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鳞状细胞癌使毗邻组织学正常的上皮发生转化，促进侧向浸润。

Squamous cell carcinoma subverts adjacent histologically normal epithelium to promote lateral invasion.

机构信息

Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, MI.

Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI.

出版信息

J Exp Med. 2021 Jun 7;218(6). doi: 10.1084/jem.20200944.

DOI:10.1084/jem.20200944
PMID:33835136
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8042603/
Abstract

Recurrent and new tumors, attributed in part to lateral invasion, are frequent in squamous cell carcinomas and lead to poor survival. We identified a mechanism by which cancer subverts adjacent histologically normal epithelium to enable small clusters of cancer cells to burrow undetected under adjacent histologically normal epithelium. We show that suppression of DMBT1 within cancer promotes aggressive invasion and metastasis in vivo and is associated with metastasis in patients. Cancer cells via TGFβ1 and TNFα also suppress DMBT1 in adjacent histologically normal epithelium, thereby subverting it to promote invasion of a small population of tumor cells. The sufficiency of DMBT1 in this process is demonstrated by significantly higher satellite tumor nests in Dmbt1-/- compared with wild-type mice. Moreover, in patients, invasion of small tumor nests under adjacent histologically normal epithelium is associated with increased risk for recurrence and shorter disease-free survival. This study demonstrates a crucial role of adjacent histologically normal epithelium in invasion and its important role in the tumor microenvironment and opens new possibilities for therapeutic strategies that reduce tumor recurrence.

摘要

复发性和新的肿瘤，部分归因于侧向侵袭，在鳞状细胞癌中很常见，导致生存不良。我们发现了一种机制，通过这种机制，癌症颠覆了相邻组织学上正常的上皮细胞，使小簇癌细胞在相邻组织学上正常的上皮细胞下悄然侵袭。我们表明，在癌症中抑制 DMBT1 会促进体内侵袭和转移，并与患者的转移相关。癌细胞还通过 TGFβ1 和 TNFα 抑制相邻组织学上正常上皮细胞中的 DMBT1，从而颠覆它以促进一小部分肿瘤细胞的侵袭。Dmbt1-/- 小鼠中明显更高的卫星肿瘤巢证明了 DMBT1 在该过程中的充分性。此外，在患者中，相邻组织学上正常的上皮细胞下小肿瘤巢的侵袭与复发风险增加和无病生存期缩短相关。这项研究表明相邻组织学上正常的上皮细胞在侵袭中的关键作用及其在肿瘤微环境中的重要作用，并为减少肿瘤复发的治疗策略开辟了新的可能性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cda0/8042603/ba557c1cfc35/JEM_20200944_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cda0/8042603/1adf1f96e20a/JEM_20200944_GA.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cda0/8042603/9b2f7abf7ac0/JEM_20200944_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cda0/8042603/3303766a1c7c/JEM_20200944_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cda0/8042603/3ef4a078769f/JEM_20200944_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cda0/8042603/a86deda36bbe/JEM_20200944_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cda0/8042603/81d3b38b13d1/JEM_20200944_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cda0/8042603/255deae85613/JEM_20200944_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cda0/8042603/86d66ee17584/JEM_20200944_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cda0/8042603/2b3d1c05d664/JEM_20200944_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cda0/8042603/d4ea900bb00a/JEM_20200944_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cda0/8042603/ba557c1cfc35/JEM_20200944_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cda0/8042603/1adf1f96e20a/JEM_20200944_GA.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cda0/8042603/9b2f7abf7ac0/JEM_20200944_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cda0/8042603/3303766a1c7c/JEM_20200944_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cda0/8042603/3ef4a078769f/JEM_20200944_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cda0/8042603/a86deda36bbe/JEM_20200944_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cda0/8042603/81d3b38b13d1/JEM_20200944_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cda0/8042603/255deae85613/JEM_20200944_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cda0/8042603/86d66ee17584/JEM_20200944_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cda0/8042603/2b3d1c05d664/JEM_20200944_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cda0/8042603/d4ea900bb00a/JEM_20200944_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cda0/8042603/ba557c1cfc35/JEM_20200944_Fig6.jpg

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