Lymphatics in Tumors

In both animal and human tumors, lymphatic structures that stain for LYVE-1/Prox1 within the cancer tissue have been detected. But these structures do not function properly as lymphatics and thus contribute the interstitial hypertension in tumors. Metastatic cells that are carried along lymph channels and may accumulate in the nodes enter the lymphatics in the margin of tumors [16].

Glossary

Contractile lymphatics: Lymphatic channels with their own smooth muscle media draining fluid from the initial lymphatics.

Initial Lymphatics: Lymphatic channels embedded in the tissue parenchyma without smooth muscle media collecting fluid from the interstitial fluid space.

Lymphatic valves: Primary valves at the junction between endothe-lial cells in initial lymphatics, secondary valves in the lumen lymphatic channels.

Lymphatic Endothelial Growth Factor: Receptor agonist (the first one discovered is vascular endothelial growth factor - C, VEGFC) with affinity to the vascular endothelial growth factor receptor (e.g. VEGFR 3) on lymphatic endothelium that stimulates lymphatic endothelial migration with lymphatic channel growth and enlargement.

Lymphatic Smooth Muscle: Smooth muscle layer in the media of contractile lymphatics with innervation, vasomotor activity, and myogenic activity.

Vascular Endothelial growth factor (VEGF): Family of growth factors binding to endothelial VEGF receptors on vascular endothelium (e.g. VEGFR 2), enhancing vascular endothelial permeability and stimulating endothelial cell migration.

Acknowledgment

Supported by NSF Grant IBN 9876379 and in part by NIH Grant HL 43026. I thank Drs. Thomas C. Skalak, Michelle Mazzoni, Fumitaka Ikomi, Mr. J. Trzewik, and Ernesto Mendoza for numerous discussions about lymphatics. Special thanks to Frank A. DeLano for assistance with the experiments.

References

1. Skalak, T. C., Schmid-Schonbein, G. W., and Zweifach, B. W. (1984). New morphological evidence for a mechanism of lymph formation in skeletal muscle. Microvasc. Res. 28, 95-112. A demonstration of the tight association between arteriolar motion and lymphatic pumping in the skeletal muscle microcirculation.

2. Banerji, S., Ni, J., Wang, S. X., Clasper, S., Su, J., Tammi, R., Jones, M., and Jackson, D. G. (1999). LYVE-1, a new homologue of the CD44 glycoprotein, is a lymph-specific receptor for hyaluronan. J. Cell

Biol. 144, 789-801. Description of a molecular marker relatively specific for lymphatics.

3. Ohhashi, T., and Azuma, T. (1984). Sympathetic effects on spontaneous activity in bovine mesenteric lymphatics. Am. J. Physiol. 247, H610-H615.

4. McHale, N. G., Roddie, I. C., and Thornbury, K. D. (1980). Nervous modulation of spontaneous contractions in bovine mesenteric lymphatics. J. Physiol. 309, 461-472.

5. Unthank, J. L., and Bohlen, H. G. (1988). Lymphatic pathways and role of valves in lymph propulsion from small intestine. Am. J. Phys-iol. 254 (Gastrointest., Liver Physiol 17), G389-G398. A comprehensive three-dimensional reconstruction of the microlymphatic network in the intestine of several species.

6. Podgrabinska, S., Braun, P., Velasco, P., Kloos, B., Pepper, M. S., and Skobe, M. (2002). Molecular characterization of lymphatic endothelial cells. Proc. Natl. Acad. Sci. USA 99, 16069-16074. Gene expression profile of lymphatic endothelial cells in culture.

7. Mendoza, E., and Schmid-Schonbein, G. W. (2003). A model for mechanics of primary lymphatic valves. J. Biomech. Eng. 125, 407-414.

8. Castenholz, A. (1984). Morphological characteristics of initial lymphatics in the tongue as shown by scanning electron microscopy. Scan. Electron Microsc. 1984, 1343-1352. Scanning electron microscopic images of lymphatic endothelial junctions before and after partial separation by mechanical tension.

9. Intaglietta, M., and Gross, J. F. (1982). Vasomotion, tissue fluid flow and the formation of lymph. Int. J. Microcirc. Clin. Exp. 1, 55-65. The report demonstrates that arteriolar vasomotion serves to pump lymphatics.

10. Ikomi, F., and Schmid-Schonbein, G. W. (1996). Lymph pump mechanics in the rabbit hind leg. Am. J. Physiol. 271, H173-H183.

11. Macqueen, H. A., Waights, V., and Pond, C. M. (1999). Vascularisation in adipose depots surrounding immune-stimulated lymph nodes. J. Anat. 194(Pt 1), 33-38.

12. Wigle, J. T., and Oliver, G. (1999). Prox1 function is required for the development of the murine lymphatic system. Cell 98, 769-778.

13. Lymboussaki, A., Partanen, T. A., Olofsson, B., Thomas-Crusells, J., Fletcher, C. D., de Waal, R. M., Kaipainen, A., and Alitalo, K. (1998). Expression of the vascular endothelial growth factor C receptor VEGFR-3 in lymphatic endothelium of the skin and in vascular tumors. Am. J. Pathol. 153, 395-403. The study shows vascular endothelial growth factor C receptor-3 labeling of lymphatic endothe-lial cells.

14. Makinen, T., Jussila, L., Veikkola, T., Karpanen, T., Kettunen, M. I., Pulkkanen, K. J., Kauppinen, R., Jackson, D. G., Kubo, H., Nishikawa, S., Yla-Herttuala, S., and Alitalo, K. (2001). Inhibition of lymphangio-genesis with resulting lymphedema in transgenic mice expressing soluble VEGF receptor-3. Nat. Med. 7, 199-205.

15. Boardman, K. C., and Swartz, M. A. (2003). Interstitial flow as a guide for lymphangiogenesis. Circ. Res. 92, 801-808. An illustration of the initial lymphatics in the mouse skin and their growth in the direction of the lymph flow.

16. Padera, T.P., Katambi, A., di Tomaso, E., Mauta Carreira, C., Brwon, E. B., Boucher, Y., Choi, N. C. Mathisen, D., Wain, J., Mark, E. J., Munn, L. L., and Jain, R. K. (2002). Lymphatic metastasis in the absence of functional intratumor lymphatics. Science 296, 1883-1886.

The report illustrates that although tumors may have lymphatics, these lymphatics have no normal function. Metastatic cells enter lymphatics that surround the tumor

Capsule Biography

Dr. Schmid-Schonbein has headed the Microcirculation Laboratory at the University of California, San Diego, since 1979. He was President of the Microcirculatory Society in 2003. His laboratory primarily focuses on cell mechanics and transport in living tissues; his work is supported by grants from the NIH and NSF.

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