András Piffkó,Sean P Pitroda,Hua Laura Liang,Ralph R Weichselbaum
{"title":"双调节蛋白作为转移性癌症辐射诱导全身效应的中介:平衡局部控制与远处进展。","authors":"András Piffkó,Sean P Pitroda,Hua Laura Liang,Ralph R Weichselbaum","doi":"10.1158/1078-0432.ccr-25-2598","DOIUrl":null,"url":null,"abstract":"Metastasis-directed therapies such as stereotactic body radiotherapy (SBRT) are increasingly employed in metastatic cancer patients with limited disease burden. While effective for local control, emerging evidence suggests SBRT may have unintended systemic effects that reshape the tumor-immune landscape. A recent study identifies amphiregulin (AREG), an EGFR ligand, as a key mediator of radiation-induced changes in metastatic behavior. In clinical cohorts and murine models, SBRT led to marked AREG upregulation. Rather than promoting tumor cell proliferation directly, AREG acted through the myeloid compartment, inducing monocyte differentiation into immunosuppressive macrophages and enabling immune escape. Elevated AREG-either at baseline or following SBRT-was associated with increased metastatic progression and inferior survival. Mechanistically, AREG signaling induced CD47 expression on tumor cells, further impairing macrophage-mediated clearance. Therapeutically, AREG blockade, especially combined with anti-CD47 antibodies, synergized with radiotherapy to suppress both local and distant disease in preclinical models. These findings reveal both challenges and opportunities: while radiation effectively suppresses new metastatic seeding, it may reorganize the biological ecosystem in ways that unmask dormant disease. Understanding these dual effects offers therapeutic opportunities through combination approaches targeting radiation-induced pathways. AREG emerges as both a biomarker and therapeutic target. Integrating biomarker-informed strategies with metastasis-directed therapies may be essential for achieving durable disease control and optimizing outcomes in metastatic cancer.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"104 1","pages":""},"PeriodicalIF":10.2000,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Amphiregulin as a Mediator of Radiation-Induced Systemic Effects in Metastatic Cancer: Balancing Local Control with Distant Progression.\",\"authors\":\"András Piffkó,Sean P Pitroda,Hua Laura Liang,Ralph R Weichselbaum\",\"doi\":\"10.1158/1078-0432.ccr-25-2598\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Metastasis-directed therapies such as stereotactic body radiotherapy (SBRT) are increasingly employed in metastatic cancer patients with limited disease burden. While effective for local control, emerging evidence suggests SBRT may have unintended systemic effects that reshape the tumor-immune landscape. A recent study identifies amphiregulin (AREG), an EGFR ligand, as a key mediator of radiation-induced changes in metastatic behavior. In clinical cohorts and murine models, SBRT led to marked AREG upregulation. Rather than promoting tumor cell proliferation directly, AREG acted through the myeloid compartment, inducing monocyte differentiation into immunosuppressive macrophages and enabling immune escape. Elevated AREG-either at baseline or following SBRT-was associated with increased metastatic progression and inferior survival. Mechanistically, AREG signaling induced CD47 expression on tumor cells, further impairing macrophage-mediated clearance. Therapeutically, AREG blockade, especially combined with anti-CD47 antibodies, synergized with radiotherapy to suppress both local and distant disease in preclinical models. These findings reveal both challenges and opportunities: while radiation effectively suppresses new metastatic seeding, it may reorganize the biological ecosystem in ways that unmask dormant disease. Understanding these dual effects offers therapeutic opportunities through combination approaches targeting radiation-induced pathways. AREG emerges as both a biomarker and therapeutic target. 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Amphiregulin as a Mediator of Radiation-Induced Systemic Effects in Metastatic Cancer: Balancing Local Control with Distant Progression.
Metastasis-directed therapies such as stereotactic body radiotherapy (SBRT) are increasingly employed in metastatic cancer patients with limited disease burden. While effective for local control, emerging evidence suggests SBRT may have unintended systemic effects that reshape the tumor-immune landscape. A recent study identifies amphiregulin (AREG), an EGFR ligand, as a key mediator of radiation-induced changes in metastatic behavior. In clinical cohorts and murine models, SBRT led to marked AREG upregulation. Rather than promoting tumor cell proliferation directly, AREG acted through the myeloid compartment, inducing monocyte differentiation into immunosuppressive macrophages and enabling immune escape. Elevated AREG-either at baseline or following SBRT-was associated with increased metastatic progression and inferior survival. Mechanistically, AREG signaling induced CD47 expression on tumor cells, further impairing macrophage-mediated clearance. Therapeutically, AREG blockade, especially combined with anti-CD47 antibodies, synergized with radiotherapy to suppress both local and distant disease in preclinical models. These findings reveal both challenges and opportunities: while radiation effectively suppresses new metastatic seeding, it may reorganize the biological ecosystem in ways that unmask dormant disease. Understanding these dual effects offers therapeutic opportunities through combination approaches targeting radiation-induced pathways. AREG emerges as both a biomarker and therapeutic target. Integrating biomarker-informed strategies with metastasis-directed therapies may be essential for achieving durable disease control and optimizing outcomes in metastatic cancer.
期刊介绍:
Clinical Cancer Research is a journal focusing on groundbreaking research in cancer, specifically in the areas where the laboratory and the clinic intersect. Our primary interest lies in clinical trials that investigate novel treatments, accompanied by research on pharmacology, molecular alterations, and biomarkers that can predict response or resistance to these treatments. Furthermore, we prioritize laboratory and animal studies that explore new drugs and targeted agents with the potential to advance to clinical trials. We also encourage research on targetable mechanisms of cancer development, progression, and metastasis.