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.