Metastatic site-specific polarization of macrophages in intracranial breast cancer metastases

Abstract

In contrast to primary tumors, the understanding of macrophages within metastases is very limited. In order to compare macrophage phenotypes between different metastatic sites, we established a pre-clinical mouse model of intracranial breast cancer metastasis in which cancer lesions develop simultaneously within the brain parenchyma and the dura. This mimics a situation that is commonly occurring in the clinic. Flow cytometry analysis revealed significant differences in the activation state of metastasis-associated macrophages (MAMs) at the two locations. Concurrently, gene expression analysis identified significant differences in molecular profiles of cancer cells that have metastasized to the brain parenchyma as compared to the dura. This included differences in inflammation-related pathways, NF-kB1 activity and cytokine profiles. The most significantly upregulated cytokine in brain parenchyma- versus dura-derived cancer cells was Lymphotoxin β and a gain-of-function approach demonstrated a direct involvement of this factor in the M2 polarization of parenchymal MAMs. This established a link between metastatic site-specific properties of cancer cells and the MAM activation state.

Multitargeted Nanoparticles Deliver Synergistic Drugs across the Blood–Brain Barrier to Brain Metastases of Triple Negative Breast Cancer Cells and Tumor‐Associated Macrophages

“…TAM population within brain tumor microenvironment has been reported to include both tissue‐resident microglia and bone marrow‐derived macrophages 11b. In the present study, the low levels of TMEM119 + microglia in the metastasis regions (Figure a) indicate that most TAMs were likely recruited from the circulation instead of recruitment from the local microenvironment.…”

“…In addition to targeting cancer cells, increasing evidence suggests that targeting stromal cells in the tumor microenvironment (TME) would be of therapeutic significance due to their important role in promoting cancer progression . Of various types of stromal cells, tumor‐associated macrophages (TAMs) are the most abundant cell type in the metastatic microenvironments, including brain metastases . In breast cancer, high TAM density is associated with poor patient prognosis and low efficacy of chemotherapeutic drugs and anticancer immune‐modulating agents 11c,12.…”

“…Of various types of stromal cells, tumor‐associated macrophages (TAMs) are the most abundant cell type in the metastatic microenvironments, including brain metastases . In breast cancer, high TAM density is associated with poor patient prognosis and low efficacy of chemotherapeutic drugs and anticancer immune‐modulating agents 11c,12. Therefore, inhibition or re‐polarization of TAMs by targeting their surface receptors with small molecule inhibitors, monoclonal antibodies, or drug‐encapsulated nanoparticles has shown therapeutic benefit in both preclinical and clinical studies .…”

Foe or friend? Janus-faces of the neurovascular unit in the formation of brain metastases

“…74 Breast cancer cells metastasized to the brain parenchyma may enhance activation of microglia/ macrophages towards the M2 state, with reduced expression of MHC (major histocompatibility complex) class II, CD11c, iNOS (inducible nitric oxide synthase) and arginase-1 and higher expression of CD206 (mannose receptor). 161 In vitro no upregulation of M2-specific cytokines was observed in microglial cells cocultured with breast cancer cells. 76 Therefore, cytokine profile of activated microglia of brain metastatic lesions needs to be clarified.…”

“…Tumor-associated microglia/ macrophages are predominantly resident microglia, but can also be monocytes/macrophages entering the brain from the bone marrow. 161 Interestingly, microglial reaction is heterogeneous throughout metastatic growth. Some extravasated cells or lesions recruit large amounts of activated and reactive microglia, while others can be completely free of microglial cells.…”