Molecular Control of Lymphatic Metastasis in Lung Cancer

Abstract

Lymph node metastasis in lung cancer is a strong independent predictor of poor prognosis, and designation of the tumor “nodal” status is a challenging and central component of the lung carcinoma TNM staging system. In recent years, genetic studies in mouse models as well as pathologic human lung cancer studies have revealed a variety of molecules that may critically regulate thoracic lymph node metastasis. These include important lymphatic endothelial growth factors such as VEGF-C and VEGF-D as well as the pro-angiogenic factors VEGF-A and FGF-2 (often overexpressed by lung carcinoma cells) that stimulate the growth of lymphatic conduit in both the primary tumor and the downstream lymph nodes. This process of pathologic lymphangiogenesis correlates with lymph node metastasis and poor prognosis in lung cancer. Certain families of chemokines also appear to be critical for driving the process of tumor–lymphatic invasion, where the cognate chemokine receptors (e.g., CXCR4 or CCR7) are often overexpressed by carcinoma cells. In addition to lymphatic growth factors and chemokine effectors, a variety of molecules may facilitate interactions of lymphatic endothelial cells with growth factors, chemokines and their receptors, as well as the extracellular matrix. These include proteoglycans and integrins, and their roles in coordinating tumor-lymphatic interactions in the lung carcinoma microenvironment may be critical for lymph node metastasis.