HIF-1 regulates CD47 expression in breast cancer cells to promote evasion of phagocytosis and maintenance of cancer stem cells

Zhang, Huimin; Lu, Haiquan; Xiang, Lisha; Bullen, John W.; Zhang, Chuanzhao; Samanta, Debangshu; Gilkes, Daniele M.; He, Jing; Semenza, Gregg L.

doi:10.1073/pnas.1520032112

Cited by 339 publications

(276 citation statements)

References 62 publications

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“…Reported previously by us and others (60,61), SIRPα expression in macrophages is decreased following LPS stimulation, suggesting a dynamic nature for the CD47-SIRPα-mediated inhibition especially on infection or activation of TLR. The expression of CD47 on cells can also be changed under different conditions (62)(63)(64). Also reported by us, alteration of clustering structures of SIRPα on macrophages or CD47 on tissue cells affects phagocytosis (65,66).…”

Section: Discussionmentioning

confidence: 76%

Cd47-Sirpα interaction and IL-10 constrain inflammation-induced macrophage phagocytosis of healthy self-cells

Bian

Shi

Guo

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

121

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Rapid clearance of adoptively transferred Cd47-null (Cd47−/−) cells in congeneic WT mice suggests a critical self-recognition mechanism, in which CD47 is the ubiquitous marker of self, and its interaction with macrophage signal regulatory protein α (SIRPα) triggers inhibitory signaling through SIRPα cytoplasmic immunoreceptor tyrosine-based inhibition motifs and tyrosine phosphatase SHP-1/2. However, instead of displaying self-destruction phenotypes, Cd47−/− mice manifest no, or only mild, macrophage phagocytosis toward self-cells except under the nonobese diabetic background. Studying our recently established Sirpα-KO (Sirpα−/−) mice, as well as Cd47−/− mice, we reveal additional activation and inhibitory mechanisms besides the CD47-SIRPα axis dominantly controlling macrophage behavior. Sirpα−/− mice and Cd47−/− mice, although being normally healthy, develop severe anemia and splenomegaly under chronic colitis, peritonitis, cytokine treatments, and CFA-/LPS-induced inflammation, owing to splenic macrophages phagocytizing self-red blood cells. Ex vivo phagocytosis assays confirmed general inactivity of macrophages from Sirpα−/− or Cd47−/− mice toward healthy self-cells, whereas they aggressively attack toward bacteria, zymosan, apoptotic, and immune complex-bound cells; however, treating these macrophages with IL-17, LPS, IL-6, IL-1β, and TNFα, but not IFNγ, dramatically initiates potent phagocytosis toward self-cells, for which only the Cd47-Sirpα interaction restrains. Even for macrophages from WT mice, phagocytosis toward Cd47−/− cells does not occur without phagocytic activation. Mechanistic studies suggest a PKC-Syk–mediated signaling pathway, to which IL-10 conversely inhibits, is required for activating macrophage self-targeting, followed by phagocytosis independent of calreticulin. Moreover, we identified spleen red pulp to be one specific tissue that provides stimuli constantly activating macrophage phagocytosis albeit lacking in Cd47−/− or Sirpα−/− mice.

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Section: Discussionmentioning

confidence: 76%

Cd47-Sirpα interaction and IL-10 constrain inflammation-induced macrophage phagocytosis of healthy self-cells

Bian

Shi

Guo

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

121

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“…Hypoxic signaling can promote resistance to T cell–mediated killing by increasing the expression of programmed death–ligand 1 (PD-L1) on tumor cells and myeloid-derived suppressor cells (MDSCs), and by enhancing CTLA-4 expression on CD8 + T cells, respectively [reviewed in ( 57 )]. Additionally, hypoxic tumor cells evade innate immune recognition through the up-regulation of CD47, a cell surface molecule that interacts with signal regulatory protein alpha (SIRP α) on the surface of macrophages to block phagocytosis ( 58 ).…”

Section: Mechanisms Of Hif-mediated Metastasismentioning

confidence: 99%

Hypoxic control of metastasis

Rankin

Giaccia

2016

Science

1,038

870

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Metastatic disease is the leading cause of cancer-related deaths and involves critical interactions between tumor cells and the microenvironment. Hypoxia is a potent microenvironmental factor promoting metastatic progression. Clinically, hypoxia and the expression of the hypoxia-inducible transcription factors HIF-1 and HIF-2 are associated with increased distant metastasis and poor survival in a variety of tumor types. Moreover, HIF signaling in malignant cells influences multiple steps within the metastatic cascade. Here we review research focused on elucidating the mechanisms by which the hypoxic tumor microenvironment promotes metastatic progression. These studies have identified potential biomarkers and therapeutic targets regulated by hypoxia that could be incorporated into strategies aimed at preventing and treating metastatic disease.

