Key mechanism behind cancer spread is explained

The progression of cancer cells from one part of the body to another (“metastasis”) is one of the biggest problems in curing cancer, therefore this research brings new hope of future therapies to fight cancer. The discovery has been made by Dr Victoria Sanz-Moreno in the research team led by Professor Chris Marshall at The Institute of Cancer Research, in work funded by Cancer Research UK.

Professor Marshall says:

“The spreading of cancer cells from one part of the body to another, called metastasis, is one of the biggest causes of death from cancer. By explaining a key part of that process, our research brings new hope for future therapies to fight cancer.

“The research has found the constant competition between two proteins called ‘Rac’ and ‘Rho’ is responsible for allowing the cancer cells to change shape and spread through the body.

“We have shown that cells from melanoma (an aggressive type of skin cancer) are able to rapidly alternate between two different forms of movement where cells have either a round shape or a more stretchy “elongated” shape.

“Together with Dr Erik Sahai and Dr Sophie Pinner at the Cancer Research UK London Research Institute we have been able to see cells in live tumours carrying out these different forms of movement. These alternate shapes and ways of moving may enable tumour cells to deal with different situations during cancer spread. For example, tests indicated that a round shaped tumour cell may have more durability to survive in our bloodstream than elongated shaped tumour cells.”

The Rac process involves a protein called NEDD9, (which has previously been shown to be involved in melanoma metastasis) activating Rac through another protein called DOCK3. This Rac activity serves a dual purpose, both encouraging the cell to become elongated and simultaneously suppressing the competing Rho activity. Conversely, when cells adopt the round form a protein activated by Rho, called ARHGAP22, switches off Rac activation.

Dr Victoria Sanz-Moreno says: “Until now the conversion between different types of movement of individual cancer cells had been observed but the key players had not been identified. We are excited to discover that the amount and the activity of these proteins in the tumour cell regulates its shape and the mechanism for it to move and invade surrounding tissue. We hope these insights can be used to help develop future therapies”.

Dr Lesley Walker, Cancer Research UK director of cancer information, said: “Successful treatment tends to be much more difficult if the cancer has spread. This exciting study has shed light on some of the key molecules involved in the signalling pathways that encourage cells to move around the body. Knowing more about how cancer spreads will hopefully lead to the identification of new drug targets which will enable scientists to develop anti-cancer drugs to block these pathways.”

Melanoma cells were being studied in this research and their behaviour is also expected to occur in many other types of cancer. Melanomas are a major target for cancer therapies because although they are the least common, they are the most serious type of skin cancer. There are about 160,000 new cases of melanoma worldwide each year, including the rarer types that affect the bowel or eye rather than the skin (2).

(1) “Rac activation and inactivation control plasticity of tumor cell movement”. Copies of this paper in Cell are available upon request. It will appear in the print issue of Cell on 31 October 2008.

(2) Ries LAG, et al, eds. SEER Cancer Statistics Review, 1975-2000. Bethesda, MD: National Cancer Institute; 2003: Tables XVI-1-9.

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