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Lysyl Oxidase-related Protein-1 Promotes Tumor Fibrosis and Tumor Progression in Vivo¹

Department of Cell Biology and Anatomy, The Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, 31096, Israel [G. A., Z. V., Y. K., N. G., O. K., G. N.]; Department of Pathology, Carmel Medical Center, Haifa, 34632, Israel [E. S., M. R.]; Department of Biological Regulation, Weizmann Institute of Science, Rehovot, 76100, Israel [H. D., M. N.]; and Laboratory of Molecular and Cellular Cardiology, Department of Cardiology, Carmel Medical Center, Haifa, 34632, Israel [T. C.]

The lysyl oxidase gene family members function as extracellular matrix modulating enzymes. We have found that another member of this family, lysyl oxidase related protein-1 (LOR-1), is highly expressed in metastatic breast cancer-derived cell lines but not in the nonmetastatic estrogen-dependent MCF-7 cells. Furthermore, LOR-1 expression in periductal tumor cells of breast carcinomas is significantly correlated with increased tumor malignancy. MCF-7 cells expressing recombinant LOR-1 formed estrogen-dependent tumors that developed much slower than tumors derived from empty vector-transfected MCF-7 cells. The cells of these LOR-1-expressing tumors were surrounded by a high concentration of dense collagen fibers, and the tumors contained many fibrotic foci. Induction of fibrosis in vivo by lysyl oxidase-like enzymes has never been observed before and suggests that LOR-1 may function as an autonomous inducer of fibrosis. The appearance of fibrotic foci in spontaneous breast cancer tumors is correlated with poor prognosis and metastasis, and we, therefore, examined the invasiveness of the LOR-1-expressing tumors. LOR-1-expressing MCF-7 cells invaded the pseudocapsules surrounding the tumors. In contrast, vector-transfected MCF-7 cells did not invade the pseudocapsules. This observation suggests that LOR-1 enhances the malignancy of the tumors. Furthermore, the LOR-1-expressing tumor cells invaded blood vessels, nerves, and muscles adjacent to the tumor, indicating that the LOR-1-expressing MCF-7 cells acquired metastatic properties. We conclude that LOR-1 promotes tumor fibrosis and tumor invasiveness simultaneously, which indicates that these two processes may be associated.

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