Background

Endothelial cells line the inside of all blood vessels. They maintain the structural integrity of arteries, veins and small capillary vessels by forming tight junctions with each other and by maintaining the basement membrane that forms a surrounding layer outside the endothelial cells.

The basement membrane holds these endothelial cells in place. The endothelial cells also play a very important role in transporting substances between the blood stream and the surrounding tissues.

Endothelial cells are relatively dormant in adults. They only grow during wound healing when the surrounding tissue has been damaged and in the walls of the uterus during the female menstrual cycle.

Role of Endothelial cells in cancer biology

Endothelial cells also have important interactions with cancers. Cancers, like all other tissues in the body, require a blood supply to provide nutrients and to remove the biochemical waste.

Small cancers can make do with the existing blood supply of the tissue they are growing in but they require their own blood supply to grow beyond this.

Growing cancers produce and release chemical signals which stimulate the development of new blood vessels. The growth of endothelial cells to form new blood vessels is called angiogenesis and it involves the release of enzymes from these cells that dissolve and remodel the surrounding tissue to accommodate the new blood vessel.

Cancers that develop the ability to recruit and form new blood vessels can then grow further and invade the surrounding structures or spread to other organs via the blood or lymphatic system, a process called metastasis. This requires further interaction with endothelial cells as they must penetrate through the endothelial cells into a blood vessel, then leave the blood supply to colonise the new site. The endothelial cells forming the new blood supply to the cancer, play an important role in delivering circulating anti-cancer drugs to the cancer during chemotherapy.

Endothelial cells as allies in cancer treatment

Endothelial cells have been recognised as a potential “target” for new cancer treatment strategies. It should be possible to block the growth of endothelial cells to form new blood vessels (angiogenesis) and prevent the cancer from growing. The appeal of this approach is that it should specifically disrupt the cancer and not the normal tissues as there is little endothelial cell growth in adults. Dr Falkman’s team at the Harvard Medical School, Boston, U.S.A. has developed several antiangiogenic drugs and have shown that two such drugs, angiostatin and endostatin can cure mice of their cancers. Many other new agents with similar anit-angiogenic activity have been developed by others around the world and some old drugs such as thalidomide, have been rediscovered. Those same properties of thalidomide which caused birth defects by interfering with the normal development of the blood supply are now being used in the treatment of cancers. We are investigating how thalidomide can be best combined with chemotherapy (see Thalidomide and brain cancer & translational research).

Another approach involves inhibiting the enzymes released from endothelial cells during angiogenesis. These enzymes degrade the surrounding tissue and provide space to accommodate new blood vessel growth. Many of these enzymes are also released by metastasising cancers. Inhibition of these enzymes should be anit-angiogenic and anti-metastatic. Professor Chris Parish and his team at the John Curtin School for Medical Research, Australian National University have developed PI88, an inhibitor of one of these enzymes called heparanase. In collaboration with Professor Parish and Progen, we have been investigating how best to combine PI88 with conventional anti-cancer drugs.

There is evidence that the endothelial cells of newly-formed blood vessels are different from those found in older, well established blood vessels. We are investigating these differences at the molecular level with the view to targeting new treatments at these differences and manipulating the transport and delivery of anti-cancer drugs across these cells to improve their targeting to the cancer.

Anti-angiogenic and chemotherapeutic drugs combined

We have been investigating the most effective way of combining anti-angiogenic drugs with conventional chemotherapy. Our preliminary results have shown that in our breast cancer model system, the anti-angiogenic drug PI88 alone is effective at reducing cancer size. When combined with cisplatin chemotherapy there is a further reduction in the size of the cancer in addition to that achieved with chemotherapy alone.

These studies are being extended to include other chemotherapeutic drugs and other types of cancer such as brain cancer. We are also investigating the anti-angiogenic activity of thalidomide in these models as well as in a clinical trial for mesothelioma within our translational research program.