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“…In hypoxic breast cancer cells, HIFs activate the transcription of target genes that play important roles in tumor growth, angiogenesis, metabolic reprogramming, motility, invasion, metastasis, and resistance to chemotherapy (15,16). Recent studies have demonstrated that HIFs are required for the specification and/or maintenance of BCSCs in response to hypoxia (17)(18)(19)(20)(21) or chemotherapy (22,23), leading to direct or indirect transcriptional regulation of genes encoding the pluripotency factors NANOG, SOX2, and KLF4. In addition, HIF-1α is required for hypoxia-induced epithelial-mesenchymal transition (24), which is also linked to the BCSC phenotype (25).…”

mentioning

confidence: 99%

Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m ⁶ A-demethylation of NANOG mRNA

Zhang

Samanta

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

870

818

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N 6 -methyladenosine (m 6 A) modification of mRNA plays a role in regulating embryonic stem cell pluripotency. However, the physiological signals that determine the balance between methylation and demethylation have not been described, nor have studies addressed the role of m 6 A in cancer stem cells. We report that exposure of breast cancer cells to hypoxia stimulated hypoxiainducible factor (HIF)-1α-and HIF-2α-dependent expression of AlkB homolog 5 (ALKBH5), an m 6 A demethylase, which demethylated NANOG mRNA, which encodes a pluripotency factor, at an m 6 A residue in the 3′-UTR. Increased NANOG mRNA and protein expression, and the breast cancer stem cell (BCSC) phenotype, were induced by hypoxia in an HIF-and ALKBH5-dependent manner. Insertion of the NANOG 3′-UTR into a luciferase reporter gene led to regulation of luciferase activity by O 2 , HIFs, and ALKBH5, which was lost upon mutation of the methylated residue. ALKBH5 overexpression decreased NANOG mRNA methylation, increased NANOG levels, and increased the percentage of BCSCs, phenocopying the effect of hypoxia. Knockdown of ALKBH5 expression in MDA-MB-231 human breast cancer cells significantly reduced their capacity for tumor initiation as a result of reduced numbers of BCSCs. Thus, HIF-dependent ALKBH5 expression mediates enrichment of BCSCs in the hypoxic tumor microenvironment.hypoxia-inducible factors | metastasis | pluripotency factors | self-renewal | tumorigenesis B reast cancer has the highest incidence of all cancers affecting women (1). It is also the leading cause of cancer-related death for women worldwide (2). Although progress has been made in treating early-stage breast cancer, there is no effective strategy to prevent or treat metastasis, which is the major cause of breast cancer-related mortality (3). Within breast cancers, a small subpopulation of cells, which are designated as tumor-initiating cells or breast cancer stem cells (BCSCs), have the unique property of generating daughter BCSCs, which are capable of infinite proliferation through self-renewal, and transient amplifying cells, which are capable of a limited number of cell divisions and give rise to differentiated breast cancer cells (4, 5). Only BCSCs are capable of forming a secondary (recurrent or metastatic) tumor (5, 6). As in the case of ES cells (ESCs) (7), the BCSC phenotype is specified by the expression of core pluripotency factors, including Kruppel-like factor 4 (KLF4), Octamer-binding transcription factor 4 (OCT4), SRY-box 2 (SOX2), and NANOG (8-12). Delineation of the molecular mechanisms that regulate the BCSC phenotype is needed to better understand metastasis and design more effective therapies.Intratumoral hypoxia is a common finding in advanced cancers. The median partial pressure of oxygen (pO 2 ) within primary breast cancers is 10 mm Hg [1.4% (vol/vol) O 2 ], compared with 65 mm Hg [9.3% (vol/vol) O 2 ] in normal breast tissue (13). Hypoxia-inducible factors (HIFs) HIF-1 and HIF-2 are heterodimeric transcriptional activators, consisting of an O 2 -regu...

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HIF-1 regulates CD47 expression in breast cancer cells to promote evasion of phagocytosis and maintenance of cancer stem cells

Cited by 339 publications

References 62 publications

Cd47-Sirpα interaction and IL-10 constrain inflammation-induced macrophage phagocytosis of healthy self-cells

Cd47-Sirpα interaction and IL-10 constrain inflammation-induced macrophage phagocytosis of healthy self-cells

Hypoxic control of metastasis

Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m ⁶ A-demethylation of NANOG mRNA

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HIF-1 regulates CD47 expression in breast cancer cells to promote evasion of phagocytosis and maintenance of cancer stem cells

Cited by 339 publications

References 62 publications

Cd47-Sirpα interaction and IL-10 constrain inflammation-induced macrophage phagocytosis of healthy self-cells

Cd47-Sirpα interaction and IL-10 constrain inflammation-induced macrophage phagocytosis of healthy self-cells

Hypoxic control of metastasis

Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m 6 A-demethylation of NANOG mRNA

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Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m ⁶ A-demethylation of NANOG mRNA