Τίτλος:
Mutant p53 cancers reprogram macrophages to tumor supporting macrophages via exosomal miR-1246
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
TP53 mutants (mutp53) are involved in the pathogenesis of most human cancers. Specific mutp53 proteins gain oncogenic functions (GOFs) distinct from the tumor suppressor activity of the wild-type protein. Tumor-associated macrophages (TAMs), a hallmark of solid tumors, are typically correlated with poor prognosis. Here, we report a non-cell-autonomous mechanism, whereby human mutp53 cancer cells reprogram macrophages to a tumor supportive and anti-inflammatory state. The colon cancer cells harboring GOF mutp53 selectively shed miR-1246-enriched exosomes. Uptake of these exosomes by neighboring macrophages triggers their miR-1246-dependent reprogramming into a cancer-promoting state. Mutp53-reprogammed TAMs favor anti-inflammatory immunosuppression with increased activity of TGF-β. These findings, associated with poor survival in colon cancer patients, strongly support a microenvironmental GOF role for mutp53 in actively engaging the immune system to promote cancer progression and metastasis. © 2018 The Author(s).
Συγγραφείς:
Cooks, T.
Pateras, I.S.
Jenkins, L.M.
Patel, K.M.
Robles, A.I.
Morris, J.
Forshew, T.
Appella, E.
Gorgoulis, V.G.
Harris, C.C.
Περιοδικό:
Nature Communications
Εκδότης:
Nature Publishing Group
Λέξεις-κλειδιά:
calnexin; gamma interferon; gelatinase B; intercellular adhesion molecule 1; interleukin 10; interleukin 13; interleukin 4; interleukin 8; microRNA; microRNA 1246; microRNA 21; microRNA 29b; monocyte chemotactic protein 1; mutant protein; protein p53; proteome; transforming growth factor beta; tumor necrosis factor; unclassified drug; vasculotropin; microRNA; MIRN1246 microRNA, human; mutant protein; protein p53; transforming growth factor beta1, cancer; cell; gene expression; immune system; mutation; protein; tumor, animal experiment; animal model; Article; cancer survival; cell communication; colon carcinogenesis; colon carcinoma; colorectal carcinoma; controlled study; down regulation; enzyme degradation; enzyme linked immunosorbent assay; epithelial mesenchymal transition; exosome; extracellular matrix; human; human cell; immunohistochemistry; indel mutation; macrophage; mass spectrometry; missense mutation; mouse; mRNA expression level; nonhuman; nuclear reprogramming; polarization; protein expression; reverse transcription polymerase chain reaction; RNA processing; TGF beta signaling; transmission electron microscopy; tumor microenvironment; upregulation; Western blotting; animal; colon tumor; exosome; genetics; macrophage; metabolism; mutation; tumor cell line, Animals; Cell Line, Tumor; Colonic Neoplasms; Exosomes; Humans; Macrophages; Mice; MicroRNAs; Mutant Proteins; Mutation; Transforming Growth Factor beta1; Tumor Suppressor Protein p53
DOI:
10.1038/s41467-018-03224-w
