Characterization of macrophage - cancer cell crosstalk in estrogen receptor positive and triple-negative breast cancer

Abstract

Tumor heterogeneity may broadly influence the activation of tumor-associated macrophages. We aimed to dissect how breast cancer cells of different molecular characteristics contribute to macrophage phenotype and function. Therefore, we performed whole transcriptome sequencing of human monocytes that were co-cultured with estrogen receptor positive (ER+) or triple-negative (TNBC) breast cancer cell lines and studied the biological responses related to the differential gene activation in both monocytes and cancer cells by pathway analysis. ER+ and TNBC cancer cell lines induced distinctly different macrophage phenotypes with different biological functions, cytokine and chemokine secretion, and morphology. Conversely, ER+ and TNBC breast cancer cell lines were distinctly influenced by the presence of macrophages. ER+ cells demonstrated up-regulation of an acute phase inflammatory response, IL-17 signaling and antigen presentation pathway, whereas thioredoxin and vitamin D3 receptor pathways were down-regulated in the respective macrophages. The TNBC educated macrophages down-regulated citrulline metabolism and differentiated into M2-like macrophages with increased MMR protein expression and CCL2 secretion. These data demonstrate how different cancer cells educate the host cells to support tumor growth and might explain why high infiltration of macrophages in TNBC tumors associates with poor prognosis.

Basal‐like breast cancer engages tumor‐supportive macrophages via secreted factors induced by extracellular S100A4

“…We showed that upon S100A4 stimulation, basal‐like BCCs secrete factors that trigger monocyte‐to‐macrophage differentiation and polarization. This is in line with previous studies demonstrating that basal‐like/TNBC, compared to luminal BC, have superior abilities to recruit macrophages (Espinoza et al ., 2016; Sousa et al ., 2015), modulate their polarization, and stimulate protumorigenic functions (Hollmen et al ., 2015; Sousa et al ., 2015; Stewart et al ., 2012; Su et al ., 2014). The current study adds to the previous knowledge by revealing a strong potentiating influence of S100A4, which is expressed at elevated levels in basal‐like/TNBC as also reported previously (Egeland et al ., 2017).…”

A CCL8 gradient drives breast cancer cell dissemination

“…This cluster harbors several chemoattractive cytokines many of which previously have been associated with tumorigenesis primarily through generation of a tumor-promoting proinflammatory microenvironment (Figure 1a, refs 10, 11, 12). …”

Spheroids Formation on Non‐Adhesive Surfaces by Liquid Overlay Technique: Considerations and Practical Approaches

“…[3] In the last few decades, with the development of 2D cells co-cultures, these models gained the ability to better represent the cellular heterogeneity found in different human tissues. For instance, tumor cellular heterogeneity has been mimicked by seeding cancer cells along with stem-like cells, [4] fibroblasts, [5] macrophages, [6] among others. Additionally, the central nervous system architecture has been reproduced by growing embryonic cortical neurons in the presence of cortical microglia, [7] while hepatocyte/Kupffer cells co-cultures have been used to study immune-related responses to drugs.…”