06 May 2012 - CLIC3 - a cancer cell’s helper

Copyright © Wellcome trust centre for Cell-Matrix Research

People die of cancer when cells from a tumour spread to other parts of the body, in a process called metastasis. In order for cancer cells to do this, they invade the web of protein and sugar fibres that surround cells in tissues, called the extracellular matrix (ECM). Cells are hooked onto the ECM by proteins called integrins, which can use these integrin ‘hooks’ to push and pull their way through the matrix. Cancer cells rely on integrins to invade the ECM and to spread to other parts of the body.

Discovery: Integrin proteins are constantly recycled and replaced, and this process starts with them being removed from the cell membrane. The cell then decides whether to destroy the integrin, or recycle it to the edge of the cell that is fighting its way through the ECM. We have now discovered that a protein called Rab25 protects against the spreading of pancreatic and ovarian cancer cells. Rab25 causes cells to destroy the integrins, rather than recycle them. Without their integrins, the cells find it difficult to move through the ECM, and into the rest of the body. However, another protein called CLIC3 is sometimes able to rescue integrins from being destroyed, and instead recycles them back to the edge of the cell. This means that if CLIC3 is present at higher levels than usual, which often happens in cancer, Rab25 can’t prevent cancer cells from invading the ECM.

Importance: The discovery that CLIC3 acts as a kind of ‘helper’ for pancreatic and ovarian cancer cell invasion, lends itself to becoming a potential target for future cancer treatments. Inhibiting CLIC3 from working would prevent cells in the primary tumours from being able to spread to other parts of the body.

Dozynkiewicz, M.A., Jamieson, N.B., MacPherson, I., Grindlay, J., van den Berghe, P., von Thun, A., Morton, J.P., Gourley, C., Timpson, P., Nixon, C., McKay, C.J., Carter, R., Strachan, Anderson, K.,  Sansom, O.J.,  Caswell, P.T., Norman, J.C. (2012). Rab25 and CLIC3 collaborate to promote integrin recycling from late endosomes/lysosomes and drive cancer progression. Dev Cell. 22, 131-45.