Apoptosis in the Pancreatic Cancer Tumor Microenvironment-The Double-Edged Sword of Cancer-Associated Fibroblasts.
Apoptosis in the Pancreatic Cancer Tumor Microenvironment-The Double-Edged Sword of Cancer-Associated Fibroblasts.
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DOI：
10.3390/cells10071653
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发表时间：
2021-07-01
期刊：
影响因子：
6
通讯作者：
Beatson R
中科院分区：
文献类型：
--
作者：
Pfeifer E;Burchell JM;Dazzi F;Sarker D;Beatson R
胰腺导管腺癌（PDAC）预后差。这归因于疾病在呈现时已经是晚期并且具有特别侵袭性的肿瘤生物学。PDAC肿瘤微环境（TME）的特征在于致密的促结缔组织增生基质，主要由癌症相关成纤维细胞（CAF）、细胞外基质（ECM）和显示免疫抑制表型的免疫细胞组成。由于诊断的晚期、免疫效应细胞的耗尽和缺乏可操作的基因组靶点，标准治疗仍然是诱导肿瘤的方案，如化疗。巧合的是，已经出现的是，直接诱导癌细胞的凋亡可以在TME中促进致癌过程，包括CAF和免疫细胞朝向促肿瘤发生表型的教育。细胞毒疗法对CAF的直接作用也可能增强肿瘤发生。由于认识到CAF是PDAC中驱动肿瘤发生的主要细胞类型，具有各种肿瘤支持功能，因此已经努力尝试靶向它们。然而，迄今为止，靶向CAF的努力在临床试验中显示出令人失望的结果。在复杂的单细胞分析的帮助下，现在认识到PDAC中的CAF是具有肿瘤支持和肿瘤抑制功能的异质性群体。因此，在PDAC中靶向CAF是否是有效的治疗策略仍存在争议。在这篇综述中，我们讨论了细胞毒性疗法和诱导PDAC细胞凋亡如何通过周围基质细胞的教育促进肿瘤发生，特别关注靶向CAF产生的潜在促肿瘤结果。此外，我们探索治疗途径，以潜在地避免PDAC CAF中细胞凋亡的致癌作用。
Pancreatic ductal adenocarcinoma (PDAC) is associated with poor prognosis. This is attributed to the disease already being advanced at presentation and having a particularly aggressive tumor biology. The PDAC tumor microenvironment (TME) is characterized by a dense desmoplastic stroma, dominated by cancer-associated fibroblasts (CAF), extracellular matrix (ECM) and immune cells displaying immunosuppressive phenotypes. Due to the advanced stage at diagnosis, the depletion of immune effector cells and lack of actionable genomic targets, the standard treatment is still apoptosis-inducing regimens such as chemotherapy. Paradoxically, it has emerged that the direct induction of apoptosis of cancer cells may fuel oncogenic processes in the TME, including education of CAF and immune cells towards pro-tumorigenic phenotypes. The direct effect of cytotoxic therapies on CAF may also enhance tumorigenesis. With the awareness that CAF are the predominant cell type in PDAC driving tumorigenesis with various tumor supportive functions, efforts have been made to try to target them. However, efforts to target CAF have, to date, shown disappointing results in clinical trials. With the help of sophisticated single cell analyses it is now appreciated that CAF in PDAC are a heterogenous population with both tumor supportive and tumor suppressive functions. Hence, there remains a debate whether targeting CAF in PDAC is a valid therapeutic strategy. In this review we discuss how cytotoxic therapies and the induction of apoptosis in PDAC fuels oncogenesis by the education of surrounding stromal cells, with a particular focus on the potential pro-tumorigenic outcomes arising from targeting CAF. In addition, we explore therapeutic avenues to potentially avoid the oncogenic effects of apoptosis in PDAC CAF.
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影响因子：
11.2
作者：
Bavik, C;Coleman, I;Nelson, PS
通讯作者：
Nelson, PS
影响因子：
7.2
作者：
de Gramont A;Faivre S;Raymond E
通讯作者：
Raymond E
影响因子：
4.3
作者：
Bonuccelli, Gloria;Tsirigos, Aristotelis;Lisanti, Michael P.
通讯作者：
Lisanti, Michael P.
影响因子：
29.4
作者：
Bachem, MG;Schneider, E;Adler, G
通讯作者：
Adler, G
DOI：
10.1158/1078-0432.ccr-18-1955
发表时间：
2019-04-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Bernard V;Semaan A;Huang J;San Lucas FA;Mulu FC;Stephens BM;Guerrero PA;Huang Y;Zhao J;Kamyabi N;Sen S;Scheet PA;Taniguchi CM;Kim MP;Tzeng CW;Katz MH;Singhi AD;Maitra A;Alvarez HA
通讯作者：
Alvarez HA