Nathanson S David
Department of Surgery, Josephine Ford Cancer Center, Henry Ford Health System, Detroit, Michigan, USA.
Cancer. 2003 Jul 15;98(2):413-23. doi: 10.1002/cncr.11464.
The mechanisms by which malignant tumors leave the primary tumor site, invade lymphatics, and metastasize to regional lymph nodes (RLNs) are complex and interrelated. Although the phenomenon of lymph node metastasis has been recognized for over 200 years, the exact mechanisms have only recently been the subject of intense interest and sophisticated experimentation. Sentinel lymph node biopsy has rapidly entered the clinical mainstream for melanoma and breast carcinoma, and this technique has provided confirmation of the orderly anatomic progression of tumor cells from primary site to the RLNs through lymphatic capillaries and trunks. Exciting studies involving the pathophysiology of interstitial fluid pressure in tumors and the peritumoral extracellular matrix have focused on lymphatic flow and tumor microenvironment and microcirculation. Molecular techniques have led to the definition of unique markers found on lymphatic endothelial cells. These markers have enabled scientists to identify peritumoral and intratumoral lymphatics and to visualize the ingrowth of tumor cells into the lumena of lymphatic capillaries. Tumor-secreted cytokines, such as vascular endothelial growth factors (VEGF)-C and -D, bind to VEGF receptors on lymphatic endothelial cells and induce proliferation and growth of new lymphatic capillaries; this process is similar to the well-known mechanism of angiogenesis, which results from the proliferation of new blood vessel capillaries. Lymphangiogenesis is associated with an increased incidence of RLN metastasis, and it is possible that this step is essential to the metastatic process. Directional movement toward lymphatics and lymph nodes appears to follow a chemokine gradient, and it is likely that some tumor cells that express certain types of chemokine receptors are more likely to metastasize to the RLNs. In contrast, tumor cells that do not express specific receptors that are responsive to lymphatic chemokines may not metastasize. New knowledge regarding the molecules involved in these processes should enable improvements in prognostic and possibly therapeutic approaches to the management of malignant tumors.
恶性肿瘤离开原发肿瘤部位、侵入淋巴管并转移至区域淋巴结（RLNs）的机制复杂且相互关联。尽管淋巴结转移现象已被认识超过200年，但确切机制直到最近才成为深入研究和精密实验的主题。前哨淋巴结活检已迅速成为黑色素瘤和乳腺癌临床的主流技术，该技术证实了肿瘤细胞从原发部位通过毛细淋巴管和淋巴管干有序地向RLNs进行解剖学转移。涉及肿瘤间质液压力和肿瘤周围细胞外基质病理生理学的激动人心的研究聚焦于淋巴流动、肿瘤微环境和微循环。分子技术已导致在淋巴管内皮细胞上发现独特的标志物。这些标志物使科学家能够识别肿瘤周围和肿瘤内的淋巴管，并使肿瘤细胞向毛细淋巴管腔内生的情况可视化。肿瘤分泌的细胞因子，如血管内皮生长因子（VEGF）-C和-D，与淋巴管内皮细胞上的VEGF受体结合，诱导新的毛细淋巴管增殖和生长；这一过程类似于众所周知的血管生成机制，后者是由新的血管毛细血管增殖导致的。淋巴管生成与RLN转移发生率增加相关，并且这一步骤可能对转移过程至关重要。向淋巴管和淋巴结的定向移动似乎遵循趋化因子梯度，并且表达某些类型趋化因子受体的一些肿瘤细胞可能更有可能转移至RLNs。相比之下，不表达对淋巴趋化因子有反应的特定受体的肿瘤细胞可能不会发生转移。关于这些过程中涉及的分子的新知识应能改善恶性肿瘤管理中的预后方法，甚至可能改善治疗方法。
