Increased neutrophil infiltration as a body-wide effect in pancreatic cancer development.
Increased neutrophil infiltration as a body-wide effect in pancreatic cancer development.
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中性粒细胞浸润增加在胰腺癌发展中的全身效应。
DOI：
10.1016/j.ebiom.2022.104089
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发表时间：
2022-07
期刊：
影响因子：
11.1
通讯作者：
Pan, Sheng
中科院分区：
文献类型：
--
作者：
Chen, Ru;Pan, Sheng
长期以来，癌症一直被认为是一种系统性疾病，即使从远处的解剖部位也能积极地扰乱正常的宿主器官。这样的扰动可能会引起这些器官内基因表达和蛋白质网络的改变，最终可能影响生物体的生理机能，并可能导致肿瘤本身以外的组织损伤。我们现在已经了解了大量的肿瘤组织和邻近正常组织的基因表达图谱。然而，我们对其他全身非肿瘤器官的了解仍然有限。早期的一项研究为皮下脑癌模型中肿瘤对全身转录组的影响提供了一些线索。在最近一期的《电子生物医学》杂志上，Jiang及其同事提供了胰腺癌小鼠模型早期胰腺上皮内瘤变（PanIN）和晚期胰腺导管腺癌（PDAC）的全身分子改变的新见解。4研究发现，PDAC小鼠非肿瘤器官中差异表达基因（DEGs）的数量普遍比PanIN小鼠高数倍。这并不奇怪，因为肿瘤驱动的全身扰动程度预计会随着肿瘤的进展而增加。比较小鼠七个器官的转录组：肝、肺、结肠、胃、肾、心脏和大脑，来自有和没有PanIN或PDAC的动物，不同器官的deg数量差异很大，与对照组相比，结肠的deg数量最高，而大脑受癌症或胰腺前体影响的水平最低。有趣的是，从早期到晚期，肝脏和肺部的deg数量大幅增加，并且在晚期疾病的所有七个小鼠器官中，肝脏和肺部的基因上调数量最多。我们很容易推测，携带pdac的动物的肝脏和肺部基因扰动的高负担可能在一定程度上说明了为什么肝脏和肺部是胰腺癌转移的两个最常见的部位。近年来，越来越多的证据表明，中性粒细胞参与了肿瘤发生、生长和转移的每一步。在胰腺癌中，与正常胰腺相比，中性粒细胞浸润胰腺肿瘤的水平更高；中性粒细胞浸润高的PDAC患者预后较差。有趣的是，Jiang及其同事的研究发现，在PDAC早期，多个器官的中性粒细胞浸润增加。中性粒细胞浸润在肝脏和肺部最为突出，这也是PDAC最常见的两个转移部位。中性粒细胞被认为是通过肿瘤细胞释放的趋化因子和其他信号分子募集到胰腺肿瘤的。但是中性粒细胞是如何在非肿瘤器官中积累的呢？研究表明，原发肿瘤部位释放的肿瘤源性因子可以系统性地调节远处肿瘤部位的潜在转移。事实上，在远处的早期中性粒细胞积累可能是未来转移的指示。Jiang及其同事的研究进一步证明了中性粒细胞在PDAC小鼠模型的非肿瘤器官中滤过。正如巨噬细胞可以有几种功能亚型一样，中性粒细胞也可以有不同的功能亚型。PanIN期中性粒细胞具有较大的迁移能力，但不具有免疫抑制特性。相反，在PDAC晚期，中性粒细胞迁移较少，免疫抑制更强。在这种情况下，需要更多的工作来描述和理解导致中性粒细胞积累和激活的因素。
Cancer has long been considered a systemic disease that can actively perturb normal host organs even from distant anatomic sites. 1 Such perturbations will likely induce alterations in gene expression and protein networks within those organs that could ultimately affect the organism’s physiology 1 and may cause tissue damage beyond the tumor itself. 2 We now know a great deal of gene expression landscapes in tumor tissues and the adjacent normal tissues. However, our knowledge of other body-wide non-tumor organs is still limited. An earlier study provided some clues of the tumor effects on body-wide transcriptomes in a subcutaneous brain cancer model. 3 In a recent issue of eBioMedicine, Jiang and colleagues provided new insights into the bodywide molecular alterations in early pancreatic intraepithelial neoplasia,(PanIN) and late stage pancreatic ductal adenocarcinoma (PDAC) of mouse models of pancreatic cancer. 4 The study found that the number of DEGs (differentially expressed gene) in the non-tumor organs was generally several-fold higher in mice with PDAC than with PanIN. This is not surprising as the degree of tumor-driven systemic perturbations is expected to increase with tumor progression. Comparing the transcriptomes of seven mouse organs: liver, lung, colon, stomach, kidney, heart, and brain, from animals with and without PanIN or PDAC, the number of DEGs varied greatly at the different organs, with the colon