June 13, 2011 There is an intimate and complex relationship between inflammation and cancer; and it is well established that tumors secrete many different chemicals that attract host cells which drive inflammation and help to support tumor growth. Now, a new study published by Cell Press in the June issue of the journal Cancer Cell identifies a single protein that is required for trafficking of immune cells involved in inflammation. The research opens up new avenues for therapeutics that can indirectly suppress malignancy by disrupting the inflammatory response.
"Tumors induce inflammatory responses that stimulate tumor survival and progression. Therefore, targeting tumor inflammation could provide substantial therapeutic benefit to most, if not all, cancer patients," says senior study author, Dr. Judith A. Varner from the University of California, San Diego. "However, effective suppression of tumor inflammation requires identification and targeting of mechanisms that are common to the many diverse inflammatory pathways that are activated during tumor growth."
In their study, Dr. Varner and colleagues investigated the mechanisms that control tumor growth and inflammation by looking at molecular signals that are commonly activated by multiple diverse tumor-derived chemical signals. The researchers made the unexpected discovery that a single enzyme called PI3Kinase gamma served as a convergent point for a wide range of signaling pathways that controlled both tumor inflammation and progression.
A variety of experimental approaches with mouse and human cells demonstrated that disrupting PI3Kinase gamma prevented invasion of inflammatory cells into the tumor. Tumors developed more slowly and metastasis was suppressed in mice lacking PI3Kinase gamma even though cancer cells did not express PI3Kinase gamma and inhibitors had no direct effect on the tumor cells. The PI3Kinase gamma inhibitors indirectly interfered with the progression of cancer by preventing inflammation. Importantly, because the inhibitors do not directly influence tumor cells, it is not likely that they will develop resistance to PI3Kinase gamma inhibitors.
"Our studies show that PI3Kinase gamma is an excellent target for cancer therapeutics, as this enzyme is primarily expressed in specific immune cells and is a gatekeeper of tumor inflammation and tumor progression," concludes Dr. Varner. "We found that PI3Kinase gamma inhibitors strongly suppressed tumor growth and progression in mice without apparent side effects. Thus, selective inhibitors of PI3Kinase gamma could serve as relatively nontoxic therapeutics to suppress tumor malignancy by blocking diverse pathways promoting tumor inflammation."
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- Michael C. Schmid, Christie J. Avraamides, Holly C. Dippold, Irene Franco, Philippe Foubert, Lesley G. Ellies, Lissette M. Acevedo, Joan R.E. Manglicmot, Xiaodan Song, Wolfgang Wrasidlo, Sara L. Blair, Mark H. Ginsberg, David A. Cheresh, Emilio Hirsch, Seth J. Field, Judith A. Varner. Receptor Tyrosine Kinases and TLR/IL1Rs Unexpectedly Activate Myeloid Cell PI3Kγ, A Single Convergent Point Promoting Tumor Inflammation and Progression. Cancer Cell, Volume 19, Issue 6, 715-727, 14 June 2011 DOI: 10.1016/j.ccr.2011.04.016
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