Published online before print January 15, 2009

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(American Journal of Pathology. 2009;174:371-379.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.080538

Profiling Bladder Cancer Organ Site-Specific Metastasis Identifies LAMC2 as a Novel Biomarker of Hematogenous Dissemination

Steven Christopher Smith^*, Brian Nicholson^*, Matthew Nitz^*, Henry F. Frierson, Jr, Mark Smolkin, Garret Hampton, Wael El-Rifai and Dan Theodorescu^*||

From the Departments of Molecular Physiology and Biological Physics,^* Pathology, Public Health Sciences, Division of Biostatistics and Epidemiology, Medicine,|| and the Paul Mellon Urologic Cancer Institute,| University of Virginia Health System, Charlottesville, Virginia; and the Genomics Institute of the Novartis Research Foundation, San Diego, California

Little is known about which genes mediate metastasis in bladder cancer, which accounts for much of the mortality of this disease. We used human bladder cancer cell lines to develop models of two clinically common metastatic sites, lung and liver, and evaluated their gene expression with respect to human tumor tissues. Parental cells were injected into either the murine spleen to generate liver metastases or tail vein to generate lung metastases with sequential progeny derived by re-injection and comparisons made of their organ-specific nature by crossed-site injections. Both genomic and transcriptomic analyses of organ-selected cell lines found salient differences and shared core metastatic profiles, which were then screened against gene expression data from human tumors. The expression levels of laminin V gamma 2 (LAMC2) contained in the core metastatic signature were increased as a function of human tumor stage, and its genomic location was in an area of gain as measured by comparative genomic hybridization. Using immunohistochemistry in a human bladder cancer tissue microarray, LAMC2 expression levels were associated with tumor grade, but inversely with nodal status. In contrast, in node-negative patients, LAMC2 expression was associated with visceral metastatic recurrence. In summary, LAMC2 is a novel biomarker of bladder cancer metastasis that reflects the propensity of cells to metastasize via either lymphatic or hematogenous routes.

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