1. Pollard, J. W. (2004) Nature Reviews Cancer 4, 71 – 78. 2. Joyce, J. A. & Pollard, J. W. (2009) Nat Rev Cancer 9, 239–252. 3. Condeelis, J. & Pollard, J. W. (2006) Cell 124, 263–266. 4. Lin, E. Y., Li, J. F., Gnatovskiy, L., Deng, Y., Zhu, L., Grzesik, D. A., Qian, B., Xue, X. N., & Pollard, J. W. (2006) Cancer research 66, 11238–11246. O2 Involvement of the p53 Tumor Suppressor in Tumor-Stroma Interactions
Neta Moskovits1, Jair Bar3, Yoseph Addadi2, Michal Neeman2, Varda Rotter1, Moshe Oren 1 1 Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel, Selisistat 2 Biological Regulation, Weizmann Institute of Science, Rehovot, Israel, 3 Cancer Research Center, Sheba Medical Center, Tel-Hashomer, Israel The tumor suppressor functions of p53 have been extensively studied within tumor cells and cells that are at risk of becoming tumorous. However, recent studies indicate that p53 also possesses non cell-autonomous tumor suppressor activities. Thus, we report that p53 can exert its tumor suppressor activity also within the stromal compartment of the DMXAA in vitro tumor. SRT1720 purchase Consequently, co-injection of p53-null fibroblasts together with PC3 human prostate cancer cells selectively augments tumor growth, while wild type fibroblasts fail to exert a similar effect. p53-deficient fibroblasts produce elevated levels of secreted proteins such as SDF-1/CXCL12, which
may facilitate tumor growth and spread. Conversely, tumor-associated mutant p53 isoforms increase the expression of SDF-1 in fibroblasts. In addition to quenching SDF-1 production by stromal fibroblasts, p53 also represses the expression Thalidomide of the SDF-1 receptor CXCR4. Of note, siRNA-mediated downregulation of SDF-1 production attenuates the ability of p53-null fibroblasts to augment tumor growth. Quenching p53 function in adjacent stromal fibroblasts may therefore provide tumor cells with a selective growth advantage. Indeed, we found that epithelial tumor cells can repress p53 activation in fibroblasts. This ability is acquired when epithelial cells undergo neoplastic transformation.
Interestingly, this p53-repressive effect of tumor cells is exerted more readily in cancer-associated fibroblasts (CAFs). All these findings implicate p53 in a non cell-autonomous tumor suppressor mechanism, exerted from stromal cells and affecting adjacent tumor cells. Activation of stromal p53 might therefore attenuate tumor progression even if the cancer cells themselves do not harbor wt p53 anymore O3 Cleavage of Galectin-3 by Matrix Metalloproteinases Regulates Breast Cancer Progression and Metastasis Avraham Raz 1 1 Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA For reasons largely unknown, Caucasian women are at a significantly higher risk of developing breast cancer than Asian women.