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Survival in patients with metastatic renal cell carcinoma (RCC) depends upon the organ involved with disease. Furthermore, patients with RCC lung metastases tend to respond with greater efficiency to interferon-alpha than patients with other organ-involvement. Low doses of interferon alpha inhabit RCC growth in part through down-regulation of proangiogenic factors and inhibition of angiogenesis. We hypothesize that organ-specific growth of RCC reflects organ-dependent expression of progression-related genes and that this expression may impact the ability of interferon-alpha to inhibit the growth of metastatic RCC in different sites of metastasis. The kidneys of nude mice were injected with the human RCC cell line, SN2-PM6 which will metastasize frequently to the lung and less frequently to other organs. The mice were sacrificed and the primary tumor and all spontaneous metastases were preserved in formalin and paraffin. We assessed gene expression using in situ hybridization for basic fibroblast growth factor (IL-8), vascular endothelial growth factor (VEGF), interleukin (IL)-8, matrix-metalloprotease (MMP)-2 and -9, and E-cadherin. Relative gene levels was assessed by image analysis and expressed relative to expression of tumor grown in the kidney. