Editors' ChoiceCancer

Coming Back at You with PI3K

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Science's STKE  07 Jun 2005:
Vol. 2005, Issue 287, pp. tw213
DOI: 10.1126/stke.2872005tw213

The treatment of many solid cancers involves surgical removal of the primary tumor, a process that, dismayingly, may itself potentiate the growth of residual disease. Coffey et al. developed a model system in which they generated flank tumors in mice and measured the growth of primary tumors and recurrent tumors after surgical removal of most of the tumor. In immunocompromised mice with tumors of human origin and non-immunocompromised mice with tumors derived from the murine 3LL cell line, recurrent tumors grew more rapidly than primary tumors. Apoptosis (determined by morphological changes and TUNEL immunohistochemistry or by propidium iodide uptake) was reduced in recurrent compared with primary tumors, and the growth and metastatic capability of cells isolated from recurrent tumors was greater than that of cells isolated from primary tumors. Moreover, epithelial cells isolated from recurrent tumors showed greater resistance to tumor necrosis factor apoptosis-inducing ligand (TRAIL). Gene expression profiling indicated that expression of the gene encoding the phosphoinositide 3-kinase (PI3K) p85α inhibitory subunit (Pik3r1) was decreased in recurrent tumors when compared with its expression in primary tumors. However, expression of the gene encoding the PI3K p110γ catalytic subunit (Pik3CA) was increased in recurrent tumors. Consistent with a shift in PI3K activity, phosphorylation of Akt was increased in recurrent tumors. LY294002, an inhibitor of PI3K, increased the susceptibility of recurrent tumor cells to TRAIL without affecting that of primary tumor cells and, when administered postoperatively, slowed recurrent tumor growth and prolonged survival. Thus, accelerated growth of tumors following surgery may involve increased PI3K activity, and inhibition of PI3K activity in the immediate postoperative period could potentially mitigate this effect.

J. C. Coffey, J. H. Wang, M. J. F. Smith, A. Laing, D. Bouchier-Hayes, T. G. Cotter, H. P. Redmond, Phosphoinositide 3-kinase accelerates postoperative tumor growth by inhibiting apoptosis and enhancing resistance to chemotherapy-induced apoptosis: Novel role for an old enemy. J. Biol. Chem. 280, 20968-20977 (2005). [Abstract][Full Text]

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