Jagged Ligands Enhance the Pro-Angiogenic Activity of Multiple Myeloma Cells.
Jagged Ligands Enhance the Pro-Angiogenic Activity of Multiple Myeloma Cells.
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DOI：
10.3390/cancers12092600
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发表时间：
2020-09-11
期刊：
影响因子：
5.2
通讯作者：
Chiaramonte R
中科院分区：
文献类型：
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作者：
Palano MT;Giannandrea D;Platonova N;Gaudenzi G;Falleni M;Tosi D;Lesma E;Citro V;Colombo M;Saltarella I;Ria R;Amodio N;Taiana E;Neri A;Vitale G;Chiaramonte R
配体的Jagged家族在多发性骨髓瘤进展期间异常表达，并有助于激活骨髓瘤细胞和附近骨髓细胞群中的Notch信号传导，从而激活几种促肿瘤效应。这项工作阐明，在体外，在体内以及在患者的骨髓活检，不同的机制，肿瘤细胞衍生的锯齿状蛋白1和2有助于骨髓瘤相关的血管生成。这些包括诱导骨髓瘤和骨髓基质细胞分泌VEGF的能力，沿着直接激活内皮细胞中的促血管生成Notch信号通路。本研究为多发性骨髓瘤的锯齿状导向治疗提供了理论依据。多发性骨髓瘤（MM）是一种主要发生在骨髓（BM）内的不可治愈的浆细胞恶性肿瘤。在MM进展期间，肿瘤细胞和BM微环境中发生不同的修饰，包括血管生成转变，其特征在于内皮细胞组织网络、迁移和表达血管生成因子（包括血管内皮生长因子（VEGF））的能力增加。在这里，我们研究了Notch配体Jagged 1和Jagged 2在疾病进展过程中发生的失调对MM细胞和BM基质细胞（BMSC）血管生成潜力的功能结果。通过RNA干扰或可溶性肽给药调节Jagged 1 -2表达，并在体外分析对MM细胞系诱导人肺动脉细胞（HPAEC）血管生成或间接增加BMSC血管生成潜力的能力的影响;在斑马鱼模型和MM患者的BM活检中进行体内验证。总之，我们的结果表明MM衍生的Jagged配体（1）通过直接触发HPAEC中的Notch激活或刺激血管生成因子的释放来增加肿瘤细胞血管生成潜力，即，VEGF;和（2）刺激BMSC以通过VEGF分泌促进血管生成。在MM进展期间观察到的BM中Notch活化的促血管生成作用提供了靶向Jagged配体的疗法的潜力的进一步证据。
The Jagged family of ligands are aberrantly expressed during multiple myeloma progression and contributes to activate Notch signaling both in myeloma cells and in the nearby bone marrow cell populations activating several pro-tumor effects. This work elucidates, in vitro, in vivo as well as in patients’ bone marrow biopsies, different mechanisms by which tumor cell-derived Jagged1 and 2 contribute to myeloma-associated angiogenesis. These include the ability to induce myeloma and bone marrow stromal cell secretion of VEGF along with a direct activation of the pro-angiogenic Notch signaling pathway in endothelial cells. This research provides a rational for a Jagged-directed therapy in multiple myeloma. Multiple myeloma (MM) is an incurable plasma cell malignancy arising primarily within the bone marrow (BM). During MM progression, different modifications occur in the tumor cells and BM microenvironment, including the angiogenic shift characterized by the increased capability of endothelial cells to organize a network, migrate and express angiogenic factors, including vascular endothelial growth factor (VEGF). Here, we studied the functional outcome of the dysregulation of Notch ligands, Jagged1 and Jagged2, occurring during disease progression, on the angiogenic potential of MM cells and BM stromal cells (BMSCs). Jagged1–2 expression was modulated by RNA interference or soluble peptide administration, and the effects on the MM cell lines’ ability to induce human pulmonary artery cells (HPAECs) angiogenesis or to indirectly increase the BMSC angiogenic potential was analyzed in vitro; in vivo validation was performed on a zebrafish model and MM patients’ BM biopsies. Overall, our results indicate that the MM-derived Jagged ligands (1) increase the tumor cell angiogenic potential by directly triggering Notch activation in the HPAECs or stimulating the release of angiogenic factors, i.e., VEGF; and (2) stimulate the BMSCs to promote angiogenesis through VEGF secretion. The observed pro-angiogenic effect of Notch activation in the BM during MM progression provides further evidence of the potential of a therapy targeting the Jagged ligands.
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影响因子：
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作者：
Colombo M;Thümmler K;Mirandola L;Garavelli S;Todoerti K;Apicella L;Lazzari E;Lancellotti M;Platonova N;Akbar M;Chiriva-Internati M;Soutar R;Neri A;Goodyear CS;Chiaramonte R
通讯作者：
Chiaramonte R
影响因子：
20.3
作者：
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通讯作者：
Gabrilovich, Dmitry I.
影响因子：
5.2
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通讯作者：
Axelson, Hakan
影响因子：
3.7
作者：
Ghiabi P;Jiang J;Pasquier J;Maleki M;Abu-Kaoud N;Rafii S;Rafii A
通讯作者：
Rafii A
影响因子：
11.2
作者：
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通讯作者：
Bellido T