Pin Yeo Kim, Khoo Karen, Tham Muly, Karwai Tan, Hwee Thiam Chung, Puaux Anne-Laure, Phua Meow Ling Cindy, Kato Masashi, Angeli Veronique, Abastado Jean-Pierre
Department of Microbiology, Immunology Programme, Life Science Institute, Yoon Loo Lin School of Medicine, National University of Singapore, Singapore.
Singapore Immunology Network, BMSI, A-STAR, Singapore.
Oncotarget. 2015 Dec 29;6(42):44806-18. doi: 10.18632/oncotarget.6326.
Resection of infiltrated tumor-draining lymph nodes (TDLNs) is a standard practice for the treatment of several cancers including breast cancer and melanoma. However, many randomized prospective trials have failed to show convincing clinical benefits associated with LN removal and the role of TDLNs in cancer dissemination is poorly understood. Here, we found in a well-characterized spontaneous mouse model of uveal melanoma that the growth of the primary tumor was accompanied by increased lymphangiogenesis and cancer cell colonization in the LNs draining the eyes. But, unexpectedly, early resection of the TDLNs increased the growth of the primary tumor and associated blood vessels as well as promoted cancer cell survival and dissemination. These effects were accompanied by increased tumor cell proliferation and expression of phosphorylated AKT. Topical application of a broad anti-inflammatory agent, Tobradex, or an oral treatment with cyclooxygenase-2 specific inhibitor, Celecoxib, reversed tumor progression observed after complete lymphadenectomy. Our study confirms the importance of tumor homeostasis in cancer progression by showing the enhancing effects of TDLN removal on tumor growth and cancer cell dissemination, and suggests that TDLN resection may only be beneficial if used in combination with anti-inflammatory drugs such as Tobradex and Celecoxib.
切除浸润性肿瘤引流淋巴结（TDLN）是包括乳腺癌和黑色素瘤在内的多种癌症治疗的标准做法。然而，许多随机前瞻性试验未能显示出与淋巴结切除相关的令人信服的临床益处，并且对TDLN在癌症扩散中的作用了解甚少。在这里，我们在一个特征明确的葡萄膜黑色素瘤自发小鼠模型中发现，原发性肿瘤的生长伴随着眼引流淋巴结中淋巴管生成增加和癌细胞定植。但是，出乎意料的是，早期切除TDLN会增加原发性肿瘤和相关血管的生长，并促进癌细胞的存活和扩散。这些效应伴随着肿瘤细胞增殖增加和磷酸化AKT的表达。局部应用广谱抗炎药托百士（Tobradex）或口服环氧合酶-2特异性抑制剂塞来昔布（Celecoxib）可逆转完全淋巴结切除后观察到的肿瘤进展。我们的研究通过显示切除TDLN对肿瘤生长和癌细胞扩散的增强作用，证实了肿瘤内环境稳定在癌症进展中的重要性，并表明只有与托百士和塞来昔布等抗炎药物联合使用，切除TDLN才可能有益。
