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  • September 28, 2009
    Found: Protein that stops spread of cancer

    jean-zhao.jpgJean Zhao, PhD 

    Mature cells are designed to stay in one place, anchored in the tissues that provide them with nutrients and growth signals. Normally, when cells detach themselves from their neighborhood and drift away, the body deems them potentially dangerous and assigns a molecular "death squad" to kill them.

    This special type of cell killing is called "anoikis," from the Greek word for "homelessness." Some cancer cells, however, can evade these death squads. When they break loose from their moorings, they survive and can metastasize (spread) to other parts of the body.

    In a recent issue of the journal Science Signaling, Jean Zhao, PhD, and a team of fellow Dana-Farber scientists added a new piece to the puzzle of explaining how a series of molecular changes enables free-floating cancer cells to survive and spread.

    The researchers discovered that a little-known protein called SIK1 has a previously unsuspected role in the destruction of unattached cells. In laboratory studies they found that when SIK1 is disabled in cancer cells, these cells can survive a loss of attachment and migrate through the blood stream. Further, an analysis of samples of human breast cancers revealed that patients lacking SIK1 activity in their tumors had a worse prognosis.

    "When a cell is displaced from its original site, it usually dies," explains Zhao. "In response to a cell's loss of anchorage, the protein P53 [a well-known tumor-suppressing gene] becomes activated. P53 is a major regulator of apoptosis [cell self-destruction] and anoikis, the specific type of apoptosis that kills cells that have lost their anchorage."

    Scientists still don't understand precisely how the detachment of a cell triggers P53 activation. But they've shown in mice that if a tumor is stripped of a functioning P53, it is more prone to metastasize – in other words, cancer cells can disable P53 so that they don't need to be tied down to their original location.

    Zhao and her colleagues have now demonstrated that P53 needs a signal from SIK1, a little-studied protein in a family of proteins known as kinases, so that it can set anoikis in motion. If SIK1 is knocked out experimentally, or somehow disabled in a cancer cell, it is resistant to cell death.

    In their experiments, the Dana-Farber team  – including lead author Hailing Cheng, PhD, and contributors Pixu Liu, MD, PhD; ZhigangWang, MD, PhD; Lihua Zou, PhD; Stephanie Santiago; J. Dirk Iglehart, MD; Alexander Miron, PhD; Andrea Richardson, MD, PhD; and William Hahn, MD, PhD  – showed that when human cells lacking SIK1 were injected into mice, they did not cause large tumors to form. But further examination showed that the animals' lungs contained tiny "micrometastases" – minuscule clumps of cancer cells. This suggests to the scientists that precancerous cells without SIK1 activity can metastasize even before a tumor develops. Once they have spread around the body, the cells may undergo further changes making them cancerous.

    These results, says Zhao, may explain a "longstanding clinical mystery." About 10 percent of patients are diagnosed with cancer of unknown primary (CUP), meaning physicians can't find the original site of the malignancy. So it's possible that CUP stems from precancerous cells that didn't initially form a tumor, but traveled through the circulatory system and later became full-fledged cancer cells.

    "Our findings add to the picture that metastasis is not a result of tumor formation but is a parallel, independent process," Zhao says. "Metastases can develop before, after, or in parallel to the primary tumor."

    Richard Saltus 

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