Macrophage-Induced Lymphangiogenesis and Metastasis following Paclitaxel Chemotherapy Is Regulated by VEGFR3.
Macrophage-Induced Lymphangiogenesis and Metastasis following Paclitaxel Chemotherapy Is Regulated by VEGFR3.
复制标题
DOI：
10.1016/j.celrep.2016.09.083
复制
发表时间：
2016-10-25
期刊：
影响因子：
8.8
通讯作者：
Shaked Y
中科院分区：
文献类型：
--
作者：
Alishekevitz D;Gingis-Velitski S;Kaidar-Person O;Gutter-Kapon L;Scherer SD;Raviv Z;Merquiol E;Ben-Nun Y;Miller V;Rachman-Tzemah C;Timaner M;Mumblat Y;Ilan N;Loven D;Hershkovitz D;Satchi-Fainaro R;Blum G;Sleeman JP;Vlodavsky I;Shaked Y
虽然化疗强烈限制或逆转肿瘤生长，但宿主组织对治疗的反应可以通过促进肿瘤再生长和/或转移来抵消其抗肿瘤活性，从而限制治疗效果。本研究表明，表达血管内皮生长因子受体3 （VEGFR3）的巨噬细胞浸润化疗后的肿瘤在转移中发挥重要作用。它们这样做的部分原因是由于组织蛋白酶释放诱导淋巴管生成，导致肝素酶上调VEGF-C。我们发现来自化疗小鼠的巨噬细胞足以以vegfr3依赖的方式触发初始肿瘤中的淋巴管活性和结构。阻断VEGF-C/VEGFR3轴抑制化疗诱导的巨噬细胞的活性，导致治疗肿瘤中淋巴管生成减少。总之，我们的研究结果表明，在化疗小鼠中，破坏VEGF-C/VEGFR3轴不仅直接抑制淋巴管生成，还阻断巨噬细胞的促转移活性。化疗促进巨噬细胞在肿瘤中的定植，巨噬细胞诱导化疗肿瘤中的淋巴管生成，巨噬细胞以VEGFR3依赖的方式分泌组织蛋白酶、VEGF-C和肝素酶，阻断巨噬细胞中的VEGFR3可抑制淋巴管生成和随后的转移。Alishekevitz等人现在发现，大量表达VEGFR3的巨噬细胞可将其转移到化疗肿瘤中。在治疗的肿瘤部位，巨噬细胞通过VEGF-C/VEGFR3轴促进淋巴管生成和随后的转移。在治疗的肿瘤中阻断VEGFR3通过抑制促转移性巨噬细胞活性来阻碍转移。
While chemotherapy strongly restricts or reverses tumor growth, the response of host tissue to therapy can counteract its anti-tumor activity by promoting tumor re-growth and/or metastases, thus limiting therapeutic efficacy. Here, we show that vascular endothelial growth factor receptor 3 (VEGFR3)-expressing macrophages infiltrating chemotherapy-treated tumors play a significant role in metastasis. They do so in part by inducing lymphangiogenesis as a result of cathepsin release, leading to VEGF-C upregulation by heparanase. We found that macrophages from chemotherapy-treated mice are sufficient to trigger lymphatic vessel activity and structure in naive tumors in a VEGFR3-dependent manner. Blocking VEGF-C/VEGFR3 axis inhibits the activity of chemotherapy-educated macrophages, leading to reduced lymphangiogenesis in treated tumors. Overall, our results suggest that disrupting the VEGF-C/VEGFR3 axis not only directly inhibits lymphangiogenesis but also blocks the pro-metastatic activity of macrophages in chemotherapy-treated mice. Chemotherapy promotes macrophage colonization of tumors Macrophages induce lymphangiogenesis in chemotherapy-treated tumors Macrophages secrete cathepsins, VEGF-C, and heparanase in a VEGFR3-dependent manner Blocking VEGFR3 in macrophages inhibits lymphangiogenesis and subsequent metastasis Alishekevitz et al. now find that macrophages expressing VEGFR3 home in large numbers to chemotherapy-treated tumors. At the treated tumor site, macrophages promote lymphangiogenesis and subsequent metastasis via the VEGF-C/VEGFR3 axis. Blocking VEGFR3 in treated tumors hinders metastasis through the inhibition of pro-metastatic macrophage activity.
登录
查看更多内容
影响因子：
11.2
作者：
Hoshida, Tohru;Isaka, Naohide;Jain, Rakesh K.
通讯作者：
Jain, Rakesh K.
影响因子：
6.4
作者：
BARNER, M;KRAMER, MD;VLODAVSKY, I
通讯作者：
VLODAVSKY, I
影响因子：
11.2
作者：
Gingis-Velitski, Svetlana;Loven, David;Shaked, Yuval
通讯作者：
Shaked, Yuval
影响因子：
11.2
作者：
Hughes R;Qian BZ;Rowan C;Muthana M;Keklikoglou I;Olson OC;Tazzyman S;Danson S;Addison C;Clemons M;Gonzalez-Angulo AM;Joyce JA;De Palma M;Pollard JW;Lewis CE
通讯作者：
Lewis CE
影响因子：
20.3
作者：
Hagemann T;Biswas SK;Lawrence T;Sica A;Lewis CE
通讯作者：
Lewis CE