Squamous cell carcinoma subverts adjacent histologically normal epithelium to promote lateral invasion.
Animals
Calcium-Binding Proteins
/ metabolism
Carcinoma, Squamous Cell
/ metabolism
Cell Line, Tumor
Disease-Free Survival
Epithelium
/ metabolism
Humans
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Neoplasm Invasiveness
/ pathology
Neoplasm Recurrence, Local
/ metabolism
Tumor Microenvironment
/ physiology
Journal
The Journal of experimental medicine
ISSN: 1540-9538
Titre abrégé: J Exp Med
Pays: United States
ID NLM: 2985109R
Informations de publication
Date de publication:
07 06 2021
07 06 2021
Historique:
received:
09
05
2020
revised:
04
01
2021
accepted:
16
02
2021
entrez:
9
4
2021
pubmed:
10
4
2021
medline:
2
10
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33835136
pii: 211968
doi: 10.1084/jem.20200944
pmc: PMC8042603
pii:
doi:
Substances chimiques
Calcium-Binding Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NCI NIH HHS
ID : P50 CA097248
Pays : United States
Organisme : NIDCR NIH HHS
ID : R01 DE022567
Pays : United States
Organisme : NIDCR NIH HHS
ID : R35 DE027551
Pays : United States
Organisme : NIH HHS
ID : U42 OD010918
Pays : United States
Informations de copyright
© 2021 Singh et al.
Déclaration de conflit d'intérêts
Disclosures: The authors declare no competing interests exist.
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