led IkB kinasea (IKKa) turns down the expression of a single gene called Maspin, which has well-established anti-metastatic activity in breast and prostate cancers.
They found that the production of Maspin is repressed by a series of events triggered by tumor inflammatory cells, with the result that prostate cancer cells spread.
"An excellent inverse correlation between IKKa activation and Maspin production was detected, such that advanced prostate cancer cells contain high amounts of activated IKKa in their nuclei and express little or no Maspin," said Karin.
He noted that a perfect correlation between nuclear accumulation of activated IKKa and reduced maspin expression was also seen in human prostate cancer, and both correlated with the clinical stage of the disease.
Karin and his colleagues discovered a signaling pathway that increased metastases in a mouse model of prostate cancer. The pathway is activated by a ligand that binds to a Receptor that Activates Nuclear factor Kappa-B (RANK).
RANK ligand has been shown in previous studies to be an important inflammatory protein (cytokine) that can lead to bone loss through activation of bone resorbing cells.
RANK ligand, produced by inflammatory cells that invade advanced prostate tumors, triggers a chain reaction in which IKKa is activated, allowing it to enter the nucleus of the cancer cell, repressing Maspin. IKKa is a key linchpin in the pathway that turns off the Maspin gene and activates the metastatic program.
The new results also support the view that RANK ligand is a general promoter of prostate, and possibly breast, cancer metastasis. "Maspin is a very potent inhibitor of metastasis; in a patient with metastasis, cells have found a way to turn off Maspin, which may depend on invasion of the tumor with RANK ligand-producing cells that activate IKKa," said Karin.
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