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Midkine 作为与年龄相关的变化和乳腺肿瘤发生增加的驱动因素。

Midkine as a driver of age-related changes and increase in mammary tumorigenesis.

机构信息

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.

Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

出版信息

Cancer Cell. 2024 Nov 11;42(11):1936-1954.e9. doi: 10.1016/j.ccell.2024.09.002. Epub 2024 Oct 3.

DOI:10.1016/j.ccell.2024.09.002
PMID:39366375
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11560576/
Abstract

Aging is a pivotal risk factor for cancer, yet the underlying mechanisms remain poorly defined. Here, we explore age-related changes in the rat mammary gland by single-cell multiomics. Our findings include increased epithelial proliferation, loss of luminal identity, and decreased naive B and T cells with age. We discover a luminal progenitor population unique to old rats with profiles reflecting precancerous changes and identify midkine (Mdk) as a gene upregulated with age and a regulator of age-related luminal progenitors. Midkine treatment of young rats mimics age-related changes via activating PI3K-AKT-SREBF1 pathway and promotes nitroso-N-methylurea-induced mammary tumorigenesis. Midkine levels increase with age in human blood and mammary epithelium, and higher MDK in normal breast tissue is associated with higher breast cancer risk in younger women. Our findings reveal a link between aging and susceptibility to tumor initiation and identify midkine as a mediator of age-dependent increase in breast tumorigenesis.

摘要

衰老是癌症的一个关键风险因素，但潜在的机制仍不清楚。在这里，我们通过单细胞多组学方法来研究大鼠乳腺的年龄相关性变化。我们的研究结果包括上皮细胞增殖增加、腔细胞特征丧失以及幼稚 B 和 T 细胞随年龄减少。我们发现了一个仅在老年大鼠中存在的腔前体细胞群体，其特征反映了癌前变化，并确定中期因子（Mdk）是一个随年龄上调的基因，也是与年龄相关的腔前体细胞的调节剂。Mdk 处理年轻大鼠可通过激活 PI3K-AKT-SREBF1 通路模拟与年龄相关的变化，并促进亚硝脲诱导的乳腺肿瘤发生。人血液和乳腺上皮中的 Midkine 水平随年龄增长而增加，正常乳腺组织中更高的 MDK 与年轻女性中更高的乳腺癌风险相关。我们的研究结果揭示了衰老与肿瘤起始易感性之间的联系，并确定了中期因子（Mdk）是乳腺肿瘤发生中年龄依赖性增加的介质。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a25/11560576/f0708054b172/nihms-2025123-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a25/11560576/33d4a397ccde/nihms-2025123-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a25/11560576/efdb23a6b5a6/nihms-2025123-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a25/11560576/61069482fe93/nihms-2025123-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a25/11560576/3e8a01e1df2e/nihms-2025123-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a25/11560576/17173f36df5d/nihms-2025123-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a25/11560576/f0708054b172/nihms-2025123-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a25/11560576/33d4a397ccde/nihms-2025123-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a25/11560576/efdb23a6b5a6/nihms-2025123-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a25/11560576/61069482fe93/nihms-2025123-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a25/11560576/3e8a01e1df2e/nihms-2025123-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a25/11560576/17173f36df5d/nihms-2025123-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a25/11560576/f0708054b172/nihms-2025123-f0007.jpg

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