Tumor Microenvironment Features and Chemoresistance in Pancreatic Ductal Adenocarcinoma: Insights into Targeting Physicochemical Barriers and Metabolism as Therapeutic Approaches.
Tumor Microenvironment Features and Chemoresistance in Pancreatic Ductal Adenocarcinoma: Insights into Targeting Physicochemical Barriers and Metabolism as Therapeutic Approaches.
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DOI：
10.3390/cancers13236135
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发表时间：
2021-12-06
期刊：
影响因子：
5.2
通讯作者：
Cardone RA
中科院分区：
文献类型：
--
作者：
Carvalho TMA;Di Molfetta D;Greco MR;Koltai T;Alfarouk KO;Reshkin SJ;Cardone RA
胰腺导管腺癌（PDAC）预后极差。缺乏早期诊断和缺乏合适的生物标志物加上对现有治疗方案的耐药性使PDAC成为最致命的癌症之一。尽管在诊断和治疗方面取得了进展，但PDAC的预后仍然令人沮丧。PDAC有一个突出的促结缔组织增生基质微环境，包括一个致密的细胞外基质连同一系列的活化细胞类型，缺氧，和酸性细胞外pH值。这种活化促结缔组织增生基质妥协的治疗，但尽管认识到其重要性，它还没有被全面研究在这方面的作用。此外，PDAC代谢重编程也被发现是治疗失败的关键因素之一。在这里，我们批判性地回顾了各种基质成分在确定对现有治疗药物的耐药性方面的作用，希望其全面的理解，如果在适当的联合治疗中使用，可能会使这种恶性肿瘤更易于管理。目前，PDAC患者的中位总生存期很少超过1年，总5年生存率约为9%。这些数字预计将在未来恶化，由于缺乏了解的因素参与其强大的耐药性。化疗仍然是大多数PDAC患者的唯一治疗选择;然而，可用的治疗策略是不够的。化疗耐药的相关因素包括促结缔组织增生基质的形成，其可重新编程细胞代谢，两者均导致对治疗的反应受损。PDAC基质由免疫细胞、内皮细胞和癌症相关成纤维细胞组成，这些细胞嵌入与缺氧和酸性细胞外pH相关的突出、致密的细胞外基质中。虽然PDAC启动涉及多个基因突变，但这种促纤维增生基质在推动进展、转移和化疗耐药性方面发挥重要作用。阐明PDAC耐药的机制是设计新方法以提高患者生存率的先决条件。在这篇综述中，我们提供了一个概述的基质功能，以及它们如何有助于PDAC治疗的化疗耐药性。通过强调PDAC治疗中基质室作用的新范例，我们希望激发旨在改善患者结局的新概念。
Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor prognosis. The lack of early diagnosis and the absence of suitable biomarkers coupled with resistance to available therapeutic options has made PDAC one of the deadliest cancers. Despite advances in diagnostics and therapeutics, the prognosis of PDAC remains dismal. PDAC has a prominent desmoplastic stromal microenvironment that includes a dense extracellular matrix together with a series of activated cell types, hypoxia, and an acidic extracellular pH. This activated desmoplastic stroma compromises treatments yet, despite the recognition of its importance, it has not been comprehensively studied in this role. Moreover, PDAC metabolic reprogramming has also been found to be one of the key factors involved in treatment failure. Here, we critically review the role of the various stromal components in determining resistance to available therapeutics with the hope that its comprehensive understanding, if employed in the appropriate combination therapy, may make this recalcitrant cancer more manageable. Currently, the median overall survival of PDAC patients rarely exceeds 1 year and has an overall 5-year survival rate of about 9%. These numbers are anticipated to worsen in the future due to the lack of understanding of the factors involved in its strong chemoresistance. Chemotherapy remains the only treatment option for most PDAC patients; however, the available therapeutic strategies are insufficient. The factors involved in chemoresistance include the development of a desmoplastic stroma which reprograms cellular metabolism, and both contribute to an impaired response to therapy. PDAC stroma is composed of immune cells, endothelial cells, and cancer-associated fibroblasts embedded in a prominent, dense extracellular matrix associated with areas of hypoxia and acidic extracellular pH. While multiple gene mutations are involved in PDAC initiation, this desmoplastic stroma plays an important role in driving progression, metastasis, and chemoresistance. Elucidating the mechanisms underlying PDAC resistance are a prerequisite for designing novel approaches to increase patient survival. In this review, we provide an overview of the stromal features and how they contribute to the chemoresistance in PDAC treatment. By highlighting new paradigms in the role of the stromal compartment in PDAC therapy, we hope to stimulate new concepts aimed at improving patient outcomes.
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影响因子：
--
作者：
Anderson M;Marayati R;Moffitt R;Yeh JJ
通讯作者：
Yeh JJ
影响因子：
3
作者：
Altan, Bolag;Kaira, Kyoichi;Shirabe, Ken
通讯作者：
Shirabe, Ken
影响因子：
29.4
作者：
Bachem, MG;Schneider, E;Adler, G
通讯作者：
Adler, G
影响因子：
24.5
作者：
Apte, MV;Haber, PS;Wilson, JS
通讯作者：
Wilson, JS
影响因子：
8.8
作者：
Anastasiou D
通讯作者：
Anastasiou D