Angiogenesis Program

LICR is developing therapies to prevent angiogenesis, the formation of new blood vessels that provide tumors with nutrients and oxygen, and lymphangiogenesis, the formation of new lymphatic vessels. Both processes provide a mechanism for cancer cells to spread around the body.

Introduction

Without a supply of nutrients and oxygen, a tumor would not be able to grow more than a few millimeters in size. To obtain the nutrients and oxygen that it needs, tumor cells send signals that stimulate the formation of new blood vessels from the surrounding tissue. This process of blood vessel formation, called angiogenesis, leads to a rich network of blood vessels in and around the tumor. The ability of the tumor cells to detach from the main tumor mass and then invade those blood vessels, facilitates the migration of cancer cells to distant tissues (metastasis). Tumors use a process very similar to angiogenesis, called lymphangiogenesis, to increase the number of, and gain access to, vessels in the lymphatic system. The lymphatic system circulates fluid, known as lymph, from interstitial (around cells) spaces in body tissues and into the bloodstream, and is another route through which many cancers metastasize. The lymphatic system also plays a vital role in immunology, as the lymph contains lymphocytes, mostly B cells and T cells, which are major components of the immune system.

The LICR Angiogenesis Program is an international collaboration of scientific teams with expertise in the areas of cell and vascular (blood vessel) biology, biochemistry, and genetics. Investigators in the Program, such as Drs. Marc Achen (Melbourne), Kari Alitalo (Helsinki), Ulf Eriksson (Stockholm), Carl-Henrik Heldin (Uppsala), Ralf Pettersson (Stockholm), Anne Ridley (London), Steven Stacker (Melbourne), and Seppo Ylä-Herttuala (Kuopio), are preeminent experts in scientific fields pertaining to angiogenesis and lymphangiogenesis. The Program is building on the seminal research of these investigators to devise therapies that can be used to treat cancer by preventing angiogenesis and/or lymphangiogenesis, or the metastasis of tumor cells via those processes.

The Angiogenic Process

Melanoma

Malignant melanoma cells (stained purple) can only survive within a certain diameter of a central blood vessel (containing red blood cells in the middle of the cancer cluster)...

The processes of tumor angiogenesis and lymphangiogenesis begin with the cancer cells producing proteins known as angiogenic growth factors. Growth factors involved in angiogenesis include the five members of the vascular endothelial growth factor (VEGF) family, three of which (VEGF-B, VEGF-C, and VEGF-D) were discovered by members of the Angiogenesis Program group, and the four members of the platelet-derived growth factor (PDGF) family, two of which (PDGF-C and PDGF-D) were discovered by members of the Angiogenesis Program group.

The growth factors diffuse into the surrounding tissues, and bind to specific receptors on endothelial cells (ECs) of pre-existing blood vessels, or precursor cells that circulate in the blood. These receptors include the three members of the VEGF receptor (VEGFR) family and two members of the PDGF receptor (PDGFR) family (VEGFR-3 was discovered by LICR investigators). The binding of VEGF to its receptor activates signal transduction pathways, which direct the endothelial cells to proliferate (increase in number), and to make the proteins required for blood vessel formation. PDGF/R signaling helps vessel maturation by recruitment of supporting cells, and the reinforcement and stabilization of the new vessels. The intricacies of the signal transduction pathways downstream of VEGF/R and PDGF/R are being investigated through Research Programs in the Biochemistry discipline.

Numerous specialized proteins are required for angiogenesis. Initially, enzymes that dissolve holes in the existing blood vessels are produced, allowing proliferating endothelial cells to migrate out of the blood vessel in the direction of the tumor. Other enzymes, the matrix metalloproteinases (MMPs), dissolve the ‘matrix’ (extracellular protein meshwork) in front of the migrating ECs, and adhesion molecules called integrins assist the ECs in moving toward the tumor, which continues to secrete the growth factors. The ECs eventually form a new blood vessel. Finally, smooth muscle cells called pericytes congregate around the vessel to provide structural support. Blood flow to the tumor then begins.

The Lymphangiogenic Process

Whilst lymphangiogenesis and angiogenesis appear to be closely related, the exact mechanisms behind the lymphangiogenic process are, as yet, unclear. LICR scientists have discovered that VEGF-C, VEGF-D and VEGFR-3 in particular, seem to be vital for lymphangiogenesis, and current research is focused on elucidating the exact processes of lymphatic vessel formation. These studies are likely to identify other potential targets for therapy.

Anti-angiogenic Cancer Therapies

The inhibition of angiogenesis and/or lymphangiogenesis is an attractive potential cancer treatment option as these processes are common to all tumors, irrespective of the underlying genetic mutation, or the tissue of origin. LICR scientists are investigating several ‘anti-angiogenic’ drugs and monoclonal antibodies (mAbs) that block VEGF family members and PDGF binding to their respective receptors, thus preventing the initiation of signal transduction. Because these growth factors and growth factor receptors frequently have increased expression (are present in greater numbers) in cancer, targeting either presents a minimal chance of damaging normal tissues.

However, LICR investigators have also found that inhibiting angiogenesis or lymphangiogenesis may have some shortcomings, as they are normal biological processes with important roles to play in healthy tissues. For example, the formation of small blood vessels to heart tissue damaged by disease or ischemia (heart-attack) may be hindered by an anti-angiogenic therapy. Because of these findings, LICR investigators are also investigating therapeutic approaches for localized delivery of anti-angiogenic therapies to minimize the risk of inhibiting angiogenesis and lymphangiogenesis that are not related to cancer. LICR expects the first early phase clinical trials of some of its anti-angiogenic factors to commence in 2005.

Other Angiogenic Therapies

Cancer is not the only disease in which angiogenesis is implicated; blindness caused by diabetes or age-related macular degeneration, psoriasis, and rheumatoid arthritis all have an angiogenic component. As much of LICR’s angiogenesis research has implications for conditions such as these, the Angiogenesis Program is also exploring therapeutic strategies for important diseases other than cancer.

In addition to anti-angiogenic drugs, LICR scientists are examining the potential for pro-angiogenic drugs to treat diseases of ischemia (inadequate flow of blood), such as peripheral vascular disease. In these situations, blood vessels occluded by atherosclerotic process cannot deliver enough blood to muscles. A natural response to ischemia is the development of collateral vessels which bypass occluded sites of the vasculature. It is possible that local delivery of angiogenic growth factors or genes encoding these growth factors may improve muscle perfusion by growing new collateral vessels and capillaries in the ischemic muscle. Growth factors discovered by LICR investigators are potential candidates for therapeutic angiogenesis for both myocardial ischemia and peripheral vascular disease.

LICR investigators are also investigating pro-lymphangiogenic agents to treat lymphedema, a disfiguring and disabling condition resulting from the incomplete or blocked drainage of lymph, which accumulates in tissues and causes them to swell. Lymphedema can be caused by a hereditary disease, infection by a parasite, or damage from the removal of lymphoid tissue or lymph nodes, a procedure that some cancer patients must go through. It is thought that pro-lymphangiogenic drugs will stimulate lymphangiogenesis, and the new lymphatic vessels will clear accumulated lymph, thus preventing lymphedema, or ameliorating the disease in cases where extensive fibrosis has occurred.

Key Publications

Centers Involved in this Research