The role of midkine in tumor-associated lymphangiogenesis and metastasis of ocular malignant melanoma.

中期因子在肿瘤相关淋巴管生成和眼部恶性黑色素瘤转移中的作用。

• 批准号: 268657020
• 负责人: Dr. Jacobus J. Bosch
• 金额: --
• 依托单位: Zentrum für Augenheilkunde
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/268657020?language=en
• 关键词: role; midkine; tumor; associated; lymphangiogenesis

Malignant melanoma is the most frequent cancer of the eye. Despite availability of effective treatment options for primary conjunctival and uveal melanoma, none of these therapies prevent development of metastases and to date there is no therapy that increases survival in metastastic conjunctival and uveal melanoma of the eye. Previously, we identified that outgrowth of new lymphatic vessels from preexisting ones (lymphangiogenesis) is a decisive risk factor for metastatic spread and an indicator of poor prognosis in ocular melanoma. In the first funding period, we investigated the underlying cellular and molecular mechanisms both in vitro and in vivo in a novel mouse model of conjunctival melanoma. This led us to identify midkine as a key cytokine in tumor-associated lymphangiogenesis, immune cell infiltration and metastasis in uveal and conjunctival melanoma.In the second funding period, we plan to study in depth the molecular signaling mechanisms and cellular function of midkine in ocular melanoma. Specifically, we will focus on the role of midkine in ocular melanoma-associated lympangiogenesis and metastasis both in vitro and in vivo. In addition, the role of midkine in the tumormicroenvironment, specifically tumor cell-stroma interaction via lymphatic endothelial cells and infiltration of tumor-associated macrophages will be addressed. Based on these findings we will explore whether targeting midkine could be a novel anti-(lymph)angiogenic therapy for attenuation of tumor metastasis and recurrence in our novel mouse model of metastatic conjunctival melanoma.

恶性黑色素瘤是最常见的眼部癌症。尽管对于原发性结膜和葡萄膜黑色素瘤有有效的治疗选择，但这些疗法都不能阻止转移的发展，并且迄今为止还没有任何疗法可以提高眼睛转移性结膜和葡萄膜黑色素瘤的生存率。此前，我们发现，现有淋巴管长出新淋巴管（淋巴管生成）是眼黑色素瘤转移扩散的决定性危险因素，也是眼部黑色素瘤预后不良的指标。在第一个资助期间，我们在一种新型结膜黑色素瘤小鼠模型中研究了体外和体内的潜在细胞和分子机制。这使得我们确定中期因子是葡萄膜和结膜黑色素瘤中肿瘤相关淋巴管生成、免疫细胞浸润和转移的关键细胞因子。在第二个资助期，我们计划深入研究中期因子在眼黑色素瘤中的分子信号机制和细胞功能。具体来说，我们将重点关注中期因子在体外和体内眼部黑色素瘤相关淋巴管生成和转移中的作用。此外，中期因子在肿瘤微环境中的作用，特别是通过淋巴内皮细胞的肿瘤细胞-基质相互作用以及肿瘤相关巨噬细胞的浸润也将得到解决。基于这些发现，我们将探讨靶向中期因子是否可以成为一种新型抗（淋巴）血管生成疗法，用于在我们的新型转移性结膜黑色素瘤小鼠模型中减轻肿瘤转移和复发。