A distinguishing gene signature shared by tumor-infiltrating Tie2-expressing monocytes, blood "resident" monocytes, and embryonic macrophages suggests common functions and developmental relationships.
We previously showed that Tie2-expressing monocytes (TEMs) have nonredundant proangiogenic activity in tumors. Here, we compared the gene expression profile of tumor-infiltrating TEMs with that of tumor-associated macrophages (TAMs), spleen-derived Gr1(+)Cd11b(+) neutrophils/myeloid-derived suppressor cells, circulating "inflammatory" and "resident" monocytes, and tumor-derived endothelial cells (ECs) by quantitative polymerase chain reaction-based gene arrays. TEMs sharply differed from ECs and Gr1(+)Cd11b(+) cells but were highly related to TAMs. Nevertheless, several genes were differentially expressed between TEMs and TAMs, highlighting a TEM signature consistent with enhanced proangiogenic/tissue-remodeling activity and lower proinflammatory activity. We validated these findings in models of oncogenesis and transgenic mice expressing a microRNA-regulated Tie2-GFP reporter. Remarkably, resident monocytes and TEMs on one hand, and inflammatory monocytes and TAMs on the other hand, expressed coordinated gene expression profiles, suggesting that the 2 blood monocyte subsets are committed to distinct extravascular fates in the tumor microenvironment. We further showed that a prominent proportion of embryonic/fetal macrophages, which participate in tissue morphogenesis, expressed distinguishing TEM genes. It is tempting to speculate that Tie2(+) embryonic/fetal macrophages, resident blood monocytes, and tumor-infiltrating TEMs represent distinct developmental stages of a TEM lineage committed to execute physiologic proangiogenic and tissue-remodeling programs, which can be co-opted by tumors.
Pucci
Ferdinando
F
Angiogenesis and Tumor Targeting Research Unit, San Raffaele Institute, Olgettina 58, Milan, Italy.
Venneri
Mary Anna
MA
Biziato
Daniela
D
Nonis
Alessandro
A
Moi
Davide
D
Sica
Antonio
A
Di Serio
Clelia
C
Naldini
Luigi
L
De Palma
Michele
M
D000818:Animals; D001773:Blood Cells / Q000276:immunology / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000235:genetics; D004622:Embryo, Mammalian / Q000276:immunology* / Q000378:metabolism; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D008264:Macrophages / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009000:Monocytes / Q000378:metabolism* / Q000473:pathology / Q000502:physiology; D009369:Neoplasms / Q000235:genetics / Q000276:immunology*; D020411:Oligonucleotide Array Sequence Analysis; D042787:Receptor, TIE-2 / Q000235:genetics / Q000378:metabolism*
D042787:Receptor, TIE-2