Osteoclast-like stromal giant cells in breast cancer likely belong to the spectrum of immunosuppressive tumor-associated macrophages

Abstract

Background: Breast cancer with osteoclast-like stromal giant cells (OSGC) is an exceedingly rare morphological pattern of invasive breast carcinoma. The tumor immune microenvironment (TIME) of these tumors is populated by OSGC, which resemble osteoclasts and show a histiocytic-like immunophenotype. Their role in breast cancer is unknown. The osteoclast maturation in the bone is regulated by the expression of cytokines that are also present in the TIME of tumors and in breast cancer tumor-associated macrophages (TAMs). TAMs-mediated anti-tumor immune pathways are regulated by miRNAs akin to osteoclast homeostasis. Here, we sought to characterize the different cellular compartments of breast cancers with OSGC and investigate the similarities of OSGC with tumor and TIME in terms of morphology, protein, and miRNA expression, specifically emphasizing on monocytic signatures.Methods and Results: Six breast cancers with OSGC were included. Tumor-infiltrating lymphocytes (TILs) and TAMs were separately quantified. The different cellular populations (i.e., normal epithelium, cancer cells, and OSGC) were isolated from tissue sections by laser-assisted microdissection. After RNA purification, 752 miRNAs were analyzed using a TaqMan Advanced miRNA Low-Density Array for all samples. Differentially expressed miRNAs were identified by computing the fold change (log2Ratio) using the Kolmogorov-Smirnov test and p values were corrected for multiple comparisons using the false discovery rate (FDR) approach. As a similarity analysis among samples, we used the Pearson test. The association between pairs of variables was investigated using Fisher exact test. Classical and non-classical monocyte miRNA signatures were finally applied. All OSGC displayed CD68 expression, TILs (range, 45–85%) and high TAMs (range, 35–75%). Regarding the global miRNAs profile, OSGC was more similar to cancer cells than to non-neoplastic ones. Shared deregulation of miR-143-3p, miR-195-5p, miR-181a-5p, and miR-181b-5p was observed between OSGC and cancer cells. The monocyte-associated miR-29a-3p and miR-21-3p were dysregulated in OSGCs compared with non-neoplastic or breast cancer tissues.Conclusion: Breast cancers with OSGC have an activated TIME. Shared epigenetic events occur during the ontogenesis of breast cancer cells and OSGC but the innumophenotype and miRNA profiles of the different cellular compartmens suggest that OSGC likely belong to the spectrum of M2 TAMs.

Undifferentiated carcinoma of the liver with osteoclast-like giant cells: a case report and literature review

“…They express a series of cytokines, chemokines, tumor growth, metastasis, and immunosuppression [ 46 ]. Sajjadi [ 47 ] found several similarities between OGCs and M2 tumor-associated macrophages, particularly in their morphology and immunophenotype, and a miRNA monocytic signature. Hatano [ 48 ] established an in vivo OGC maturation model, and OGCs in the tumor environment accelerated the growth of tumors independent of macrophage colony-stimulating factor or receptor activator of nuclear factor-kappa B ligand.…”

Squamous cell carcinoma of uterine cervix with osteoclast‑like giant cells: A case report

“…Although the nature of the OGCs remains uncertain some researchers propose a syncytial fusion of macrophages, mirroring the process observed in osteoclastogenesis. The osteoclast maturation is regulated by the expression of cytokines, which are also expressed in tumor-associated macrophages and immune cells, so it is hypothesized that OGCs share molecular features with macrophages present within the tumor (13)(14)(15). In fact, in the context of breast and pancreas cancer, it has been noted that this type of tumors present a highly vascularized microenvironment alongside inflammatory cells (lymphocytes, histiocytes) (15,16).…”

“…The osteoclast maturation is regulated by the expression of cytokines, which are also expressed in tumor-associated macrophages and immune cells, so it is hypothesized that OGCs share molecular features with macrophages present within the tumor (13)(14)(15). In fact, in the context of breast and pancreas cancer, it has been noted that this type of tumors present a highly vascularized microenvironment alongside inflammatory cells (lymphocytes, histiocytes) (15,16). In other locations such as skin or uterine cervix these characteristics are not so well defined.…”

Macrophage response mediated by extracellular matrix: recent progress

“…Among the enriched miRNAs in MBVs, three were selected according to the sequencing results. All of these miRNAs, miR-125b-5p [93,94], miR-143-3p [95,96], and miR-145-5p [97][98][99], has been reported to contribute to pro-regenerative macrophage phenotype polarization. miRNA inhibition resulted in gene expression patterns opposite those of macrophages treated with MBVs.…”