Matrix metalloproteinases contribute distinct roles in neuroendocrine prostate carcinogenesis, metastasis, and angiogenesis progression.
Prostate cancer is the leading form of cancer in men. Prostate tumors often contain neuroendocrine differentiation, which correlates with androgen-independent progression and poor prognosis. Matrix metalloproteinases (MMP), a family of enzymes that remodel the microenvironment, are associated with tumorigenesis and metastasis. To evaluate MMPs during metastatic prostatic neuroendocrine cancer development, we 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). These mice have a stereotypical pattern of tumorigenesis and metastasis. MMP-2, MMP-7, and MMP-9 activities increased concurrently with the transition to invasive metastatic carcinoma, but they were expressed in different prostatic cell types: stromal, luminal epithelium, and macrophages, respectively. CR2-TAg mice treated with AG3340/Prinomastat, an MMP inhibitor that blocks activity of MMP-2, MMP-9, MMP-13, and MMP-14, had reduced tumor burden. CR2-TAg animals were crossed to mice homozygous for null alleles of MMP-2, MMP-7, or 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, whereas deficiencies in MMP-7 or MMP-9 did not influence tumor growth or survival. Mice deficient for MMP-7 had reduced endothelial area coverage and decreased vessel size, and mice lacking MMP-9 had increased numbers of invasive foci and increased perivascular invasion, as well as decreased tumor blood vessel size. Together, these results suggest distinct contributions by MMPs to the progression of aggressive prostate tumor and to helping tumors cleverly find alternative routes to malignant progression.
Littlepage
Laurie E
LE
Department of Anatomy, University of California, San Francisco, California 94143-0452, USA.
Sternlicht
Mark D
MD
Rougier
Nathalie
N
Phillips
Joanna
J
Gallo
Eugenio
E
Yu
Ying
Y
Williams
Kurt
K
Brenot
Audrey
A
Gordon
Jeffrey I
JI
Werb
Zena
Z
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008175:Lung Neoplasms / Q000201:enzymology / Q000556:secondary; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020783:Matrix Metalloproteinase 7 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000201:enzymology / Q000473:pathology; D018358:Neuroendocrine Tumors / Q000098:blood supply / Q000201:enzymology* / Q000473:pathology*; D009930:Organic Chemicals / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000201:enzymology* / Q000473:pathology*; D017154:Stromal Cells / Q000201:enzymology / Q000473:pathology
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D009930:Organic Chemicals; C113282:prinomastat; D020782:Matrix Metalloproteinases; D020783:Matrix Metalloproteinase 7; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9