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基质激活素 A 在人胰腺癌细胞和小鼠转移中的作用。

Role of stromal activin A in human pancreatic cancer and metastasis in mice.

机构信息

Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.

Department of Medicine, University of Washington College of Medicine, 1959 NE Pacific Street, RR-512, Box 356020, Seattle, WA, 98195-6420, USA.

出版信息

Sci Rep. 2021 Apr 12;11(1):7986. doi: 10.1038/s41598-021-87213-y.

DOI:10.1038/s41598-021-87213-y
PMID:33846512
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8042028/
Abstract

Pancreatic ductal adenocarcinoma (PDAC) has extensive stromal involvement and remains one of the cancers with the highest mortality rates. Activin A has been implicated in colon cancer and its stroma but its role in the stroma of PDAC has not been elucidated. Activin A expression in cancer and stroma was assessed in human PDAC tissue microarrays (TMA). Activin A expression in human TMA is significantly higher in cancer samples, with expression in stroma correlated with shorter survival. Cultured pancreatic stellate cells (PSC) were found to secrete high levels of activin A resulting in PDAC cell migration that is abolished by anti-activin A neutralizing antibody. KPC mice treated with anti-activin A neutralizing antibody were evaluated for tumors, lesions and metastases quantified by immunohistochemistry. KPC mice with increased tumor burden express high plasma activin A. Treating KPC mice with an activin A neutralizing antibody does not reduce primary tumor size but decreases tumor metastases. From these data we conclude that PDAC patients with high activin A expression in stroma have a worse prognosis. PSCs secrete activin A, promoting increased PDAC migration. Inhibition of activin A in mice decreased metastases. Hence, stroma-rich PDAC patients might benefit from activin A inhibition.

摘要

胰腺导管腺癌 (PDAC) 广泛涉及基质，仍然是死亡率最高的癌症之一。激活素 A 已被牵连到结肠癌及其基质中，但它在 PDAC 基质中的作用尚未阐明。在人类 PDAC 组织微阵列 (TMA) 中评估了癌症和基质中的激活素 A 表达。人类 TMA 中的激活素 A 表达在癌症样本中显着更高，基质中的表达与较短的生存时间相关。发现培养的胰腺星状细胞 (PSC) 分泌高水平的激活素 A，导致 PDAC 细胞迁移，而抗激活素 A 中和抗体可消除这种迁移。通过免疫组织化学评估接受抗激活素 A 中和抗体治疗的 KPC 小鼠的肿瘤、病变和转移的定量。肿瘤负担增加的 KPC 小鼠表达高水平的血浆激活素 A。用激活素 A 中和抗体治疗 KPC 小鼠不会减小原发性肿瘤的大小，但会减少肿瘤转移。从这些数据中我们得出结论，基质中激活素 A 高表达的 PDAC 患者预后更差。PSC 分泌激活素 A，促进 PDAC 迁移增加。在小鼠中抑制激活素 A 可减少转移。因此，富含基质的 PDAC 患者可能受益于激活素 A 抑制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8786/8042028/5ef9c87b2089/41598_2021_87213_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8786/8042028/2a5fda325d5a/41598_2021_87213_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8786/8042028/b24526f78b6d/41598_2021_87213_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8786/8042028/41dd03bc14c2/41598_2021_87213_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8786/8042028/5ef9c87b2089/41598_2021_87213_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8786/8042028/2a5fda325d5a/41598_2021_87213_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8786/8042028/b24526f78b6d/41598_2021_87213_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8786/8042028/41dd03bc14c2/41598_2021_87213_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8786/8042028/5ef9c87b2089/41598_2021_87213_Fig4_HTML.jpg

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