Ovarian cancer stem cells and macrophages reciprocally interact through the WNT pathway to promote pro-tumoral and malignant phenotypes in 3D engineered microenvironments.
Animals
Cell Line, Tumor
Coculture Techniques
Female
Gene Expression Regulation, Neoplastic
Humans
Macrophages
/ immunology
Mice
Neoplasm Transplantation
Neoplastic Stem Cells
/ immunology
Ovarian Neoplasms
/ immunology
Phenotype
Spheroids, Cellular
/ immunology
Tumor Microenvironment
Wnt Signaling Pathway
Journal
Journal for immunotherapy of cancer
ISSN: 2051-1426
Titre abrégé: J Immunother Cancer
Pays: England
ID NLM: 101620585
Informations de publication
Date de publication:
19 07 2019
19 07 2019
Historique:
received:
14
02
2019
accepted:
07
07
2019
entrez:
21
7
2019
pubmed:
22
7
2019
medline:
25
6
2020
Statut:
epublish
Résumé
Innate immune cells such as macrophages are abundantly present within malignant ascites, where they share the microenvironment with ovarian cancer stem cells (CSC). To mimic this malignant ascites microenvironment, we created a hanging-drop hetero-spheroid model to bring CSCs and macrophages in close association. Within these hetero-spheroids, CD68 Our results indicate that CSCs drive the upregulation of M2 macrophage marker CD206 within hetero-spheroids, compared to bulk ovarian cancer cells, implying an inherently more immuno-suppressive program. Moreover, an increased maintenance of elevated aldehyde dehydrogenase (ALDH) activity is noted within hetero-spheroids that include pre-polarized CD206 Our data implies that macrophage- initiated WNT signaling could play a significant role in the maintenance of stemness, and the resulting phenotypes of chemoresistance and invasiveness. Our results indicate paracrine WNT activation during CSC/M2 macrophages interaction constitutes a positive feedback loop that likely contributes to the more aggressive phenotype, which makes the WNT pathway a potential target to reduce the CSC and M2 macrophage compartments in the tumor microenvironment.
Sections du résumé
BACKGROUND
Innate immune cells such as macrophages are abundantly present within malignant ascites, where they share the microenvironment with ovarian cancer stem cells (CSC).
METHODS
To mimic this malignant ascites microenvironment, we created a hanging-drop hetero-spheroid model to bring CSCs and macrophages in close association. Within these hetero-spheroids, CD68
RESULTS
Our results indicate that CSCs drive the upregulation of M2 macrophage marker CD206 within hetero-spheroids, compared to bulk ovarian cancer cells, implying an inherently more immuno-suppressive program. Moreover, an increased maintenance of elevated aldehyde dehydrogenase (ALDH) activity is noted within hetero-spheroids that include pre-polarized CD206
CONCLUSIONS
Our data implies that macrophage- initiated WNT signaling could play a significant role in the maintenance of stemness, and the resulting phenotypes of chemoresistance and invasiveness. Our results indicate paracrine WNT activation during CSC/M2 macrophages interaction constitutes a positive feedback loop that likely contributes to the more aggressive phenotype, which makes the WNT pathway a potential target to reduce the CSC and M2 macrophage compartments in the tumor microenvironment.
Identifiants
pubmed: 31324218
doi: 10.1186/s40425-019-0666-1
pii: 10.1186/s40425-019-0666-1
pmc: PMC6642605
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
190Subventions
Organisme : NIDCR NIH HHS
ID : R00 DE024173
Pays : United States
Organisme : NIDCR NIH HHS
ID : R01 DE026728
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA046592
Pays : United States
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