Tumor cell integrin β4 and tumor stroma E-/P-selectin cooperatively regulate tumor growth in vivo.
Anoikis
Chemoattraction
E-selectin
Integrin β4
Myeloid-derived suppressor cell
P-selectin
Tumor-infiltrating leukocyte
Journal
Journal of hematology & oncology
ISSN: 1756-8722
Titre abrégé: J Hematol Oncol
Pays: England
ID NLM: 101468937
Informations de publication
Date de publication:
17 03 2023
17 03 2023
Historique:
received:
08
09
2022
accepted:
13
02
2023
entrez:
18
3
2023
pubmed:
19
3
2023
medline:
22
3
2023
Statut:
epublish
Résumé
The immunological composition of the tumor microenvironment has a decisive influence on the biological course of cancer and is therefore of profound clinical relevance. In this study, we analyzed the cooperative effects of integrin β4 (ITGB4) on tumor cells and E-/P-selectin on endothelial cells within the tumor stroma for regulating tumor growth by shaping the local and systemic immune environment. We used several preclinical mouse models for different solid human cancer types (xenograft and syngeneic) to explore the role of ITGB4 (shRNA-mediated knockdown in tumor cells) and E-/P-selectins (knockout in mice) for tumor growth; effects on apoptosis, proliferation and intratumoral signaling pathways were determined by histological and biochemical methods and 3D in vitro experiments; changes in the intratumoral and systemic immune cell composition were determined by flow cytometry and immunohistochemistry; chemokine levels and their attracting potential were measured by ELISA and 3D invasion assays. We observed a very robust synergism between ITGB4 and E-/P-selectin for the regulation of tumor growth, accompanied by an increased recruitment of CD11b These findings suggest a distinct vulnerability of ITGB4
Sections du résumé
BACKGROUND
The immunological composition of the tumor microenvironment has a decisive influence on the biological course of cancer and is therefore of profound clinical relevance. In this study, we analyzed the cooperative effects of integrin β4 (ITGB4) on tumor cells and E-/P-selectin on endothelial cells within the tumor stroma for regulating tumor growth by shaping the local and systemic immune environment.
METHODS
We used several preclinical mouse models for different solid human cancer types (xenograft and syngeneic) to explore the role of ITGB4 (shRNA-mediated knockdown in tumor cells) and E-/P-selectins (knockout in mice) for tumor growth; effects on apoptosis, proliferation and intratumoral signaling pathways were determined by histological and biochemical methods and 3D in vitro experiments; changes in the intratumoral and systemic immune cell composition were determined by flow cytometry and immunohistochemistry; chemokine levels and their attracting potential were measured by ELISA and 3D invasion assays.
RESULTS
We observed a very robust synergism between ITGB4 and E-/P-selectin for the regulation of tumor growth, accompanied by an increased recruitment of CD11b
CONCLUSIONS
These findings suggest a distinct vulnerability of ITGB4
Identifiants
pubmed: 36932441
doi: 10.1186/s13045-023-01413-9
pii: 10.1186/s13045-023-01413-9
pmc: PMC10022201
doi:
Substances chimiques
Chemokines
0
Integrin beta4
0
P-Selectin
0
ITGB4 protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
23Informations de copyright
© 2023. The Author(s).
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