A Unidirectional Transition from Migratory to Perivascular Macrophage Is Required for Tumor Cell Intravasation

Abstract

SummaryTumor-associated macrophages (TAMs) are critical for tumor metastasis. Two TAM subsets support cancer cell intravasation: migratory macrophages guide cancer cells toward blood vessels, where sessile perivascular macrophages assist their entry into the blood. However, little is known about the inter-relationship between these functionally distinct TAMs or their possible inter-conversion. We show that motile, streaming TAMs are newly arrived monocytes, recruited via CCR2 signaling, that then differentiate into the sessile perivascular macrophages. This unidirectional process is regulated by CXCL12 and CXCR4. Cancer cells induce TGF-β-dependent upregulation of CXCR4 in monocytes, while CXCL12 expressed by perivascular fibroblasts attracts these motile TAMs toward the blood vessels, bringing motile cancer cells with them. Once on the blood vessel, the migratory TAMs differentiate into perivascular macrophages, promoting vascular leakiness and intravasation.

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

“…In this context, we discussed the literature demonstrating that monocytes which infiltrate tumors can potentially become streaming macrophages, and eventually perivascular macrophages, following a unidirectional transition driven by blood vessel‐derived chemotactic gradients . Although this is direct evidence of phenotypic plasticity in these TAMs, one could argue it is indirect evidence of lineage plasticity, as well.…”

“…Increased TAM influxes, as observed during chemotherapy treatment, exert significant pro‐angiogenic pressure on existing endothelia. Indeed, under the control of the CXCL12/CXCR4 signaling pathway, TAMs newly recruited into neoplastic tissues have been shown to transition into perivascular TAMs that express TIE2 and VEGFA . The pharmacologic suppression of CXCR4 causes a reduction in the number of perivascular TIE2 + TAMs, and therefore, a reduction in tumor revascularization and recurrence following treatment with chemotherapy .…”

Monocyte heterogeneity and functions in cancer

“…Though these cells are morphologically and transcriptionally distinct from both blood monocytes and TAMs, they also appear to be heterogeneous, therefore requiring further investigation. There may be an important spatiotemporal component to monocyte differentiation, as TAMs derived from recently arriving monocytes are more frequently found in collagenous stromal tumor regions and later found in perivascular regions, where they regulate vascular permeability and tumor cell intravasation . Taken together, these results suggest that the differentiation trajectory of recruited classical monocytes is complex, depending on spatial and temporal heterogeneity within the tumor microenvironment.…”

“…For example, treatment with clodronate liposomes results in reduced tumor vascular density in mouse models of metastatic liver cancer and xenografted melanoma, but whether the effect is mediated by depletion of circulating monocytes or TAMs is unclear . Recent evidence suggests that Mϕ differentiation is necessary for supporting vascular function in tumors …”

“…Classical monocytes are believed to be a major source of TAMs, as they are robustly recruited to primary tumors and metastatic sites, while nonclassical monocytes display much lower levels of recruitment . Although CCR2‐deficient monocytes have impaired recruitment into murine breast tumors compared to wild‐type mice, CCR2‐deficient mice do not display reduced accumulation of TAMs in PyMT breast tumors, indicating that CCR2 signaling may not be required for TAM accumulation. TAMs can be proliferative, which could provide a compensatory mechanism when monocyte recruitment is impaired .…”