Tumor-derived adenosine promotes macrophage proliferation in human hepatocellular carcinoma.
J Hepatol
; 74(3): 627-637, 2021 03.
Article
en En
| MEDLINE
| ID: mdl-33137360
ABSTRACT
BACKGROUND & AIMS:
Macrophages (MÏ) represent a major component of tumor tissues and play an important role in both tumor progression and therapeutic response. Although tumor MÏ are generally considered to be derived from circulating monocytes, emerging evidence indicates that tissue MÏ pools can be maintained by self-renewal. We aimed to elucidate the contribution, phenotype, and regulatory mechanisms of proliferating MÏ in human hepatocellular carcinoma (HCC).METHODS:
Flow cytometry analyses were performed to examine the presence and phenotype of proliferating MÏ in fresh HCC tissues. Dual immunofluorescence staining was applied to analyze the prognostic value of proliferating MÏ. The underlying regulatory mechanisms were examined using human monocyte-derived MÏ.RESULTS:
Tumor-infiltrating MÏ exhibited a significantly higher proliferative capacity than MÏ in non-tumor tissues. A higher level of MÏ proliferation was positively correlated with MÏ density in the tumor and a poor prognosis in patients with HCC. Proliferating MÏ were less differentiated (with increased CD206 expression) and were induced by the tumor cell-derived soluble small molecule, adenosine, but not proteins, lipids, or large peptides. Mechanistic studies demonstrated that autocrine granulocyte-macrophage colony-stimulating factor (GM-CSF) released by tumor-stimulated MÏ could enhance A2A receptor expression on MÏ and function synergistically with adenosine to elicit MÏ proliferation in HCC.CONCLUSIONS:
Local MÏ proliferation is an important mechanism for MÏ accumulation in HCC tissues. Tumor-derived adenosine functions synergistically with autocrine GM-CSF released from activated MÏ, which promotes MÏ proliferation. Thus, selective modulation of MÏ accumulation at the source may provide a novel strategy for cancer therapy. LAYSUMMARY:
Tumor-associated macrophages (TAMs) have been reported to play an essential role in both tumor progression and therapeutic response. A fundamental understanding of the mechanisms that regulate macrophage accumulation in tumors will undoubtedly lead to the development of strategies to target macrophages with high specificity and efficiency. The current study unveils a novel mechanism by which local proliferation is linked to macrophage accumulation in the tumor milieu, identifying potential targets for future immune-based anticancer therapies.Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Adenosina
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Carcinoma Hepatocelular
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Proliferación Celular
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Macrófagos Asociados a Tumores
/
Neoplasias Hepáticas
Tipo de estudio:
Observational_studies
/
Prognostic_studies
/
Risk_factors_studies
Límite:
Adolescent
/
Adult
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Aged
/
Aged80
/
Female
/
Humans
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Male
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Middle aged
Idioma:
En
Revista:
J Hepatol
Asunto de la revista:
GASTROENTEROLOGIA
Año:
2021
Tipo del documento:
Article