Zena Werb, Ph.D., is Professor and vice-chair of anatomy at the University of California, San Francisco (UCSF). After receiving a BSc in biochemistry from the University of Toronto, she attained a Ph.D. in cell biology from Rockefeller University, where she worked with Dr. Zanvil Cohn on macrophages. Dr. Werb went on to complete a postdoctoral fellowship at Strangeways Research Laboratory in Cambridge, England, and subsequently joined the faculty of UCSF, where she is a member of the UCSF Helen Diller Family Comprehensive Cancer Center and Cardiovascular Research. She has published more than 425 papers and received many honors and awards, including the Charlotte Friend Award of AACR. She is an elected member of the National Academy of Sciences and of the Institute of Medicine and a fellow of the American Academy of Arts and Sciences. She has been a member of the AACR Board of Directors.
A summary of the March 2010 article from Dr. Werb in Cancer Research is available below:
Matrix Metalloproteinases Contribute Distinct Roles in Neuroendocrine Prostate Carcinogenesis, Metastasis, and Angiogenesis Progression
Laurie E. Littlepage, Mark D. Sternlicht, Nathalie Rougier, Joanna Phillips, Eugenio Gallo, Ying Yu, Kurt Williams, Audrey Brenot, Jeffrey I. Gordon, and Zena Werb
Cancer Research 2010;70(6):2224–34.
Although most human prostate carcinomas respond to hormonal therapy, they often become more aggressive and resistant to therapy. Most of these carcinomas contain foci characterized by a neuroendocrine-like differentiation (NED) pattern. Increased NED is associated with tumor progression toward androgen independence and resistance to hormone-based therapies. Matrix metalloproteinases (MMPs) are a family of enzymes that cleave various components of extracellular matrix, basement membrane, growth factors, and cell surface receptors. Stromal and inflammatory cells, not tumor cells, typically synthesize MMPs, which then regulate the tumor microenvironment and tumor cells. Several MMPs are overexpressed in prostate cancer progression, and androgen ablation/castration increases levels of MMPs.
Werb and colleagues used transgenic mice expressing SV40 large T antigen in their prostatic neuroendocrine cells under the control of transcriptional regulatory elements from the mouse cryptdin-2 gene (CR2-TAg) to study the factors regulating the growth of these tumors. These mice exhibit the tumorigenic and metastatic characteristics of neuroendocrine prostate tumors. The authors report that MMP-2, MMP-7, and MMP-9 activity increased with the transition to invasive metastatic carcinoma with expression occurring differentially in stroma, luminal epithelia, and macrophages, respectively. CR2-TAg mice were then crossed with mice homozygous for null alleles of MMP-2, MMP-7, and MMP-9 genes. At 24 weeks, CR2-Tag;MMP-2–/– mice showed reduced tumor burden, prolonged survival, decreased lung metastasis, and decreased blood vessel density. Deficiencies in MMP-7 or MMP-9 did not influence tumor growth or survival, but mice deficient for MMP-7 had reduced endothelial area coverage and decreased vessel size and mice deficient in MMP-9 had an increased number of invasive foci, increased perivascular invasion, and decreased vessel size. These results show that MMPs have distinct contributions to carcinogenesis, metastasis, and angiogenesis associated with these prostate tumors in this model.