A breast cancer stem cell niche supported by juxtacrine signalling from monocytes and macrophages

Abstract

The cell-biological program termed the epithelial-mesenchymal transition (EMT) confers on cancer cells mesenchymal traits and an ability to enter the cancer stem cell (CSC) state. However, the interactions between CSCs and their surrounding microenvironment are poorly understood. Here we show that tumor-associated monocytes and macrophages (TAMs) create a CSC-niche via juxtacrine signaling with CSCs. We performed quantitative proteomic profiling and found that the EMT program upregulates the expression of CD90/Thy1 and EphA4, which mediate the physical interactions of CSCs with TAMs by directly binding with their respective counter-receptors on these cells. In response, the EphA4 receptor on the carcinoma cells activates Src and NF-κB, the latter results in the secretion of a variety of cytokines by the CSCs; these cytokines serve to sustain the stem-cell state. Indeed, admixed macrophages enhance the CSC activities of carcinoma cells. These findings underscore the significance of TAMs as important components of the CSC niche.

Identification of CD90 as Putative Cancer Stem Cell Marker and Therapeutic Target in Insulinomas

“…Although it is difficult to determine which event occurs first, a likely explanation is that EMT contributes to the establishment of CSCs. EMT has been described to upregulate the expression of CD90 on breast cancer and lung cancer cells [38,40]. Furthermore, EMT has been demonstrated to occur in pNETs, since positive immunohistochemical staining of human INS and INS of Rip1tag2 mice was found for SNAI1 and TWIST [11].…”

The Coordinated Actions of TIM-3 on Cancer and Myeloid Cells in the Regulation of Tumorigenicity and Clinical Prognosis in Clear Cell Renal Cell Carcinomas

“…Furthermore, the engagement of membrane-type M-CSF expressed on cancer cells with CD115 on macrophages contributes to this cell-cell interaction (16). Moreover, TAMs support tumorigenic activities and trigger resistance to anticancer drugs by inducing cancer-stem cell properties in tumor cells (28)(29)(30). However, we did not observe myeloid cell-mediated induction of TIM-3 on RCC cell lines in vitro, although RCC tumors express TIM-3 in the vicinity of macrophages in clinical samples.…”

Tumor-induced myeloid deviation: when myeloid-derived suppressor cells meet tumor-associated macrophages

“…Indeed, TAMs can sustain CSC proliferation by releasing proinflammatory cytokines such as TNF-α and IL-6, which reinforce tumor cell proliferation through NF-κB and STAT3 signaling pathways (96,97). These same molecular pathways may be activated through a direct TAM-to-CSC contact via CD90 and ephrin A4 receptors (98). Finally, the crosstalk between CSCs and TAMs induced TAM secretion of milk fat globule EGF factor 8 (MFGE8) and IL-6, which favored CSC reservoir survival during chemotherapeutic treatment (99).…”