Stellate Cells Aid Growth-Permissive Metabolic Reprogramming and Promote Gemcitabine Chemoresistance in Pancreatic Cancer.
Stellate Cells Aid Growth-Permissive Metabolic Reprogramming and Promote Gemcitabine Chemoresistance in Pancreatic Cancer.
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DOI：
10.3390/cancers13040601
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发表时间：
2021-02-03
期刊：
影响因子：
5.2
通讯作者：
Gladhaug IP
中科院分区：
文献类型：
--
作者：
Amrutkar M;Gladhaug IP
绝大多数（超过90%）胰腺导管腺癌（PDAC）患者在发现疾病后不到五年内死亡，尽管最近的治疗进展。预后差与诊断晚、疾病进展快和肿瘤对常规化疗耐药有关。PDAC肿瘤组织的特征在于致密的纤维化和差的营养可用性。肿瘤的很大一部分由间质成纤维细胞组成，即胰腺星状细胞（PSC），已知其以多种方式促进肿瘤进展。PSC已被证明是一种替代能源，诱导耐药性，并抑制肿瘤细胞中的药物利用率，然而，潜在的确切分子机制仍然未知。在这篇文献综述中，我们讨论了最近关于PSC通过肿瘤代谢变化对PDAC总体进展的贡献以及这与治疗耐药性的关系。胰腺导管腺癌（PDAC），也称为胰腺癌（PC），其特征是总体预后不良，五年生存率低于10%。肿瘤的特征性特征是存在显著的促结缔组织增生性基质反应、代谢改变和对癌症药物（包括PDAC化疗的支柱吉西他滨）的严重耐药性。胰腺星状细胞（PSC）构成PDAC基质的主要细胞成分。PSC是细胞外基质组装所必需的，并形成肿瘤生长的支持性小生境。各种细胞因子和生长因子通过自分泌和旁分泌机制诱导PSC活化，这反过来又促进肿瘤的整体生长和转移并诱导化学抗性。为了在PDAC的营养贫乏、缺氧环境中维持生长和存活，肿瘤细胞通过几种非常规方式满足其高能量需求，这一过程通常被称为代谢重编程。越来越多的证据表明，活化的PSC不仅有助于PDAC的治疗抗性表型，而且还充当肿瘤细胞的营养供应者。然而，代谢重编程和PDAC中获得性治疗抗性之间的精确分子联系仍然难以捉摸。这篇综述强调了最近的研究结果，表明PSC在帮助PDAC的生长允许的代谢重编程和吉西他滨化疗耐药性的重要性。
The great majority, more than 90%, of patients with pancreatic ductal adenocarcinoma (PDAC) die within less than five years after detection of the disease, despite recent treatment advances. The poor prognosis is related to late diagnosis, aggressive disease progression, and tumor resistance to conventional chemotherapy. PDAC tumor tissue is characterized by dense fibrosis and poor nutrient availability. A large portion of the tumor is made up of stromal fibroblasts, the pancreatic stellate cells (PSCs), which are known to contribute to tumor progression in several ways. PSCs have been shown to act as an alternate energy source, induce drug resistance, and inhibit drug availability in tumor cells, however, the underlying exact molecular mechanisms remain unknown. In this literature review, we discuss recent available knowledge about the contributions of PSCs to the overall progression of PDAC via changes in tumor metabolism and how this is linked to therapy resistance. Pancreatic ductal adenocarcinoma (PDAC), also known as pancreatic cancer (PC), is characterized by an overall poor prognosis and a five-year survival that is less than 10%. Characteristic features of the tumor are the presence of a prominent desmoplastic stromal response, an altered metabolism, and profound resistance to cancer drugs including gemcitabine, the backbone of PDAC chemotherapy. The pancreatic stellate cells (PSCs) constitute the major cellular component of PDAC stroma. PSCs are essential for extracellular matrix assembly and form a supportive niche for tumor growth. Various cytokines and growth factors induce activation of PSCs through autocrine and paracrine mechanisms, which in turn promote overall tumor growth and metastasis and induce chemoresistance. To maintain growth and survival in the nutrient-poor, hypoxic environment of PDAC, tumor cells fulfill their high energy demands via several unconventional ways, a process generally referred to as metabolic reprogramming. Accumulating evidence indicates that activated PSCs not only contribute to the therapy-resistant phenotype of PDAC but also act as a nutrient supplier for the tumor cells. However, the precise molecular links between metabolic reprogramming and an acquired therapy resistance in PDAC remain elusive. This review highlights recent findings indicating the importance of PSCs in aiding growth-permissive metabolic reprogramming and gemcitabine chemoresistance in PDAC.
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DOI：
10.1083/jcb.201701064
发表时间：
2017-12-04
期刊：
The Journal of cell biology
影响因子：
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10.1073/pnas.1501605112
发表时间：
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影响因子：
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