A distinguishing gene signature shared by tumor-infiltrating Tie2-expressing monocytes, blood “resident” monocytes, and embryonic macrophages suggests common functions and developmental relationships

Abstract

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 tumorassociated macrophages (TAMs), spleenderived Gr1 ؉ Cd11b ؉ neutrophils/myeloidderived suppressor cells, circulating "inflammatory" and "resident" monocytes, and tumor-derived endothelial cells (ECs) by quantitative polymerase chain reactionbased 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 coopted by tumors.

Yolk-sac–derived macrophages regulate fetal testis vascularization and morphogenesis

“…In other contexts, such as in tumor vascularization, macrophages have been implicated as a source of VEGFA production (11). In this study, we showed that macrophages in the fetal gonad also express Vegfa and, like tumor-associated macrophages (36)(37)(38), express the angiogenic-associated receptors NRP1 and TEK/ TIE2. Macrophages may use these cell-surface receptors to sequester pools of the endothelial attractant factors VEGF or ANGPT and present them to endothelial cells to guide neovascularization of tumors.…”

“…Testis macrophages expressed a number of endothelial markers including Neuropilin 1 (NRP1), which is a vascular endothelial growth factor (VEGF) coreceptor that normally is expressed in endothelial cells but also has been implicated as a marker of macrophages involved in neovascularization of tumors (36)(37)(38) (Fig. S6A); endothelial-specific receptor tyrosine kinase (TEK; also called "TIE2") (Fig.…”

Emerging paradigms and questions on pro-angiogenic bone marrow-derived myelomonocytic cells

“…These observations raise the question of whether distinct monocyte/ macrophage subsets found in tumors represent distinct lineages or are rather different differentiation states originated from a common progenitor cell. For example, in the mouse, tumor-infiltrating Tie2-expressing monocytes and blood-circulating resident monocytes share gene expression gene signatures suggesting common developmental relationships and shared functions (Pucci et al, 2009).…”

Immune-mediated mechanisms influencing the efficacy of anticancer therapies

“…This has led to the misconception that there are only two types of TAMs. Recent gene expression data from several independent laboratories has discredited this oversimplified idea, showing that TAMs comprise several distinct populations and share properties of both M1 and M2 cells [203][204][205].…”