Blockade of CD47-mediated cathepsin S/protease-activated receptor 2 signaling provides a therapeutic target for hepatocellular carcinoma

Lee, Terence; Cheung, Vincent Chi-Ho; Lü, Ping; Lau, Eunice Y.; Ma, Stephanie; Tang, Kwan Ho; Tong, Man; Lo, Jessica; Ng, Irene Oi Lin

doi:10.1002/hep.27070

Cited by 177 publications

(168 citation statements)

References 29 publications

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“…CD47 is preferentially expressed on bladder, liver, and pancreatic CSCs compared with the bulk cancer cells (non-CSCs) (33)(34)(35)(36). To investigate whether CD47 plays a role in breast CSCs, we first analyzed CD47 mRNA levels in SUM159 cells, which were cultured as standard adherent monolayers or as nonadherent spheroids (mammospheres), which are highly enriched for CSCs (37).…”

mentioning

confidence: 99%

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

Zhang

Xiang

et al. 2015

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

323

256

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Increased expression of CD47 has been reported to enable cancer cells to evade phagocytosis by macrophages and to promote the cancer stem cell phenotype, but the molecular mechanisms regulating CD47 expression have not been determined. Here we report that hypoxia-inducible factor 1 (HIF-1) directly activates transcription of the CD47 gene in hypoxic breast cancer cells. Knockdown of HIF activity or CD47 expression increased the phagocytosis of breast cancer cells by bone marrow-derived macrophages. CD47 expression was increased in mammosphere cultures, which are enriched for cancer stem cells, and CD47 deficiency led to cancer stem cell depletion. Analysis of datasets derived from thousands of patients with breast cancer revealed that CD47 expression was correlated with HIF target gene expression and with patient mortality. Thus, CD47 expression contributes to the lethal breast cancer phenotype that is mediated by HIF-1.

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mentioning

confidence: 99%

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

Zhang

Xiang

et al. 2015

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

323

256

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“…Therapeutic applications for cancer. The abnormal vasculature of tumors tends to be unresponsive to NO (88), but the ability of CD47 blockade to modulate responses to radiation and redox signaling involved in innate and adaptive antitumor immunity provides therapeutic opportunities for improving the activities of both conventional cytotoxic therapies and immunotherapy of cancer (134,147,157,248). Several companies are developing biologics targeting CD47 that are designed to inhibit its interactions with SIRPa, and several of these have entered human clinical trials for cancer patients (NCT02216409, NCT02678338, NCT02953509, NCT02953782, NCT02367196, NCT02488811, and NCT02641002).…”

Section: A Redox Signaling In Stem Cellsmentioning

confidence: 99%

“…In contrast, combining CD47 knockdown or blockade with tumor irradiation or cytotoxic chemotherapy can effectively control tumor growth (134,147,160,246). Although autophagy is required for the cytoprotective effect of CD47 blockade in nonmalignant tissue (244), mechanisms by which blockade may sensitize tumor cells to radiation and chemotherapy remain to be identified.…”

Section: A Redox Signaling In Stem Cellsmentioning

confidence: 99%

“…Studies using hepatocellular and breast carcinoma stem cells have identified genes that exhibit altered expression when CD47 is knocked down or ligated by a therapeutic antibody (109,134). These include regulators of NF-jB in the hepatocellular carcinoma (134), which control oxidative stress responses.…”

Section: A Redox Signaling In Stem Cellsmentioning

confidence: 99%

“…These include regulators of NF-jB in the hepatocellular carcinoma (134), which control oxidative stress responses. The same study reported CD47-dependent expression of thioredoxin-interacting protein (TXNIP), and TXNIP was upregulated by treatment with the CD47 antibody B6H12 in triple negative breast cancer stem cells (109).…”

Section: A Redox Signaling In Stem Cellsmentioning

confidence: 99%

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Regulation of Cellular Redox Signaling by Matricellular Proteins in Vascular Biology, Immunology, and Cancer

