NEWS

Lymphangiogenesis Explored as Potential Route for Metastasis

Tracy Webb

Tumor-induced lymphangiogenesis was, until recently, a relatively unfamiliar term in the field of cancer research.

This was due to popular scientific belief that lymphatic vessels were not recruited within tumor tissue, explained Karl Plate, Ph.D., Institute of Pathology, Erlangen-Nurnberg, Germany. "Because of this dogma, little investigation has been carried out in this field." But four recently published articles have added further complexity to the study of tumor biology.

"The metastatic spread of tumor cells is responsible for the majority of cancer deaths, and, with a few exceptions, all cancers can metastasize," noted Kari Alitalo, M.D., Ph.D., Haartman Institute, University of Helsinki, Finland. It has been well documented that tumors need to induce classical tumor angiogenesis, a process of new blood vessel growth within a tumor mass, to metastasize to distant sites.

And although "it had been well established that the lymphatics were a major route of [metastatic] spread for some tumors, there has been debate in the literature as to whether lymphatics could exist within tumors because of the high interstitial pressure," said Steven Stacker, Ph.D., Ludwig Institute for Cancer Research, Victoria, Australia. Therefore, it was unknown whether lymphangiogenesis was actively induced within tumors and contributed to metastatic spread.



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Dr. Steven Stacker

 
"Lymphangiogenesis has traditionally been overshadowed by the greater emphasis placed on the blood vascular system (angiogenesis)," said Alitalo. "This is due in part to the lack of identification of lymphangiogenic factors, as well as suitable markers which distinguish the blood from the lymphatic vascular endothelium."

This all changed when an antibody specific for lymphatic vessels was developed by the laboratory of David Jackson, Ph.D., Institute of Molecular Medicine, Oxford. LYVE-1 is a receptor for hyaluronan that is present specifically on lymphatic vessel walls. Thus, an antibody against LYVE-1 has been used to distinguish lymphatic vessels from blood vessels within the tumor mass.

"The LYVE-1 antibody was absolutely crucial in these studies, because it is the first (and currently the only) highly specific marker for lymphatic endothelium," said Plate. Without it, "none of the manuscripts would have been published."

With this new tool in hand, "[tumor] lymphangiogenesis has now emerged as a process akin to [classical tumor] angiogenesis, but differently controlled," said Alitalo.

One thing the most recent research has established is that lymphangiogenesis is actively occurring within tumors, said Mihaela Skobe, Ph.D., Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Boston. "These publications show for the first time that there is active communication between the tumor and lymphatic vessels."



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Dr. Mihaela Skobe

 
Although previous imaging techniques were unable to confirm the presence of lymphatics within tumors, the LYVE-1 antibody helped to demonstrate that lymphatic vessels are indeed evident within tumors, and that these are actively proliferating, said Michael Detmar, Ph.D., who works with Skobe at the Cutaneous Biology Research Center. "This has implications for how cancer metastasizes." Like angiogenesis, a tumor "can induce its own ‘home-grown’ network of lymphatics that are connected with the surrounding lymphatic vessels."

"These publications have demonstrated that vascular endothelial growth factor (VEGF)-C and VEGF-D, ligands for the VEGF receptor-3, are the lymphangiogenic factors that induce the formation of lymphatic vessels within and around tumors," said Stacker. In addition to its involvement in tumor-induced lymphangiogenesis, the VEGF signaling pathway is involved in classical tumor angiogenesis and is being targeted for anticancer therapy. In addition, these studies demonstrated that VEGF-C- and VEGF-D-overexpressing tumors increase intratumoral lymphangiogenesis, enhancing metastatic spread via the lymphatics.

"The significance to cancer is that the lymphatics may be a key area which tumor cells use to enter the circulation. The lymphatics are thin-walled vessels for collecting extravascular fluid, which provide a low-pressure environment to return this fluid to the circulation. One could envisage that overproduction of lymphangiogenic factors may provide extra lymphatic channels, thus promoting the spread of tumor cells," said Stacker.

"These discoveries will now affect how we think about tumors. It may be that the heterogeneity we see with tumors in terms of spread could in part be explained by their expression of VEGF family members. Spread from the primary to the lymphatics and blood stream, which may have previously been attributed to general invasive properties of the tumor, may be due to active recruitment of new lymphatics by tumor-derived VEGF-D/VEGF-C," said Stacker.

A New Avenue?

Although these findings have important implications for understanding metastatic spread, Skobe said she believes that, in contrast to angiogenesis, tumor-induced lymphangiogenesis will not be ubiquitously observed in all solid tumors because lymphatic vessels are absent from certain tissues, such as the brain.

But for those tissues that have lymphatic vasculature, she believes that the presence of intratumoral lymphatics may be used as a prognostic indicator for identifying aggressive tumors. According to Skobe, even a slight increase in the number of cells that go into the lymphatic system may dramatically increase the number of metastases, since such cells encounter a markedly reduced turbulent environment compared with blood circulation, thereby promoting increased metastatic efficiency.

Will lymphatic vessels be the next cancer target for therapeutic intervention? "It needs to be figured out whether tumor lymphatic vessels and normal lymphatic vessels are different and whether any difference in gene expression can be used for specific targeting," said Plate. Although the research is still in its early stages, Skobe predicts that differences will be found, as demonstrated in studies comparing normal and tumor blood vasculature.

But before lymphatic endothelial vessel targeting becomes a therapeutic option, much work is needed. "The next step is to look at a large number of human cancers," said Detmar, to determine if tumor lymphangiogenesis in human cancers actually takes place.



             
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