Metastasis-Promoting Gene Identified

Researchers studying how cancer cells metastasize have found that the cyclin D1 gene regulates changes in the morphology of tumor-associated macrophages that enhance their ability to migrate. Their findings were published February 21, 2003, in the online edition of Molecular Biology of the Cell.

Investigators from Georgetown University's Lombardi Cancer Center (Washington, DC, USA) genetically engineered a line of mice lacking the cyclin D1 gene, which encodes the regulatory subunit of a holoenzyme that phosphorylates and inactivates the retinoblastoma protein, pRB, thereby promoting cell-cycle progression. Cyclin D1 is overexpressed in hematopoetic and epithelial malignancies, correlating with poor prognosis and metastasis in several cancer types.

Tumor-associated macrophages from mice lacking the cyclin D1 gene differed in morphology, being rounder and having fewer membrane ruffles than the macrophages from control animals. Migration of these macrophages in response to wounding, cytokine-mediated chemotaxis and transendothelial cell migration were all substantially reduced.

"Patients who do not survive their cancer often do not die from their primary cancer. Usually they die from the spread of the disease through the body. If we can understand what causes the metastasis, then we can pinpoint new targets to block the spread of disease,” said senior author Dr. Richard G. Pestell, director of the Lombardi Cancer Center. "Since cancerous cells migrate, therapy targeted to cell migration would be more selective. Killing only migrating cancer cells is thus less toxic, producing fewer side effects than current chemotherapy, which targets dividing cells of all types.”



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