Roberts

Kaur

Isenberg

2017

Antioxidants & Redox Signaling

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Significance: In contrast to structural elements of the extracellular matrix, matricellular proteins appear transiently during development and injury responses, but their sustained expression can contribute to chronic disease. Through interactions with other matrix components and specific cell surface receptors, matricellular proteins regulate multiple signaling pathways, including those mediated by reactive oxygen and nitrogen species and H 2 S. Dysregulation of matricellular proteins contributes to the pathogenesis of vascular diseases and cancer. Defining the molecular mechanisms and receptors involved is revealing new therapeutic opportunities. Recent Advances: Thrombospondin-1 (TSP1) regulates NO, H 2 S, and superoxide production and signaling in several cell types. The TSP1 receptor CD47 plays a central role in inhibition of NO signaling, but other TSP1 receptors also modulate redox signaling. The matricellular protein CCN1 engages some of the same receptors to regulate redox signaling, and ADAMTS1 regulates NO signaling in Marfan syndrome. In addition to mediating matricellular protein signaling, redox signaling is emerging as an important pathway that controls the expression of several matricellular proteins. Critical Issues: Redox signaling remains unexplored for many matricellular proteins. Their interactions with multiple cellular receptors remains an obstacle to defining signaling mechanisms, but improved transgenic models could overcome this barrier. Future Directions: Therapeutics targeting the TSP1 receptor CD47 may have beneficial effects for treating cardiovascular disease and cancer and have recently entered clinical trials. Biomarkers are needed to assess their effects on redox signaling in patients and to evaluate how these contribute to their therapeutic efficacy and potential side effects. Antioxid. Redox Signal. 27, 874-911.

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Improving the efficacy of osteosarcoma therapy: combining drugs that turn cancer cell ‘don't eat me’ signals off and ‘eat me’ signals on

et al. 2019

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The long‐term survival of osteosarcoma patients with metastatic or recurrent disease remains dismal, and new therapeutic options are urgently needed. The purpose of our study was to compare the efficacy of CD47 mAb plus doxorubicin combination therapy in mouse models of osteosarcoma with CD47 mAb and doxorubicin monotherapy. Forty‐eight NOD scid gamma (NSG) mice with intratibial MNNG/HOS tumors received CD47 mAb, doxorubicin, combination therapy, or control IgG treatment. Twenty‐four mice (n = 6 per group) underwent pre‐ and post‐treatment magnetic resonance imaging (MRI) scans with the macrophage marker ferumoxytol, bioluminescence imaging, and histological analysis. Tumor ferumoxytol enhancement, tumor flux, and tumor‐associated macrophages (TAM) density were compared between different groups using a one‐way ANOVA. Twenty‐four additional NSG mice underwent survival analyses with Kaplan–Meier curves and a log‐rank (Mantel–Cox) test. Intratibial osteosarcomas demonstrated significantly stronger ferumoxytol enhancement and significantly increased TAM quantities after CD47 mAb plus doxorubicin combination therapy compared to CD47 mAb (P = 0.02) and doxorubicin monotherapy (P = 0.001). Tumor‐bearing mice treated with CD47 mAb plus doxorubicin combination therapy demonstrated significantly reduced tumor size and prolonged survival compared to control groups that received CD47 mAb (P = 0.03), doxorubicin monotherapy (P = 0.01), and control IgG (P = 0.001). In conclusion, CD47 mAb plus doxorubicin therapy demonstrates an additive therapeutic effect in mouse models of osteosarcomas, which can be monitored with an immediately clinically applicable MRI technique.

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Blockade of CD47-mediated cathepsin S/protease-activated receptor 2 signaling provides a therapeutic target for hepatocellular carcinoma

Cited by 177 publications

References 29 publications

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

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

Regulation of Cellular Redox Signaling by Matricellular Proteins in Vascular Biology, Immunology, and Cancer

Improving the efficacy of osteosarcoma therapy: combining drugs that turn cancer cell ‘don't eat me’ signals off and ‘eat me’ signals on

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