FROM THE LYMPHATIC SYSTEM TO CANCER

The importance of the lymphatic system
In order to develop and reach a size of more than a few millimetres, a cancerous tumour needs oxygen and nutrients, which are supplied by the blood vessels. It therefore secretes a “growth factor” called VEGF (vascular endothelial growth factor, figure 1), which stimulates the formation of new vessels. This process, known as angiogenesis, has been extensively studied. However, the same cannot be said for lymphangiogenesis, a similar process, but involving the lymphatic vessels.

The lymphatic system, nevertheless, plays an important role in the body. Lymphatic vessels are present in most tissues; they collect a fluid rich in proteins and white blood cells, the lymph, which they transport to the lymph nodes. There, the lymph is filtered to remove bacteria, viruses and other pathogenic agents before being returned to the blood. However, it is also by way of the lymph that cancer metastases reach the lymph nodes before being disseminated to other parts of the body. In addition, a dysfunction of the lymphatic system can lead to diverse diseases, notably lymphoedema, which presents as swelling of the limbs. By elucidating certain of the mechanisms involved in lymphangiogenesis, Kari Alitalo paved the way to the development of new therapies making it possible to limit metastases; he has also proposed a new treatment for congenital lymphoedema.

Growth factors
Kari Alitalo purified, cloned and characterized the first growth factor stimulating the formation of lymphatic vessels and characterized the second one with his collaborators. By analogy with angiogenesis, these factors were called VEGF-C and VEGF-D. Previously, Kari Alitalo had described their receptor, which allows the growth factors to bind to the endothelial cells lining the vessels. He showed that this receptor, called VEGFR-3, is needed for the formation of blood vessels and lymphatic vessels in the embryo.

Kari Alitalo did not stop there. He demonstrated the important role played by these growth factors and their receptors in the development of cancer. He showed that VEGF-C is over-expressed in tumours and that its receptor, VEGFR-3, which is not normally present in the blood vessels, can be detected in the blood vessels and the lymphatic vessels of tumours. This permitted a better understanding of the mechanisms leading to the dissemination of metastases. VEGF-C and VEGF-D stimulate lymphangiogenesis, which results in the formation, around the tumour, of new lymphatic vessels that facilitate the passage of cancer cells to the lymph nodes (figure 2). In addition, by treating mice with gene therapy using a soluble form of VEGFR-3, Kari Alitalo obtained partial regression of metastases in their lymph nodes.

Treating lymphoedema
VEGFR-3 is not only involved in the propagation of cancer metastases. It also plays an important role in the genetics of congenital lymphoedema: certain families affected by this disease carry a mutation of the VEGFR-3 gene, which results in an inactive VEGFR-3 protein. However, Kari Alitalo came up with a potential treatment. Using VEGF-C to treat transgenic mice with this genetic defect, he succeeded in getting new lymph vessels to grow. He thus laid the foundations for a new molecular therapy for lymphoedema and the first clinical trials have just started.

The recent identification of lymphangiogenesis has renewed the interest of the biomedical community in the lymphatic system, the study of which had been neglected for many decades. Kari Alitalo has made a major contribution to this. Among other things, by elucidating the genetic and molecular basis of the functioning of the lymphatic endothelial cells, he paved the way to new therapeutic approaches, not only in the field of the lymphoedemas and cancer metastases, but also in that of cardiovascular diseases, of inflammation and of many other diseases.

With the means placed at his disposal by the 2006 Louis-Jeantet Prize for Medicine, Kari Alitalo will pursue his research on the factors involved in the regulation of angiogenesis and lymphangiogenesis. He will turn his attention in particular to the receptors Tie1 and Tie2, which are involved in the growth and stabilisation of the vessels.

Figure 1.

Schematic drawing of the interactions of blood and lymphatic endothelial growth factors and receptors
Vascular endothelial growth factor (VEGF), VEGF-B, VEGF-C, VEGF-D, VEGF-E, and placenta growth factor (PlGF) bind to cell surface receptors (VEGFR-1, VEGFR-2 and VEGFR-3), inducing receptor activation leading to changes in endothelial cells. VEGFR-2 is essential for vascular development, and is a high-affinity receptor for VEGF and the processed forms of VEGF-C and VEGF-D. VEGFR-1 is a high-affinity receptor for VEGF, VEGF-B and PlGF. VEGFR-3 is activated by VEGF-C and VEGF-D and is the primary receptor for the signalling pathway associated with lymphangiogenesis. VEGF-C and VEGF-D link angiogenesis with lymphangiogenesis, as they can stimulate both processes. A soluble version of the extracellular domain of VEGFR-3 (VEGFR-3-Ig) provides lymphangiogenesis inhibition, as it sequesters VEGF-C and VEGF-D, thereby blocking their binding to VEGFR-3. The Tie-1 and Tie-2 receptors interact with each other and regulate vessel sprouting and stabilisation. Their ligands are angiopoietins 1 to 4 (Ang1-4).

Figure 2. 

Tumor angiogenesis and lymphangiogenesis factors
Low oxygen levels in the poorly vascularised regions of tumours commonly trigger tumour angiogenesis. This stimulates the production of VEGF, which binds to endothelial cells of nearby vessels and induces them to grow and extend into the tumour, providing oxygen and nutrients. VEGF-C and VEGF-D are not induced by hypoxia, but are expressed by many tumours and their associated inflammatory cells. These growth factors stimulate lymphatic vessels to sprout and dilate, thereby enhancing tumour metastasis to the lymph nodes. Such metastasis can be inhibited in part by blocking the stimulatory pathway using VEGFR-3-Ig (see figure 1). Blood vessels appear pink and blue, lymphatic vessels grey. (Drawing by Meniscus Limited).

Professor Kari ALITALO
Research Professor of the Finnish Academy of Sciences
Molecular/Cancer Biology Laboratory
Biomedicum Helsinki
University of Helsinki
P.O.Box 63 (Haartmaninkatu 8)
FIN – 00014 HELSINKI

Phone.: +358 9 1912 5511
Fax: +358 9 1912 5510
E-mail: Kari.Alitalo@helsinki.fi
Website: http://research.med.helsinki.fi/cancerbio/