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August 10, 2005

Researchers discover new tumor defense system

Topics: Medicine

Several forms of anti-cancer therapy rely on what is known as immunotherapeutic anti-cancer strategies, therapies that encourage the body's natural defenses(sometimes called immunopotentiation), such as cytotoxic T lymphocytes (CTL), to aid in the destruction of tumors. However, immunotherapeutic methods are often not effective at removing established tumors for a number of reasons including a loss of the ability of the cytotoxic T lymphocytes to recognize the tumor and/or the existance of a physical barrier separating the lymphocytes and the tumor.

Now researchers have discovered that tumors release fatty acids that interfere with the cells that are trying to kill them. Consequently, strategies that reduce the amount of fatty acids surrounding the tumors may give a boost to anti-cancer therapeutics. The details of these findings appear in the September issue of the Journal of Lipid Research, an American Society for Biochemistry and Molecular Biology journal.

Short-term exposure of cytotoxic-T-lymphocytes to fatty acids disrupts the CTL's signaling pathways, and ultimately prevents them from killing tumor cells. What makes this a potentially important physiologic phenomenon is that tumor cells, but generally not normal cells, secrete large quantities of fatty acids and this level of secretion is increased more than 10-fold when a cytotoxic T lymphocyte (CTL) attacks a tumor cell. This tumor cell release of fatty acids may play a significant role in suppression of CTL-killing. Fatty acid inhibition of CTL-mediated killing can be reversed once the level of FA in aqueous solution level is reduced (concentration determined by a fluorescent probe developed by Torrey Pines Inst. of Molecular Studies that allows one to determine the concentration of FA in aqueous solution).

The researchers found two important factors, one - the most common type of free fatty acids, which at normal levels are essential for life, at high levels prevents the cytotoxic T lymphocytes from destroying tumor cells. Secondly - they found that human breast cancer cells, but not normal tissue from the same breast, produce very large amounts of the type of free fatty acids that block the cytotoxic T lymphocytes. Thus the cancer may have a way of defending itself against attack by the immune system, thereby reducing the potential efficacy of novel anti cancer therapies that rely on a functioning immune system."

The free fatty acids act against cytotoxic T lymphocytes by blocking a number of the lymphocytes' signaling events, by, for example, keeping certain proteins from being phosphorylated [the addition of a phosphate(PO4) group to a protein or a small molecule] and also by preventing an increase in intracellular calcium that is essential for the cytotoxic T lymphocytes to kill the tumor cells. The researchers suspect that these signaling events are being blocked at the cells' membranes.

These results from the Torrey Pines Institute for Molecular Studies raise the possibilities of new therapeutic targets for cancer, such as those that may transport free fatty acids out of the tumor. Alternatively, free fatty acid levels in the blood could be used to help gauge the aggressive potential of a tumor.

Sources and links:
Free fatty acid release from human breast cancer tissue inhibits cytotoxic T lymphocyte- mediated killing

TPIMS

Richieri, G.V., Low, P.J., Ogata, R.T., and .Kleinfeld, A.M. 1999. Binding kinetics of engineered mutants provide insight about the pathway for entering and exiting the intestinal fatty acid binding protein. Biochemistry 38:5888.

Richieri, G. V., R. T. Ogata, and A. M. Kleinfeld. 1992. A fluorescently labeled intestinal fatty acid binding protein; Interactions with fatty acids and its use in monitoring free fatty acids. J. Biol. Chem. 267:23495.

Richieri, G. V., P. J. Low, R. T. Ogata, and A. M. Kleinfeld. 1998. Thermodynamics of fatty acid binding to engineered mutants of the adipocyte and intestinal fatty acid binding proteins. J. Biol. Chem. 273:7397.

Kleinfeld, A. M., P. Chu, and C. Romero. 1997. Transport of long chain native fatty acids across lipid bilayer membranes indicates that transbilayer flip-flop is rate limiting. Biochemistry 36:14146.

Posted by Hyscience at August 10, 2005 9:32 PM



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