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。

IF 10.2 1区 医学 Q1 ONCOLOGY
András Piffkó,Sean P Pitroda,Hua Laura Liang,Ralph R Weichselbaum
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引用次数: 0

摘要

定向转移治疗,如立体定向放射治疗(SBRT)越来越多地用于转移性癌症患者,疾病负担有限。虽然对局部控制有效,但新出现的证据表明,SBRT可能会产生意想不到的系统性影响,重塑肿瘤免疫景观。最近的一项研究发现,双调节蛋白(AREG)是一种EGFR配体,是辐射诱导转移行为改变的关键介质。在临床队列和小鼠模型中,SBRT导致AREG显著上调。AREG不是直接促进肿瘤细胞增殖,而是通过髓系室起作用,诱导单核细胞分化为免疫抑制巨噬细胞,使免疫逃逸。在基线或sbrt后,areg升高与转移进展加快和生存期降低有关。在机制上,AREG信号诱导CD47在肿瘤细胞上的表达,进一步损害巨噬细胞介导的清除。在治疗上,在临床前模型中,AREG阻断,特别是与抗cd47抗体联合,与放疗协同抑制局部和远处疾病。这些发现揭示了挑战和机遇:虽然辐射有效地抑制了新的转移性播种,但它可能以揭露潜伏疾病的方式重组生物生态系统。了解这些双重效应可以通过针对辐射诱导途径的联合方法提供治疗机会。AREG是一种生物标志物和治疗靶点。将生物标志物知情策略与转移导向治疗相结合,可能是实现持久疾病控制和优化转移性癌症预后的必要条件。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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.
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来源期刊
Clinical Cancer Research
Clinical Cancer Research 医学-肿瘤学
CiteScore
20.10
自引率
1.70%
发文量
1207
审稿时长
2.1 months
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.
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