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Clues to Aggressive, Stubborn Cancers

Cancer manifests itself in many ways, not only in terms of the types of tissues it attacks, but also in the way it unfolds. Some cancers proceed slowly; others spread aggressively. Some respond predictably to chemotherapy drugs; others develop resistance. Now new research, published today in the journal Nature, is providing insight into these differences. According to the report, a genetic mutation of a protein called MAD2 may hold the key.

Earlier studies had shown that MAD2 belongs to a class of proteins known as mitotic checkpoint proteins, which ensure proper distribution of the chromosomes during cell division. Without that checkpoint, entire chromosomes can be gained or lost, and when such chromosomal instability occurs in cancer cells, it often results in aggressive cancers. The previous research had shown a correlation between the missing mitotic checkpoint and chromosomal instability in cancer cell lines, but there was no evidence for a direct link.

To that end, Memorial Sloan-Kettering Cancer Center researchers Loren S. Michel and Vasco Liberal and their colleagues genetically engineered a MAD2 mutation in a line of stable human colon cancer cells. The results were dramatic. "Although the loss of one copy of MAD2 caused only subtle decreases in the amount of MAD2 protein levels, it had a great impact on the cell's genetic behavior," Michel reports. "The tumors became highly genomically unstable and continued to grow even in the presence of chemotherapy drugs in the taxane family." In addition to affecting pre-existing cancer cells, the team found that inactivation of MAD2 in mice led to cancer, especially cancer of the lungs. "Why lung tissue is specifically affected is unknown, but it does show that disruption of this process participates in the development of cancer," Liberal notes. "Interestingly, in humans, low levels of MAD2 have been observed in breast tumor cell lines."

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