Many tumour cells would not be viable due to aberrant chromosome distribution if it was not for a special trick that they have developed. A research team led by scientists from the German Cancer Research Centre (Deutsches Krebsforschungszentrum, DKFZ) has investigated the genes that are responsible for the cancer cells’ survival strategy. The investigation involved systematically switching off each individual gene of cancer cells using the RNAi method. The researchers have now published an article in Science Translational Medicine relating to their finding that cancer cells rely on the tension of specific protein fibres to be able to multiply. Proteins that maintain this tension have now become promising targets for new, target-specific anticancer drugs: If these proteins are switched off, cancer cells die.
The two centrosomes of a cell are responsible for cell division proceeding correctly. Fibres that correctly distribute the duplicated chromosome set to the newly forming daughter cells form from these centrosomes, or polar bodies in the cytoplasm protein. Seen under the microscope, the fibres are shaped like a spindle. Cancer cells, however, often have more than two centrosomes. As a result, their spindle fibres do not necessarily assume the normal shape of a spindle with two poles; instead, they frequently have a dysfunctional, multipolar shape. Such malformed spindles distribute the chromosomes unevenly among the daughter cells, which are then no longer viable.
Hence, tumour cells only survive if they manage to partition their chromosomes correctly in spite of the extra centrosomes. In order to do this, many cancer cells have developed a special trick: They form clusters of centrosomes. Two clusters are formed per cell, making it possible for a functioning bipolar spindle to develop between the two clusters. Professor Dr. Alwin Krämer, head of a Clinical Cooperation Unit of the DKFZ and Heidelberg University Hospital, has discovered this trick and sees it as a previously underrated Achilles' heel of cancer cells, which could potentially be used for destroying them. Working alongside colleagues from DKFZ, Heidelberg University Hospital, the Mannheim Medical Faculty and the Mayo Clinic in the USA, he systematically investigated which genes enable cancer cells to form centrosome clusters and thus escape cell death.
With the support of researchers from the division of Professor Dr. Michael Boutros, DKFZ and Mannheim Medical Faculty, the investigators switched off each individual gene in the cancer cells. They then searched for multipolar, malformed spindles under the microscope and found 82 genes that play a role in centrosome clustering. The team took a closer look at 22 of these genes and investigated their particular role in clustering, which led to the discovery of a key mechanism: For the centrosomes to be bundled into clusters, the spindle fibres need to be under tension. Only tightly stretched spindle fibres will position the centrosomes close enough to each other to allow clusters to form. A broad range of proteins are responsible for this tension. If their genes are silenced, multipolar spindles form and the cancer cells die. This mechanism could be used in the development of new cancer therapies.“Such a therapy would hit the cancer very specifically, because only tumour cells have extra centrosomes and depend on clustering for their survival,” explains Alwin Krämer. As part of the DKFZ’s strategic alliance with Bayer-Schering, the researchers in Krämer’s team are now planning to screen the identified genes for suitable targets for targeted cancer therapy.
Blanka Leber, Bettina Maier, Florian Fuchs, Jing Chi, Phillip Riffel, Simon Anderhub, Ludmila Wagner, Anthony D. Ho, Jeffrey L. Salisbury, Michael Boutros und Alwin Krämer: Proteins Required for Centrosome Clustering in Cancer Cells. Science Translational Medicine, 2010, DOI: 10.1126/scitranslmed.3000915