Five Pathways of Macrophage-Mediated Tumor Metastasis

Macrophage-mediated tumor metastasis refers to the critical role of macrophages in the spread of cancer cells from the primary tumor site to other parts of the body. Understanding the involvement of macrophages in this process is critical for the development of more effective cancer treatment and metastasis prevention strategies.

The following are the five main pathways involved in macrophage-mediated tumor metastasis.

Fig. 1 Tumour-associated macrophages (TAMs) play a cancer-promoting role.¹

TAMs Promote Epithelioid Mesenchymal Transformation (EMT)

In this process, early proliferating epithelioid carcinoma cells lose cell-to-cell adhesion and tend to have a fibroblast-like phenotype with invasive and migratory properties.

At the molecular level, EMT is coordinated by the transcription factors ZEB1, Snail, and Twist. TAMs can regulate these EMT regulators through their secreted factors.

TAM-produced TNF-α can stabilize Snail through NF-kB signaling.
TAM-produced TGF-β induces Snail and ZEB1 expression through activation of the β-Catenin pathway.
GM-CSF production by MSCs induced TAM activation and CCL18 production, which in turn promoted a positive feedback loop in EMT.

At metastatic sites, TAM secretes IL-35, which reverses EMT by activating JAK2-STAT6-GATA3 signaling to promote metastatic colonization of tumor cells.

TAMs Actively Remodel the Extracellular Matrix (ECM)

TAMs express and secrete a variety of membrane-associated proteins that degrade ECM collagen fibers, such as matrix metalloproteinases (MMPs), cysteine-rich acidic secretory proteins, and histones.

Once degraded, TAMs regulate the turnover of collagen fragments by degrading lysosomes via phagocytosis and histones.

Tumor Microenvironment Metastasis (TMEM) Doorways

The TMEM doorway is characterized by the physical and dynamic association of an endothelial cell, a TAM, and a cancer cell with each other. This structure is necessary for metastatic spread of tumor cells because transient vascular permeability and tumor cell endocytosis occur simultaneously only within the TMEM.

TMEM-associated macrophages regulate vascular permeability and tumor cell endocytosis.

Extracellular Vesicles (EVs) Secreted by Monocyte-Derived Macrophages

Once exosomes from the primary tumor reach the tissue site, they are phagocytosed by tissue-resident macrophages (RTMs), which triggers pre-metastatic niche formation. Integrins on the surface of tumor exosomes drive organ tropism of tumor metastasis.

In the liver, ITGαvβ5+ exosomes bind specifically to Kupffer cells.
In pancreatic tumors, EV-delivered macrophage migration inhibitory factor remotely induces TGF-β production by hepatic kupffer cells, which results in the activation of hepatic stellate cells (HSCs).
In lung adenocarcinoma, EVs significantly induced lymph node CD68+ macrophages to upregulate CD206, PD-L1, and GLUT1, which promote pre-metastatic niche through glycolysis.

Tissue-resident Macrophages (RTMs) and Metastasis-associated Macrophages (MAMs)

Activated RTMs after receiving exosomes can further activate fibroblasts, inhibit NK cells, suppress fitness immunity, promote inflammation and immune cell recruitment, and help establish a tumor-friendly environment.

In this setting, monocytes can be recruited into the pre-metastatic ecotone of the tumor, resulting in the production of MAMs.
MAMs may have roles in cancer cell extravasation and T cell suppression, which in turn promote metastatic progression.

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Reference

Cassetta, et al. "A timeline of tumour-associated macrophage biology." Nature Reviews Cancer 23.4 (2023): 238-257.