Microenvironmental hCAP-18/LL-37 promotes pancreatic ductal adenocarcinoma by activating its cancer stem cell compartment
Microenvironmental hCAP-18/LL-37 promotes pancreatic ductal adenocarcinoma by activating its cancer stem cell compartment
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DOI：
10.1136/gutjnl-2014-308935
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发表时间：
2015-12-01
期刊：
影响因子：
24.5
通讯作者：
Heeschen, Christopher
中科院分区：
文献类型：
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作者：
Sainz, Bruno, Jr.;Alcala, Sonia;Heeschen, Christopher
目的肿瘤基质/微环境不仅为肿瘤的发展提供结构支持，更重要的是它为癌症干细胞（CSC）提供调节其自我更新和转移潜力的线索。对于胰腺导管腺癌 (PDAC) 来说确实如此，其中肿瘤相关成纤维细胞、胰腺星状细胞和免疫细胞通过微环境分泌因子为 CSC 创造丰富的旁分泌生态位。因此，了解肿瘤基质细胞在 PDAC 发育和 CSC 生物学中发挥的作用至关重要。通过设计微阵列分析、肿瘤微阵列免疫组织化学测定、体外共培养实验、重组蛋白治疗方法和体内干预研究来了解免疫调节阳离子抗菌肽 18/LL-37 的作用 (hCAP-18/LL-37) 在 PDAC 生物学中发挥作用。结果我们发现 hCAP-18/LL-37 在晚期原发性和继发性 PDAC 肿瘤的基质中强烈表达，并由基质的免疫细胞（例如肿瘤相关巨噬细胞）响应肿瘤生长因子-β 1，特别是 CSC 分泌的 Nodal/ActivinA 分泌。用重组 LL-37 治疗胰腺 CSC，通过甲酰基肽受体 2 (FPR2) 和 P2X 嘌呤受体 7 受体 (P2X7R) 依赖性机制增加多能相关基因表达、自我更新、侵袭和致瘤性，这些机制可以通过抑制这些受体来逆转。重要的是，在 K-Ras 驱动的胰腺肿瘤发生的基因工程小鼠模型中，我们还表明，通过用来自导管素相关抗菌肽（即 hCAP-18/LL-37 的鼠同源物）敲除小鼠的骨髓重建这些小鼠或通过药理学抑制 FPR2 和 FPR2 来抑制肿瘤形成。 P2X7R.结论 因此，hCAP-18/LL-37 代表了一种以前未被识别的 PDAC 微环境因子，它在胰腺 CSC 介导的肿瘤发生中发挥着关键作用。
Objectives The tumour stroma/microenvironment not only provides structural support for tumour development, but more importantly it provides cues to cancer stem cells (CSCs) that regulate their self-renewal and metastatic potential. This is certainly true for pancreatic ductal adenocarcinomas (PDAC), where tumour-associated fibroblasts, pancreatic stellate cells and immune cells create an abundant paracrine niche for CSCs via microenvironment-secreted factors. Thus understanding the role that tumour stroma cells play in PDAC development and CSC biology is of utmost importance.Design Microarray analyses, tumour microarray immunohistochemical assays, in vitro co-culture experiments, recombinant protein treatment approaches and in vivo intervention studies were performed to understand the role that the immunomodulatory cationic antimicrobial peptide 18/LL-37 (hCAP-18/LL-37) plays in PDAC biology.Results We found that hCAP-18/LL-37 was strongly expressed in the stroma of advanced primary and secondary PDAC tumours and is secreted by immune cells of the stroma (eg, tumour-associated macrophages) in response to tumour growth factor-beta 1 and particularly CSC-secreted Nodal/ActivinA. Treatment of pancreatic CSCs with recombinant LL-37 increased pluripotency-associated gene expression, self-renewal, invasion and tumourigenicity via formyl peptide receptor 2 (FPR2)- and P2X purinoceptor 7 receptor (P2X7R)-dependent mechanisms, which could be reversed by inhibiting these receptors. Importantly, in a genetically engineered mouse model of K-Ras-driven pancreatic tumourigenesis, we also showed that tumour formation was inhibited by either reconstituting these mice with bone marrow from cathelicidin-related antimicrobial peptide (ie, murine homologue of hCAP-18/LL-37) knockout mice or by pharmacologically inhibiting FPR2 and P2X7R.Conclusions Thus, hCAP-18/LL-37 represents a previously unrecognised PDAC microenvironment factor that plays a critical role in pancreatic CSC-mediated tumourigenesis.