Cancer Metastasis: Perivascular Macrophages Under Watch

Abstract

Summary: TIE2-expressing macrophages cluster around blood vessels and sustain tumor angiogenesis. Harney and colleagues now use live imaging of mouse mammary tumors to show that these perivascular macrophages also promote the transient opening of tumor blood vessels to facilitate hematogenous cancer cell dissemination and metastasis. Cancer Discov; 5(9); ©2015 AACR. See related article by Harney et al., p. 932 (5).Tumors often contain abundant macrophage infi ltrates, which are largely derived from circulating monocytes. After tumor colonization, the macrophages acquire specialized phenotypes that appear to be instructed by the distinct signals they are exposed to in different tumor microenvironments, such as perivascular, stromal, or necrotic tumor areas ( 1 ). For example, perivascular macrophages that express the angiopoietin receptor TIE2 are proangiogenic ( 2, 3 ) and molecularly distinct from other tumor macrophage subpopulations ( 4 ). In this issue of Cancer Discovery , Harney and colleagues ( 5 ) use intravital microscopy to analyze vascular permeability at sites where TIE2-expressing macrophages (TEM) make contacts with the endothelial cells (EC) that line the tumor blood vessels. They found higher vascular permeability at these sites, compared with vessel segments lacking macrophages. Furthermore, cancer cell invasion of the blood vessels (intravasation)-the fi rst step in the metastatic cascade-occurred selectively at the macrophage-EC contacts. These new fi ndings provide insight into the regulation of cancer cell dissemination by perivascular macrophages.Previous work by these authors identifi ed perivascular microanatomical structures, called "tumor microenvironment of metastasis" (TMEM), in which a macrophage, a specialized cancer cell, and a blood vessel establish tripartite contacts (ref. 6 ; Fig. 1 ). To study the properties of the TMEM ensemble in live tumors, Harney and colleagues ( 5 ) performed intravital imaging of mouse mammary tumors after the intravenous delivery of a high-molecular weight marker, which would not diffuse across the EC layer of the tumor blood vessels. Video imaging of the tumor blood vessels indeed showed that most of the injected marker had remained entrapped in the vessels. However, the authors also identifi ed discrete sites, in fact, the TMEM structures, where the marker could leak from the vessels. Computer-assisted analysis of the recorded videos revealed that leakage of the marker, which is indicative of high vascular permeability, occurred at different time points after its injection, depending on which TMEM structure was imaged. Also, vascular permeability at each TMEM site was only transient; indeed, it peaked and demised rapidly, showing a pulsating nature. Together, these observations indicate that although permeability appears erratic and ephemeral throughout the tumor vasculature, it occurs specifi cally at vascular sites harboring TMEM structures.An important result of the study ( 5 ) was that the peak of vascular permeability at the TMEM site was bot...

The emerging roles of macrophages in cancer metastasis and response to chemotherapy

“…Streaming macrophages on the other side do not express these markers, and yet, they can potentially turn into perivascular macrophages expressing TIE2. Indeed, despite the original thought that TIE2 + macrophages may either arise as tissue‐resident macrophages, or from committed TIE2 + monocyte progenitors, there is now strong evidence that hypoxia stimulates TIE2 expression . Furthermore, recent studies have collectively shown that macrophage repolarization in the tumor microenvironment can be achieved by inhibition of the CSF1/CSF1R signaling pathway, and is associated with phenotypic modifications such as activation/enhancement of CD8 + T‐cell mediated immunity and suppression of the angiogenic potential .…”

“…Further IHC/IF analyses on TMEM sites have indicated that each functional TMEM site is composed of a perivascular macrophage expressing high levels of TIE2, VEGFA, and mannose receptor (MRC1), suggesting they could represent a distinct subpopulation of M2 or M2‐like TAMs. TIE2 HIGH VEGFA HIGH MRC1 HIGH macrophages have been intensely studied as they can induce pro‐angiogenic, pro‐metastatic, immunosuppressive, and chemoresistant niches in a context‐dependent manner. For example, using the well‐described MMTV‐PyMT mouse model of breast carcinoma, it was demonstrated that VEGFA secreted by the TIE2 HIGH macrophage on TMEM sites disassembles the underlying vascular junction proteins, zonula occludens‐1 (ZO1) and vascular‐endothelial cadherin (VE‐CAD), exposing a paracellular passage that metastasizing tumor cells use to escape into the circulation .…”

“…It has also been established that hypoxia induces expression of several chemotactic factors, attracting a variety of BMDCs including monocytes, which differentiate into TAMs expressing the tyrosine kinase receptor TIE2 . TIE2 + TAMs are closely associated with tumor vasculature and support angiogenesis in an angiopoietin‐2‐ (ANG2)‐dependent manner . In this section, we focus on two microenvironmental modifications related to the increased metastatic potential of solid tumors following chemotherapy: neoangiogenesis and TMEM assembly, both of which are mediated by specialized TAM subpopulations.…”

“…TIE2 HIGH VEGFA HIGH MRC1 HIGH macrophages have been intensely studied 8,[96][97][98][99][100][101][102][103][104][105][106][107][108][109][110][111][112][113][114][115] as they can induce pro-angiogenic, pro-metastatic, immunosuppressive, and chemoresistant niches in a contextdependent manner. For example, using the well-described MMTV-PyMT mouse model of breast carcinoma, it was demonstrated that VEGFA secreted by the TIE2 HIGH macrophage on TMEM sites disassembles the underlying vascular junction proteins, zonula occludens-1 (ZO1) and vascular-endothelial cadherin (VE-CAD), exposing a paracellular passage that metastasizing tumor cells use to escape into the circulation.…”

A Comparative Approach of Tumor-Associated Inflammation in Mammary Cancer between Humans and Dogs

“…Evidences from clinical and experimental studies indicate that macrophages are versatile cells that are capable of displaying different functional activities in order to promote breast cancer progression and metastasis [20, 120, 121]. TAMs polarization in mammary tumor sites are modulated by the tumor microenvironment and these cells are “educated” adopting a role that facilitates angiogenesis, matrix breakdown, and tumor cell motility in a COX-2-dependent manner [71, 105].…”