Many New Down- and Up-Regulatory Signaling Pathways, From Known Cancer Progression Suppressors to Matrix Metalloproteinases, Differ Widely in Cells of Various Cancers

Previously we detected new signaling pathways, some downregulatory and others upregulatory, from seven known suppressors of cancer progression to the expression of eight cancer-promoting matrix metalloproteinases (MMPs) in breast cancer cells. The goals of the present study were to test whether the preceding observations occur only in breast cancer cells and, if not, whether the same downregulatory and upregulatory signaling pathways are active in cells of other human cancers, focusing on activator protein-2 alpha, E-cadherin, fibulin1D, interleukin 4, p16(INK alpha), p53, PTEN, and RKIP, and on MMP1, MMP2, MMP7, MMP13, MMP14, MMP16, MMP19, and MMP25. To this end, in the present study we tested the effects of raising the cellular levels of wild-type copies of these known suppressors of cancer progression on the expression of these MMPs. This study yielded several unexpected results. We have detected 53 new signaling pathways in cells of prostate, brain, lung, ovarian and breast human cancers, with an abundance of signaling pathways as high as similar to 40% of the cancer progression regulator/MMP pairs tested in cells of prostate and breast cancers. Cells of various cancers differed widely and sequence-specifically in the identity of their signaling pathways, so that almost 90% of the pathways were different in cells from one cancer to another. In each of 18 out of 51 signaling pathways, a known suppressor of cancer progression stimulated, rather than inhibited, the expression of a cancer-promoting MMP. Ten signaling pathways were upregulatory in cells of some cancers and downregulatory in cells of other cancers. J. Cell. Physiol. 224: 549-558, 2010. (C) 2010 Wiley-Liss, Inc.