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Angiogenesis factor may help tumors prepare the way for spread to lymph nodes


Tumor cells use VEGF-A to stimulate lymphatic vessel growth beyond primary site

Production of the protein VEGF-A, already known to stimulate the growth of blood vessels associated with tumors, also contributes in unexpected ways to the spread of cancer. In the April Journal of Experimental Medicine, researchers from Massachusetts General Hospital (MGH) and the Swiss Federal Institute of Technology describe finding that VEGF-A promotes the development of lymphatic vessels that can carry cancer cells to lymph nodes and can actually prepare the way for tumor metastasis by inducing new lymphatic vessels to grow within the nodes even before a secondary tumor has developed.

"This observation is our most surprising and exciting finding," says Michael Detmar, MD, of the MGH Cutaneous Biology Research Center, the study’s senior author. "It’s a new twist to the ’seed and soil’ hypothesis, which postulates that distinct cancer types preferentially metastasize to organs that are optimally suited for them. Our results indicate that the ’seeds’ can actively modify the ’soil’ and prepare it for later metastatic arrival."

While it is now accepted that tumors can stimulate development of their own blood supply, a process called angiogenesis, similar growth of new lymphatic vessels was not suspected until 2001. At that time Detmar and his colleagues showed that human breast tumors implanted into mice induce the growth of lymphatic vessels and that lymphangiogenesis plays a key role in tumors’ spread to lymph nodes. It had previously been believed that tumors had no functioning lymphatic vessels. The 2001 study focused on VEGF-C, the first factor identified to promote lymphatic vessel growth, and subsequent research has identified another lymphatic factor called VEGF-D, which also is active in the spread of cancer.

While VEGF-A had been believed to promote the development of new blood vessels only, recent research at the MGH and elsewhere found that it also induced proliferation of lymphatic tissue and vessels in laboratory and animal models. As a result, the MGH team decided to investigate its possible role in tumor-associated lymphangiogenesis. Research fellow Satoshi Hirakawa, MD, PhD, the study’s first author developed a strain of transgenic mice in which skin cells express a green fluorescent protein and also produce elevated levels of VEGF-A. The researchers then induced the development of benign and malignant skin tumors in both the transgenic mice and normal mice in order to identify differences that could be attributed to elevated levels of VEGF-A.

The transgenic mice were found to develop both benign papillomas and malignant squamous cell carcinomas more rapidly and more extensively than did mice with normal VEGF-A expression. Both strains of mice had increased levels of angiogenesis associated with benign and malignant tumors, but the transgenic mice also had more and larger lymphatic vessels than did the normal mice. In addition, the new lymphatic vessels were shown to carry the receptor molecule known to interact with VEGF-A.

Examination of sentinel lymph nodes – those most adjacent to the tumors – showed increased spread of malignant cells to the nodes of transgenic mice. Those cells expressed the green fluorescent protein, confirming they originated in the skin tumors. The transgenic mice were also twice as likely to develop metastases in more distant lymph nodes. Detailed analysis of the nodes themselves found greater numbers of both blood vessels and lymphatic vessels in metastatic nodes of the transgenic mice, compared with cancer-containing nodes in normal mice. In addition, the transgenic mice also had increased lymphatic development in nodes that were cancer-free, suggesting that VEGF-A-induced lymphangiogenesis takes place in lymph nodes even before a metastatic tumor develops.

Another unexpected finding was that the metastatic lymph nodes of transgenic mice, which continued to overexpress VEGF-A, actively promote further lymphatic development, a newly discovered phenomenon the researchers called lymph node lymphangiogenesis. Detmar explains that the transportation of tumor cells by the lymphatic system previously had been considered a passive process. "Our findings reveal that tumor cells, even after they have metastasized to the lymph nodes, can very actively induce the growth of the very channels that will enable transport to other nodes and the organs."

Detmar notes that this newly identified process could be a promising target for therapies designed to prevent the further spread of metastatic cancer, which has been a major challenge in cancer treatment. He is an associate professor of Dermatology at Harvard Medical School and is also a professor of Pharmacogenomics at the Swiss Federal Institute of Technology.

Additional co-authors of the study are Shohta Kodama, MD, PhD, Rainer Kunstfeld, MD, and Kentaro Kajiya, MSc, of the MGH and Lawrence Brown, MD, of Beth Israel Deaconess Medical Center. The research was supported by grants from the National Institutes of Health, the American Cancer Society Research Project and the MGH Cutaneous Biology Research Center.

Sue McGreevey | EurekAlert!
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