Inflammation May Play Role In Metastasis Of Prostate Cancer

The research, appearing online March 19 in advance of publication in the journal Nature, identifies a mechanism which triggers metastasis, which is the spread of cancer in late stages of prostate cancer development. The findings by Michael Karin, Ph.D., professor of pharmacology in UCSD's Laboratory of Gene Regulation and Signal Transduction, and colleagues may help solve the puzzle of why it takes so long for cancer to metastasize, as well as what causes it to do so. Furthermore, this new work may lead to development of anti-metastatic therapies.

A major hypothesis in cancer research has been that whether the cancer metastisizes or not is determined by genetic changes within the cancer cell itself. But this hypothesis didn't explain why metastases appear many years after the initial tumor.

"Our findings suggest that promoting inflammation of the cancerous tissue, for instance, by performing prostate biopsies, may, ironically, hasten progression of metastasis," said Karin. "We have shown that proteins produced by inflammatory cells are the 'smoking gun' behind prostate cancer metastasis. The next step is to completely indict one of them."

One in six men will be diagnosed with prostate cancer, and one in 33 will die of metastatic disease. Early tumors confined to the prostate can be treated, but no effective treatments are available for metastatic disease, according to Steven L. Gonias, M.D., Ph.D., professor and chair of the UCSD Department of Pathology, a study investigator.

"This study helps explain the paradox that, in certain types of malignancy, inflammation within a cancer may be counterproductive," said Gonias.

In research using mouse models and confirmed in human tissue, the scientists observed that a protein kinase called 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.

Malignancies progress through stages. In early, non-metastatic tumors, a high level of Maspin is present, but it is turned off in late stages. Early tumors contain low amounts of active nuclear IKKa, whereas late-stage tumors contain the highest levels of active nuclear IKKa. The researchers also found a striking elevation in expression of RANK ligand in late tumors, but it was not expressed by the cancer cells. Instead, it is expressed by invading inflammatory cells. Interference with RANK ligand production or activation, as well as interference with IKKa activation, may offer new therapeutic strategies for prevention of metastatic disease.

The study was funded by the National Institutes of Health, the U.S. Army Medical Research and Material Command, the Prostate Cancer Foundation, the Aventis-UICC Translational Cancer Research Fellowship, the Lopiccola Fellowship of the UCSD Moores Cancer Center, and the Life Science Research Fellowship. Additional contributors include first author Jun-Li Luo,Wei Tan and Olexandr Korchynskyi, UCSD Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology and Moores Cancer Center; David A. Cheresh and Jill M. Ricono, UCSD Department of Pathology and the Moores Cancer Center; and Ming Zhang, Baylor College of Medicine, Department of Molecular and Cellular Biology.