Induction of Vasculogenic Mimicry Overrides VEGF-A Silencing and Enriches Stem-like Cancer Cells in Melanoma.
Induction of Vasculogenic Mimicry Overrides VEGF-A Silencing and Enriches Stem-like Cancer Cells in Melanoma.
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DOI：
10.1158/0008-5472.can-14-1855
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发表时间：
2015-04-15
期刊：
影响因子：
11.2
通讯作者：
Hsu MY
中科院分区：
文献类型：
--
作者：
Schnegg CI;Yang MH;Ghosh SK;Hsu MY
尽管其临床重要性，但对VEGF抑制的抗性的基础尚未完全理解。在这项研究中，我们研究了适应性反应VEGF-A抑制的功能丧失分析使用质粒为基础的shRNA。最初对VEGF-A抑制有反应的肿瘤异种移植物在体内经历适应，导致获得性抗性。肿瘤中VEGF-A阻断与HIF-1α表达和CD 144+血管生成拟态（VM）增加相关，导致形成显示Tie-1和MMP-2上调的通道。CD 133+和CD 271+黑色素瘤干细胞样细胞（MSLC）聚集在血管周围的小生境。与非靶标对照对应物相比，对VEGF-A阻断具有内在抗性的黑素瘤细胞群体的肿瘤异种移植物未表现出任何这些特征。因此，最初对VEGF-A阻断敏感的黑色素瘤通过采用VM作为替代血管生成策略获得适应性抗性，从而通过HIF-1α依赖性过程在血管周围小生境中富集MSLC沉积。相反，本质上对VEGF-A阻断具有抗性的黑素瘤没有显示出促进MSLC积累的代偿性存活机制的任何证据。我们的工作强调了抗VEGF治疗的潜在风险，因为适应性耐药机制的选择性压力促进了干细胞样癌细胞的发育，这对如何设计可以改善患者预后的联合疗法产生了影响。
The basis for resistance to VEGF inhibition is not fully understood despite its clinical importance. In this study, we examined the adaptive response to VEGF-A inhibition by a loss-of-function analysis using plasmid-based shRNA. Tumor xenografts that initially responded to VEGF-A inhibition underwent an adaptation in vivo leading to acquired resistance. VEGF-A blockade in tumors was associated with HIF-1α expression and an increase in CD144+ vasculogenic mimicry (VM), leading to formation of channels displaying Tie-1 and MMP-2 upregulation. CD133+ and CD271+ melanoma stem-like cells (MSLC) accumulated in the perivascular niche. Tumor xenografts of melanoma cell populations that were intrinsically resistant to VEGF-A blockade did not exhibit any of these features, compared to non-target control counterparts. Thus, melanomas which are initially sensitive to VEGF-A blockade acquire adaptive resistance by adopting VM as an alternate angiogenic strategy, thereby enriching for deposition of MSLC in the perivascular niche through a HIF-1α-dependent process. Conversely, melanomas which are intrinsically resistant to VEGF-A blockade do not show any evidence of compensatory survival mechanisms that promote MSLC accumulation. Our work highlights the potential risk of anti-VEGF treatments owing to a selective pressure for an adaptive resistance mechanism that empowers the development of stem-like cancer cells, with implications for how to design combination therapies that can improve outcomes in patients.