Aberrant accumulation of Dickkopf 4 promotes tumor progression via forming the immune suppressive microenvironment in gastrointestinal stromal tumor.
Aged
Biomarkers
Cell Line, Tumor
Cytotoxicity, Immunologic
Disease Progression
Female
Fluorescent Antibody Technique
Gastrointestinal Stromal Tumors
/ etiology
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
Humans
Intercellular Signaling Peptides and Proteins
/ genetics
Male
Middle Aged
Prognosis
Tumor Burden
Tumor Microenvironment
/ genetics
Wnt Signaling Pathway
DKK4
GIST
immune suppression
prognosis indicator
progression
Journal
Cancer medicine
ISSN: 2045-7634
Titre abrégé: Cancer Med
Pays: United States
ID NLM: 101595310
Informations de publication
Date de publication:
Sep 2019
Sep 2019
Historique:
received:
20
02
2019
revised:
19
06
2019
accepted:
11
07
2019
pubmed:
30
7
2019
medline:
4
9
2020
entrez:
30
7
2019
Statut:
ppublish
Résumé
Drug resistance and tumor recurrence are the major concerns in clinical practices of gastrointestinal stromal tumor (GIST), with the urgent requirement for exploring undiscovered pathways driving malignancy. To deal with these, recent studies have made many efforts to explore prognosis indicators and establish potential therapeutic targets. Expression profiles of different risks of GISTs were described and abundant clinical evidences supported our findings in this study. Following exploration in vitro by cell experiments and verification in vivo using tumor microarray were taken to elucidate the underlying mechanism, which drove the malignancy in GIST. Dickkopf 4 (DKK4), as the canonical Wnt pathway antagonist, was unexpectedly and universally upregulated in high-risk GISTs, and aberrant accumulation of DKK4 was closely correlated with poor prognosis. In addition, tumor-derived DKK4 could decrease immune cells infiltration and activation in the tumor microenvironment, which decreased the antitumor effects in return. And this phenomenon was recurrent in human tumor specimens. Our findings identified DKK4 as a proper tumor biomarker for prognosis predicting and recurrence monitoring, and suggested a novel immune-escape mechanism driving malignancy in GIST, which might be a potential therapeutic target to improve the effects of canonical RTK therapy and combined immunotherapy.
Sections du résumé
BACKGROUND
BACKGROUND
Drug resistance and tumor recurrence are the major concerns in clinical practices of gastrointestinal stromal tumor (GIST), with the urgent requirement for exploring undiscovered pathways driving malignancy. To deal with these, recent studies have made many efforts to explore prognosis indicators and establish potential therapeutic targets.
METHODS
METHODS
Expression profiles of different risks of GISTs were described and abundant clinical evidences supported our findings in this study. Following exploration in vitro by cell experiments and verification in vivo using tumor microarray were taken to elucidate the underlying mechanism, which drove the malignancy in GIST.
RESULTS
RESULTS
Dickkopf 4 (DKK4), as the canonical Wnt pathway antagonist, was unexpectedly and universally upregulated in high-risk GISTs, and aberrant accumulation of DKK4 was closely correlated with poor prognosis. In addition, tumor-derived DKK4 could decrease immune cells infiltration and activation in the tumor microenvironment, which decreased the antitumor effects in return. And this phenomenon was recurrent in human tumor specimens.
CONCLUSIONS
CONCLUSIONS
Our findings identified DKK4 as a proper tumor biomarker for prognosis predicting and recurrence monitoring, and suggested a novel immune-escape mechanism driving malignancy in GIST, which might be a potential therapeutic target to improve the effects of canonical RTK therapy and combined immunotherapy.
Identifiants
pubmed: 31353847
doi: 10.1002/cam4.2437
pmc: PMC6718536
doi:
Substances chimiques
Biomarkers
0
DKK4 protein, human
0
Intercellular Signaling Peptides and Proteins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
5352-5366Subventions
Organisme : Shanghai Municipal Commission of Health and Family Planning
ID : 201540071
Organisme : Clinical Research Plan of SHDC
ID : 16CR3001A
Organisme : Shanghai Outstanding Academic Leaders Plan
Informations de copyright
© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
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