Recent studies have clarified the importance of TAM as major contributors in the regulation of both self-renewal and anticancer drug responses of cancer stem cells through distinct networks of cytokines, chemokines and growth factors. In these processes, TAM interact with and promote the tumorigenicity of cancer stem cells via
production of milk-fat globule-epidermal growth factor–VIII (MFG-E8) and IL-6 through coordinated activation of the STAT3 and sonic hedgehog pathways [51
]. Interestingly, cancer stem cells are the major subset promoting the production of MFG-E8 and IL-6 from macrophages, implying that mediators specifically regulated by cancer stem cells render macrophages with the ability to facilitate the production of tumorigenic factors such as MFG-E8 and IL-6. In this sense, TAM might serve as a component of the “immunological niche”, by which cancer stem cell activities are maintained and amplified within tumor microenvironments ().
Figure 2 TAM serves as the major components of niche microenvironments regulating cancer stem cell functions. MFG-E8 and IL-6 predominantly produced from TAM in a cancer stem cell-specific fashion trigger tumorigenesis and anticancer drug resistance in cancer (more ...)
Cancer stem cells have unique characteristics that manipulate complex signaling cascades which regulate oncogenesis, embryogenesis and self-renewal. In turn, these amplification loop lead to oncogenic addiction, stem cell maintenance, angiogenesis, and immune modulation within tumor microenvironments [52
]. Several oncogenic pathways, including Wnt/β-catenin, Notch, TGF-β/FOXO cascades, support self-renewal capacity and anticancer drug resistance in cancer stem cells [54
]. In addition, recent studies have revealed the indispensable role of the IL-6-Stat3 signal cascade in stimulating cancer stem cell activities in coordination with NF-kB-dependent inflammatory signals derived from tumor cells and their microenvironment [56
]. Moreover, Hedgehog signals have been identified as sentinels linking oncogenic aberration with the developmental program of normal and cancer stem cells [58
]. In this regards, our findings that MFG-E8 and IL-6 derived from TAM mediate self-renewal and anticancer drug resistance through activation of Stat3 and Hedgehog signals provide additional evidences that TAM play a critical role in activating distinct signals that are crucial to the maintenance of the stem cell properties of tumor cells.
Recent studies in human leukemia and lymphoma have suggested that tumor cells express the antigen CD47, which serves as a “don’t eat me” signal to tumor-associated macrophages by engaging their cognate receptor SIRT-1. Administration of a blocking antibody to CD47 induced macrophage phagocytosis of AML stem cells in vitro
and in mouse models [59
]. These findings provide the first evidence that macrophage phagocytosis serves as a critical mediator of tumor immunosurveillance against leukemia stem cells.
On the other hand, T cell immunoglobulin-mucin domain protein-3 (TIM-3), which is involved in apoptotic cell phagocytosis via
recognition of phosphatidylserine, has been identified as a functional marker for dissecting acute leukemia stem cells from bulk tumor cells [62
]. Furthermore, AML stem cells were eradicated by the administration of a TIM-3-depleting mAb [63
]. Since TIM-3 expression is detectable in macrophages and dendritic cells upon stimulation with toll-like receptor ligands such as LPS, it is of great interest to examine whether TIM-3 is detected in tumor-associated myeloid cells and to determine the functional role of myeloid cell-derived TIM-3 and its phagocytic activity in the regulation of cancer stem cell functions.
In addition, MFG-E8 not only serves as a positive modulator of cancer stem cell activities, but also functions as an immunoregulatory factor within tumor microenvironments by promoting apoptotic cell phagocytosis and inducing Foxp3+
infiltration into tumors [65
]. Moreover, TIM-4, expressed mainly on activated myeloid cells is also critically involved in the phagocytosis of apoptotic cells via
the recognition of phosphatidylserine and the triggering of immune tolerance [67
]. The TAM receptor tyrosine kinase family composed of Axl, Mer-tyrosine kinase and Tyro-3, which serve as phagocytic receptors for apoptotic cells via
recognition of Gas6, regulates innate immune responses and could be involved in the tumorigenic potentials of cancer cells [69
]. It is therefore likely that distinct sets of phagocytosis-associated molecules, such as CD47 / SIRT1, TIM-3, TIM-4, MFG-E8, Gas-6 etc
. recognize distinct tumor subtypes including cancer stem cells, which arise from different backgrounds of oncogenic or epigenetic alterations and drug responsiveness. The identification and characterization of distinct sets of receptor / ligands on phagocytic macrophages may be an ideal strategy with which to investigate the interaction of cancer stem cells and TAM, and may lead to the exploration of new therapeutic targets against cancer stem cells.