Summary and Perspectives

The lymphatic network subserves almost every organ in the body, and along its pathway are several hundred lymph nodes, the majority of which are in the head and neck region. Because of their strategic localization, LECs are intimately involved in regulating the movement of lymph and cells of the immune system between tissue interstitium and the lymphatic system. The recent ability to isolate and culture LECs has provided tools with which to study these functions.

From the patient's perspective, there are settings in which both stimulation and inhibition of lymphangiogenesis could be beneficial. In the case of the former, the feasibility of using VEGF-C gene therapy for the treatment of primary lymphedema has been clearly demonstrated in pre-clinical studies. In the case of the latter, in preclinical studies, inhibition of tumor lymphangiogenesis has been shown to reduce the formation of metastases in regional lymph nodes. However, it will be important to clearly define an appropriate therapeutic window in cancer patients, since it is likely that tumor cell dissemination will already have occurred in many patients at the time of initial presentation.

Glossary

Endothelium: The layer of flattened epithelial-like cells that lines the inner luminal surface of blood and lymphatic vessels (also known as intima) as well as the heart (also known as endocardium). The endothelium is in direct contact with blood in blood vessels and the heart, and with lymph in lymphatic vessels.

Lymph: A transparent fluid often containing lymphocytes that is found within lymphatic vessels; originates from tissue interstitium throughout the whole body; is returned to the systemic circulation via the lymphatic system; may be a milky white in the small intestine following fat absorption.

Lymphangiogenesis: The growth of new lymphatic capillaries by a process of sprouting from preexisting veins or lymphatic capillaries; may also include the differentiation of lymphatic endothelium from lymphangioblasts.

Lymphedema: Swelling of a part of the body (usually a limb) due to the accumulation of and inability to drain interstitial fluid as a consequence of absent, hypoplastic, or obstructed lymphatic vessels.

Lymphogenous metastasis: Secondary tumors that develop at sites distant from the primary tumor as a consequence of tumor cell dissemination via the lymphatic system; usually involve lymph nodes but may include other sites as well.

Bibliography

Alitalo, K., and Carmeliet, P. (2002). Molecular mechanisms of lymphan-giogenesis in health and disease. Cancer Cell 1, 219-227.

Baldwin, M. E., Stacker, S. A., and Achen M. G. (2002). Molecular control of lymphangiogenesis. BioEssays 24, 1030-1040. This is a comprehensive and up-to-date review on the molecular mechanisms of lymphangiogenesis.

McClure, C. F. W. (1921). The endothelial problem. Anat. Rec. 22. 219-237. This paper discusses much of the early work done on the development of the lymphatic system, and contrasts the so-called "centrifugal" and "centripetal" hypotheses of lymphatic endothelial origin.

Oliver, G., and Detmar, M. (2002). The rediscovery of the lymphatic system: Old and new insights into the development and biological function of the lymphatic vasculature. Genes Dev. 16, 773-783.

Pepper, M. S., and Skobe, M. (2003). Lymphatic endothelium: Morphological, molecular and functional properties. J. Cell Biol. 163, 209-213.

Pepper, M. S., Tille, J. C., Nisato, R., and Skobe, M. (2003). Lymphangiogenesis and tumor metastasis. Cell Tissue Res. 314, 167-177.

Rockson, S. G. (2001). Lymphedema. Am. J. Med. 110, 288-295.

Swartz, M. A. (2001). The physiology of the lymphatic system. Adv. Drug Deliv. Rev. 50, 3-20. This review deals in depth with the structure and function of the lymphatic vascular system.

Wilting, J., Neeff, H., and Christ, B. (1999). Embryonic lymphangiogenesis. Cell Tissue Res. 297, 1-11.

Witte, M. H., Way, D. L., Witte, C. L., and Bernas, M. (1997). Lymphangiogenesis: Mechanisms, significance and clinical implications. EXS 79, 65-112.

Capsule Biography

Michael Pepper graduated M.B.Ch.B from the University of Cape Town Medical School in 1982, and obtained his Ph.D. and M.D. degrees at the University of Geneva Medical School in 1990 and 1992, respectively. His research interests over the past 20 years have included angiogenesis and more recently lymphangiogenesis. Dr. Pepper's principal objective has been to foster the transfer of information between basic and clinical sciences.

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