ligands to signaling pathways. These contribute to drug resistance, metastasis, and relapse in PDAC. However, clinical trials targeting TME components have often reported unexpected results and still have not benefited patients. The failures in those trials and various efforts to understand the PDAC biology demonstrate the highly heterogeneous and multi-faceted TME compositions and the complexity of their interplay within TME. Hence, further functional and mechanistic insight is needed. In this review, we will present a current understanding of PDAC biology with a focus on the heterogeneity in TME and crosstalk among its components. We also discuss clinical challenges and the arising therapeutic opportunities in PDAC research.
尽管在过去几十年里人们为改进治疗方法付出了巨大努力，但胰腺导管腺癌（PDAC）仍然是最致命的人类实体瘤之一。在PDAC中，肿瘤微环境（TME）的独特特征是开发有效治疗方法的主要障碍。PDAC的TME以密集的基质、癌症相关成纤维细胞和免疫细胞群体为特征，这些细胞与包括癌症干细胞（CSCs）在内的肿瘤细胞亚群相互作用。TME的异质性还表现在无细胞成分的多样性和动态性上，包括细胞外基质（ECM）、细胞因子、生长因子以及信号通路的分泌配体。这些因素导致了PDAC的耐药性、转移和复发。然而，针对TME成分的临床试验常常报告出意想不到的结果，且仍未使患者受益。这些试验的失败以及为了解PDAC生物学所做的各种努力表明，TME的组成高度异质且多面，其内部相互作用复杂。因此，需要进一步深入了解其功能和机制。在这篇综述中，我们将阐述对PDAC生物学的当前认识，重点关注TME的异质性及其成分之间的相互作用。我们还将讨论PDAC研究中的临床挑战和新出现的治疗机会。
