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American Journal of Cancer Research (1)
PLoS ONE (1)
Baghdadi, Muhammad (2)
Chiba, Shigeki (2)
Jinushi, Masahisa (2)
Yoshiyama, Hironori (2)
Waziri, Allen (1)
Yamashina, Tsunaki (1)
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Regulation of cancer stem cell activities by tumor-associated macrophages
American Journal of Cancer Research
Recent studies revealed that tumor-associated macrophages play a decisive role in the regulation of tumor progression by manipulating tumor oncogenesis, angiogenesis and immune functions within tumor microenvironments. However, the role of cancer stem cells in the tumorigenic activities of tumor-associated macrophages during the course of transformation and treatment remains largely unknown. Recent studies have clarified the functional aspects of tumor-associated macrophages in the regulation of the tumorigenic activities and anticancer drug responsiveness of cancer stem cells through complex networks formed by distinct sets of cytokines, chemokines and growth factors. In this article we discuss recent advances and future perspectives regarding the molecular interplay between cancer stem cells and tumor-associated macrophages and provide future perspective about the therapeutic implication against treatment-resistant variants of cancer.
Cancer stem cells; tumor associated macrophages; tumor microenvironments; MFG-E8; IL-6; TIM-3; M-CSF
MFG-E8 Regulates the Immunogenic Potential of Dendritic Cells Primed with Necrotic Cell-Mediated Inflammatory Signals
Dendritic cells (DC) manipulate tissue homeostasis by recognizing dying cells and controlling immune functions. However, the precise mechanisms by which DC recognize different types of dying cells and devise distinct immunologic consequences remain largely obscure. Herein, we demonstrate that Milk-fat globule-EGF VIII (MFG-E8) is a critical mediator controlling DC immunogenicity in inflammatory microenvironments. MFG-E8 restrains DC-mediated uptake and recognition of necrotic cells. The MFG-E8-mediated suppression of necrotic cell uptake by DC resulted in the decreased proinflammatory cytokines production and activated signal components such as STAT3 and A20, which are critical to maintain tolerogenic properties of DC. Furthermore, the DC-derived MFG-E8 negatively regulates the cross-priming and effector functions of antigen-specific T cells upon recognition of necrotic cells. MFG-E8 deficiency enhances an ability of necrotic cell-primed DC to stimulate antitumor immune responses against established tumors. Our findings define what we believe to a novel mechanism whereby MFG-E8 regulates the immunogenicity of DC by modulating the modes of recognition of dying cells. Manipulating MFG-E8 levels in DC may serve as a useful strategy for controlling inflammatory microenvironments caused by various pathological conditions including cancer and autoimmunity.
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