Authors' Affiliations: Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation; Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Center for Lymphoma and Myeloma, Department of Medicine, Weill Cornell Medical College and New York-Presbyterian Hospital, New York City, New York; China-Japan Union Hospital of Jilin University, Changchun; Key Laboratory of Thrombosis and Hemostasis of Ministry of Health; and Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.
Cancer Res. 2013 Dec 15;73(24):7254-64. doi: 10.1158/0008-5472.CAN-13-0750. Epub 2013 Oct 24.
Lymphomas originate in and spread primarily along the lymphatic system. However, whether lymphatic vessels contribute to the growth and spreading of lymphomas is largely unclear. Mantle cell lymphoma (MCL) represents an aggressive non-Hodgkin's lymphoma. We found that MCL exhibited abundant intratumor lymphatic vessels. Our results demonstrated that the immunomodulatory drug lenalidomide potently inhibited the growth and dissemination of MCL in a xenograft MCL mouse model, at least in part, by inhibiting functional tumor lymphangiogenesis. Significant numbers of tumor-associated macrophages expressing vascular endothelial growth factor-C were found in both human MCL and mouse MCL xenograft samples. Lenalidomide treatment resulted in a significant reduction in the number of MCL-associated macrophages. In addition, in vivo depletion of monocytes/macrophages impaired functional tumor lymphangiogenesis and inhibited MCL growth and dissemination. Taken together, our results indicate that tumor lymphangiogenesis contributes to the progression of MCL and that lenalidomide is effective in decreasing MCL growth and metastasis most likely by inhibiting recruitment of MCL-associated macrophages.
淋巴瘤起源于淋巴系统，并主要沿淋巴系统扩散。然而，淋巴血管是否有助于淋巴瘤的生长和扩散在很大程度上尚不清楚。套细胞淋巴瘤（MCL）是一种侵袭性非霍奇金淋巴瘤。我们发现 MCL 表现出丰富的肿瘤内淋巴管。我们的结果表明，免疫调节药物来那度胺通过抑制功能性肿瘤淋巴管生成，在异种移植 MCL 小鼠模型中有力地抑制了 MCL 的生长和扩散，至少在部分程度上是如此。在人类 MCL 和小鼠 MCL 异种移植样本中均发现了大量表达血管内皮生长因子-C 的肿瘤相关巨噬细胞。来那度胺治疗导致 MCL 相关巨噬细胞数量显著减少。此外，体内单核细胞/巨噬细胞耗竭会损害功能性肿瘤淋巴管生成，并抑制 MCL 的生长和扩散。总之，我们的研究结果表明，肿瘤淋巴管生成有助于 MCL 的进展，来那度胺通过抑制募集 MCL 相关巨噬细胞，有效地减少 MCL 的生长和转移。