having the highest and the brain having the lowest levels affected by cancer or precursors in the pancreas compared to controls. Interestingly, the numbers of DEGs in liver and lung increased substantially from early stage to late stage, and liver and lung showed the highest number of upregulated genes among all seven mouse organs in late stage disease. It is tempting to speculate that the high burden of gene perturbations in the liver and lung in PDAC-bearing animals may in part suggest why liver and lung are the two most common sites of metastasis of pancreatic cancer. In recent years, mounting evidence indicates that neutrophils participate in each step of carcinogenesis, from tumor initiation to growth and metastasis. 5 In pancreatic cancer, neutrophils infiltrate pancreatic tumors at higher levels compared to normal pancreas; PDAC patients with high neutrophil infiltration have a worse prognosis. 6, 7 Interestingly, the study by Jiang and colleagues found increased neutrophil infiltration in multiple organs at early stage of PDAC. The neutrophil infiltration was most prominent in the liver and lung, again the two most common metastatic sites of PDAC. Neutrophils are thought to be recruited to the pancreatic tumors by chemokines and other signaling molecules released from tumor cells. 8 But how do neutrophils accumulate in non-tumor organs? Studies have shown that tumor-derived factors released from primary tumor site could systemically condition distant sites for potential metastases. 5 In fact, early neutrophil accumulation at distant sites may be an indication for future metastasis. 5 The study by Jiang and colleagues provides further evidence of neutrophils filtration in non-tumor organs of PDAC mouse models. Just as macrophages could be characterized by several functional subtypes, neutrophils could also have different subtypes with opposing functions. Neutrophils at the PanIN stage are found to have greater migratory capacity but not immunosuppressive qualities. 9 In contrast, the neutrophils are less migratory and more immunosuppressive at later stages of PDAC. 9 In this context, more work is needed to characterize and understand the factors leading to neutrophil accumulation and activation in the …
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影响因子：
8.8
作者：
Ino Y;Yamazaki-Itoh R;Shimada K;Iwasaki M;Kosuge T;Kanai Y;Hiraoka N
通讯作者：
Hiraoka N
影响因子：
5.2
作者：
Pratt HG;Steinberger KJ;Mihalik NE;Ott S;Whalley T;Szomolay B;Boone BA;Eubank TD
通讯作者：
Eubank TD
影响因子：
81.5
作者：
Baracos, Vickie E.;Martin, Lisa;Fearon, Kenneth C. H.
通讯作者：
Fearon, Kenneth C. H.
DOI：
10.1016/j.bbrc.2018.05.024
发表时间：
2018-06-18
影响因子：
3.1
作者：
Wang, Yufu;Fang, Tianyi;Cui, Yunfu
通讯作者：
Cui, Yunfu
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影响因子：
11.1
作者：
Jiang, Shu-Heng;Liu, Dejun;Hu, Li-Peng;Zhang, Shan;Yu, Yanqiu;Sun, Yong-Wei;Ji, Jianguang;Zhang, Zhi-Gang
通讯作者：
Zhang, Zhi-Gang