Monocyte Regulation in Homeostasis and Malignancy

Abstract

Monocytes are progenitors to macrophages and a subclass of dendritic cells (monocyte-derived dendritic cells, MoDCs), but they also act as circulating sensors that respond to environmental changes and disease. Technological advances have defined the production of classical monocytes in the bone marrow through the identification of lineage-determining transcription factors (LDTFs) and have proposed alternative routes of differentiation. Monocytes released into the circulation can be recruited to tissues by specific chemoattractants where they respond to sequential niche-specific signals that determine their differentiation into terminal effector cells. New aspects of monocyte biology in the circulation are being revealed, exemplified by the influence of cancer on the systemic alteration of monocyte subset abundance and transcriptional profiles. These changes can act to enhance the metastatic spread of primary cancers and may offer therapeutic opportunities.

Figure 1.. Monocyte differentiation in blood and tissues

Classical monocytes differentiate into non-classical monocytes through an intermediary stage. Markers are shown for human (top) and mouse (bottom). Classical monocytes extravasate into tissues to replace resident macrophages, participate in wound responses, contribute to pathogenic tissue inflammation, and promote tumor progression and metastasis. Non-classical monocytes are retained in vessels where they perform surveillance and monitor pathogenic insults. They can also extravasate at sites of metastasis and inhibit tumor cell establishment through a NK cell mediate mechanism.

Figure 2.. Differentiation of circulating monocytes from bone marrow progenitor cells

Differentiation from early progenitors through progressively restricted ones that are then released into the circulation as classical monocytes (mice and humans) is regulated by the sequential expression of transcription factors (shown at the top). Alternative pathways to non-classical monocytes have also been proposed as indicated by the arrow. HSCs; hematopoietic stem cells, CMP; common myeloid progenitor cells, GMP; granulocytic myeloid progenitor cells, MDP; bipotent macrophage dendritic cell progenitor, cMoP; unipotent common monocyte progenitor.

Figure 3.. Molecular mechanisms by which niche-specific signals promote monocyte differentiation into different macrophage phenotypes (mice and humans).

Panel A. Niche specific signals induce the expression of lineage determining factors (LDTFs) that collaborate with core macrophage LDTFs to drive the selection of new enhancers. Pre-existing and new enhancers are further influenced by the actions of broadly expressed signal-dependent transcription factors that mediate the effects of internal and external signals. Panel B. Sequence motifs enriched in Kupffer cell specific enhancers can enable inference of the transcription factors and upstream signaling pathways that drive differentiation from progenitor cells. For each motif, corresponding transcription factors, upstream signaling pathways, and sources of liver-specific signals are indicated.

Figure 4.. Origin of tumor- and metastasis-associated macrophages in mouse models of breast cancer.

Classical monocytes are recruited to both primary and metastatic sites via a CCL2-CCR2 driven chemokine signaling pathway. In the primary tumor, these recruited monocytes undergo sequential development into TAMs, which are first involved in a streaming behavior that drives tumor cell invasion via a CSF1-Epidermal growth factor (EGF) paracrine loop, before being recruited to vessels by fibroblast expressed CXCL12. On the vessel, these TAMs enhance tumor cell intravasation by expressing VEGFA. At metastatic sites, the circulating tumor cells recruit classical monocytes expressing VEGFA (causing vessel permeability) that upon arrival, promotes the extravasation of the latter. Subsequent signaling pathways (as indicated), result in monocyte differentiation through a progenitor stage (MAMPC) --that is immuno-suppressive via production of reactive oxygen species (ROS)-- into a MAM that confers survival signals to tumor cells via vascular cell adhesion protein 1 (VCAM1) engagement. These MAMs further differentiate, supporting metastatic tumor growth via the depicted signaling pathways; this process occurs in part via inhibition of cytotoxic CD8⁺ T cells and NK cell effector functions.

Figure 5.

Proportions and tumor specific phenotypes of monocyte-derived and microglia-derived tumor associated macrophages in metastatic brain tumors and glioblastoma.