Angiogenesis plays a pivotal role in the growth and metastasis of tumors, including the development and progression of cutaneous lymphomas. The chick embryo CAM model has been utilized in various studies to assess the growth rate, angiogenic potential, and metastatic capability of different tumor types and malignant cell lines. However, the precise mechanisms of angiogenesis in CTCL and the influence of Ruxolitinib or Resminostat on angiogenesis in hematological malignancies and solid tumors are not well understood. Recent in vitro and in vivo data have demonstrated the synergistic inhibition of tumorigenesis and metastasis in experimental models of CTCL when using the combination of Resminostat (HDACi) with Ruxolitinib (JAKi). The present work aims to elucidate the effects of this combination on the tumor microenvironment’s vascular components. We investigated the effects of Ruxolitinib (JAKi) in combination with Resminostat (HDACi) treatment in transendothelial migration of CTCL cells (106MyLa and SeAx) by using a transwell-based transendothelial migration assay and tumor angiogenesis in vivo. We used the CTCL chick embryo CAM model with xenografted tumors derived from implanted MyLa and SeAx cells and administered topically 15 μM ruxolitinib and 5 μM Resminostat every two days during a 5-day period. JAKi and HDACi inhibited CTCL cell transendothelial migration by 75% and 82% (p< 0.05) in both CTCL engrafted cells (MyLa and SeAx, respectively) compared to the untreated group. Moreover, the combination of ruxolitinib with resminostat blocked angiogenesis by significantly reducing the number of blood vessel formation by 49% and 34% in both MyLa and SeAx, respectively (p< 0.05), indicating that the proposed combination exerted significant anti-angiogenic effects in the CAM CTCL model. Overall, these data provide valuable insights into potential therapeutic strategies targeting angiogenesis in CTCL, paving the way for more effective treatment approaches in the future.
血管生成在肿瘤生长和转移过程中起着关键作用，包括皮肤淋巴瘤的发生与发展。鸡胚绒毛尿囊膜模型已被广泛应用于评估不同肿瘤类型及恶性细胞系的生长速率、血管生成潜能和转移能力。然而，皮肤T细胞淋巴瘤中血管生成的具体机制，以及鲁索替尼或瑞米诺司他对血液系统恶性肿瘤和实体瘤血管生成的影响尚不明确。近期体外和体内实验数据显示，在皮肤T细胞淋巴瘤实验模型中，联合使用瑞米诺司他（组蛋白去乙酰化酶抑制剂）与鲁索替尼（JAK抑制剂）能协同抑制肿瘤发生和转移。本研究旨在阐明该联合疗法对肿瘤微环境血管成分的影响。我们通过Transwell跨内皮迁移实验和体内肿瘤血管生成实验，研究了鲁索替尼联合瑞米诺司他治疗对皮肤T细胞淋巴瘤细胞（106MyLa和SeAx）跨内皮迁移的影响。我们建立了皮肤T细胞淋巴瘤鸡胚绒毛尿囊膜模型，移植了MyLa和SeAx细胞形成的异种移植瘤，并在5天实验期内每两天局部给予15μM鲁索替尼和5μM瑞米诺司他。与未处理组相比，JAK抑制剂和组蛋白去乙酰化酶抑制剂使两种皮肤T细胞淋巴瘤移植细胞（分别为MyLa和SeAx）的跨内皮迁移能力分别降低了75%和82%（p<0.05）。此外，鲁索替尼与瑞米诺司他联合用药通过显著减少血管生成数量（在MyLa和SeAx模型中分别减少49%和34%，p<0.05）来阻断血管生成，表明该联合方案在鸡胚绒毛尿囊膜皮肤T细胞淋巴瘤模型中具有显著的抗血管生成作用。总体而言，这些数据为针对皮肤T细胞淋巴瘤血管生成的潜在治疗策略提供了重要见解，为未来开发更有效的治疗方法奠定了基础。
Combination of JAKi and HDACi Exerts Antiangiogenic Potential in Cutaneous T-Cell Lymphoma
肿瘤(癌症)患者之家