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Molecular Control of Lymphatic Metastasis in Lung Cancer

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Lung Cancer Metastasis

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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.

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Acknowledgments

The authors acknowledge grant support from the American Cancer Society (RSG#116111 to MMF), the U.S. Department of Veterans Affairs (CDTA award to MMF), and NIH/NCI (RO1 CA126820-01A1 to JAV).

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Authors and Affiliations

  1. Department of Medicine, Division of Pulmonary and Critical Care, University of California, San Diego, CA, USA

    Mark M. Fuster

  2. VA San Diego Healthcare System, San Diego, CA, USA

    Mark M. Fuster

  3. Moores UCSD Cancer Center, University of California San Diego, La Jolla, CA, USA

    Judith A. Varner

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Correspondence to Mark M. Fuster .

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Editors and Affiliations

  1. Dept. Internal Medicine, University of Michigan Health System, Zina Pitcher Place 109, Ann Arbor, 48109-2200, U.S.A.

    Venkateshwar Keshamouni

  2. Dept. Internal Medicine, University of Michigan, E. Medical Center Drive 1500, Ann Arbor, 48109, U.S.A.

    Douglas Arenberg

  3. Dept. Internal Medicine, University of Michigan, E. Medical Center Drive 1500, Ann Arbor, 48109, U.S.A.

    Gregory Kalemkerian

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Fuster, M.M., Varner, J.A. (2009). Molecular Control of Lymphatic Metastasis in Lung Cancer. In: Keshamouni, V., Arenberg, D., Kalemkerian, G. (eds) Lung Cancer Metastasis. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-0772-1_9

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