A NEW way of searching for genes that cause disease has given researchers a
genetic handle on metastasis, the potentially lethal spread of tumour cells
around the body. Eric Lander of the Massachusetts Institute of Technology told
the symposium that researchers in his group had found a gene which seems to
allow melanoma鈥攕kin cancer鈥攖o invade other tissues.
He calls his pioneering method a 鈥渉ypothesis-free鈥� search for genes, because
you don鈥檛 need to know in advance how a gene might contribute to the disease.
Instead, the researchers use powerful molecular biological tools to spot
differences between people鈥攐r even individual cells鈥攖hat have the
disease and those that don鈥檛. 鈥淚鈥檓 a big fan of such ignorance-based
techniques,鈥� Lander says, 鈥渂ecause humans have a lot of ignorance, and we want
to play to our strong suit.鈥�
To find genes involved in metastasis, Lander and his MIT colleague Edwin
Clark compared the gene transcripts in two kinds of cultured cells, one from a
mouse melanoma tumour, and three from separate metastases of the melanoma. While
the melanoma cells were only weakly metastatic when injected back into mice,
cells from metastases could quickly trigger tumours all over a mouse鈥檚 body.
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Clark found that transcripts of three genes were present at much higher
levels in the metastases than in the original cancer, suggesting that these gene
transcripts were activated when the cancer spread. The same genes were activated
in human metastases as well, Lander says. Cells cultured from a weakly
metastatic human melanoma had lower levels of all three genes than cells
spreading from the tumour.
To determine whether the activated genes could cause metastasis, Clark
engineered the weakly metastatic mouse cell line to express each of the
activated genes, and then injected these cells back into mice. One gene, called
rhoC, made the cells aggressively metastatic all by itself.
RhoC protein has already been implicated in cancer because it helps relay
signals from another cancer protein called Ras which lies in the cell membrane.
Other researchers have found that more aggressive cancers often contain higher
levels of RhoC. But Lander鈥檚 experiments are the first to show that RhoC by
itself can stimulate metastasis, which suggests that it might be a potential
target for drugs. And he says he is confident the hypothesis-free approach will
uncover many more genes involved in other diseases as well.
