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

恶性黑色素瘤是眼部最常见的癌症。尽管原发性结膜和葡萄膜黑色素瘤有有效的治疗选择，但这些治疗方法都不能防止转移瘤的发展，迄今为止，还没有任何治疗方法可以提高转移性结膜和葡萄膜黑色素瘤的生存率。在此之前，我们发现从原有淋巴管中生长出新的淋巴管（淋巴管生成）是眼部黑色素瘤转移扩散的决定性危险因素，也是预后不良的一个指标。在第一个资助期，我们在体外和体内研究了一种新型结膜黑色素瘤小鼠模型的潜在细胞和分子机制。这使我们确定midkine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midkine在眼黑色素瘤中的分子信号机制和细胞功能。具体来说，我们将关注midkine在眼部黑色素瘤相关淋巴血管生成和转移中的作用，无论是在体外还是体内。此外，midkine在肿瘤微环境中的作用，特别是通过淋巴内皮细胞和肿瘤相关巨噬细胞浸润的肿瘤细胞-基质相互作用将被解决。基于这些发现，我们将探索靶向midkine是否可能成为一种新的抗（淋巴）血管生成疗法，以减少转移性结膜黑色素瘤小鼠模型中的肿瘤转移和复发。

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.