sFRP2 Supersedes VEGF as an Age-related Driver of Angiogenesis in Melanoma, Affecting Response to Anti-VEGF Therapy in Older Patients.
sFRP2 Supersedes VEGF as an Age-related Driver of Angiogenesis in Melanoma, Affecting Response to Anti-VEGF Therapy in Older Patients.
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DOI：
10.1158/1078-0432.ccr-20-0446
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发表时间：
2020-11-01
期刊：
影响因子：
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通讯作者：
Weeraratna AT
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文献类型：
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作者：
Fane ME;Ecker BL;Kaur A;Marino GE;Alicea GM;Douglass SM;Chhabra Y;Webster MR;Marshall A;Colling R;Espinosa O;Coupe N;Maroo N;Campo L;Middleton MR;Corrie P;Xu X;Karakousis GC;Weeraratna AT
血管生成被认为是肿瘤转移的关键。然而，使用贝伐单抗(阿瓦斯丁)等抗体抑制血管生成对黑色素瘤患者的生存几乎没有影响。我们已经证明，在老年人中，血管生成和转移都会增加，因此我们试图调查贝伐单抗对年龄的反应是否存在与年龄相关的差异，如果是，潜在的机制可能是什么。我们分析了Avast-M试验中1343名接受贝伐单抗治疗的黑色素瘤患者的数据，以确定贝伐单抗是否存在年龄相关性反应。我们还检测了在黑色素瘤患者中与年龄相关的血管内皮生长因子及其同源受体的表达，同时使用同基因黑色素瘤动物模型在年轻和老年小鼠中靶向血管内皮生长因子。我们还检测了与年龄相关的促血管生成因子SFRP2，以及它是否可以调节对抗血管内皮生长因子治疗的反应。我们显示，老年患者对贝伐单抗的反应很差，而年轻患者在无病生存率和总体生存率方面都有改善。我们发现，靶向血管内皮生长因子并不能抑制老龄小鼠模型中的血管生成，而SFRP2在体外和年轻小鼠中都能促进血管生成。在老年小鼠中靶向SFRP2成功地消融了血管生成，而在年轻小鼠中靶向VEGF的影响可以通过增加SFRP2来克服。血管内皮生长因子在衰老过程中降低，从而降低了对贝伐单抗的反应。尽管血管内皮生长因子减少，但由于老年肿瘤微环境中SFRP2的增加，血管生成增加。这些结果强调了将年龄作为设计靶向治疗的一个因素的重要性。
Angiogenesis is thought to be critical for tumor metastasis. However, inhibiting angiogenesis using antibodies such as bevacizumab (Avastin), has had little impact on melanoma patient survival. We have demonstrated that both angiogenesis and metastasis are increased in older individuals, and therefore sought to investigate if there was an age-related difference in response to bevacizumab, and if so, what the underlying mechanism could be. We analyzed data from the AVAST-M trial of 1343 melanoma patients treated with bevacizumab to determine if there is an age-dependent response to bevacizumab. We also examined the age-dependent expression of VEGF and its cognate receptors in melanoma patients, while using syngeneic melanoma animal models to target VEGF in young vs old mice. We also examined the age-related proangiogenic factor sFRP2 and if it could modulate response to anti-VEGF therapy. We show that older patients respond poorly to bevacizumab, whereas younger patients show improvement in both disease-free and overall survival. We find that targeting VEGF does not ablate angiogenesis in an aged mouse model, while sFRP2 promotes angiogenesis in vitro and in young mice. Targeting sFRP2 in aged mice successfully ablates angiogenesis, while the effects of targeting VEGF in young mice can be overcome by increasing sFRP2. VEGF is decreased during aging, thereby reducing response to bevacizumab. Despite the decrease in VEGF, angiogenesis is increased, due to an increase in sFRP2 in the aged tumor microenvironment. These results stress the importance of considering age as a factor for designing targeted therapies.