Osteosarcoma is the most common form of primary bone tumour occurring in children and young people and treatment usually includes a combination of surgery, chemotherapy and radiotherapy. Unfortunately, patients with aggressive osteosarcomas, that are likely to spread elsewhere in the body, don't respond as well to treatment and have a worse survival outlook.

Aggressive osteosarcomas have characteristics that cause them to rapidly expand and spread in the body, which is known as metastasis. If drugs can be found that stop one, or preferably all, of these characteristics from taking place it would prevent metastasis and dramatically improve the survival of patients with aggressive disease.

Background of the research:

A protein called angiopoietin-like 4 (ANGPTL4) is found in 76/109 osteosarcomas and appears to be most highly abundant in osteosarcoma prior to metastasis. The maim of this research was to investigate whether ANGPTL4 drives the tumour-promoting characteristics of aggressive osteosarcoma that causes it to expand and spread (metastasise). These characteristics include:

  • Rapid growth of the osteosarcoma tumour cells.

Results indicated that exposure to ANGPTL4 increased the rate at which osteosarcoma cells grow.

  • Formation of many new blood vessels. These blood vessels bring nutrients to support tumour growth and also carry metastasising cells away from the primary tumour.

The research group did not study this directly, but ANGPTL4 is known to promote the formation of new blood vessels.

  • Bone destruction. Osteosarcoma cells cause specialised bone-digesting cells called osteoclasts to become over-active. This causes excessive bone loss, which provides room for the tumour to grow in the bone and can provide an ‘escape route’ for metastasising cells.

Dr Knowles found that exposure to ANGPTL4 caused more osteoclasts to be formed and also increased the ability of these osteoclasts to digest bone.

  • The ability to survive in a new site. To metastasise osteosarcoma cells must be able to move away from the primary tumour, survive in the circulation and invade the tissue in which they will form the secondary, metastatic tumour.

ANGPTL4 increased the ability of osteosarcoma cells to migrate, although it did not affect their ability to form new tumours at a secondary site.

Results of the study:

The results from the Oxford group indicate that ANGPTL4 drives several metastasis-causing characteristics of osteosarcoma cells including rapid tumour growth, bone digestion and migration. This makes ANGPTL4 a very attractive drug target for a novel therapy that could block several of the different aspects of disease progression, potentially preventing metastasis and dramatically improving the chance of survival for patients with aggressive disease.

Dr Knowles is now studying how treatment with an ANGPTL4 blocking antibody affects osteosarcoma disease progression in a research laboratory model of disease. This could in time lead to investigations in human disease, with the ideal of identifying a strategy to prevent metastasis and improve survival for patients with aggressive osteosarcoma.

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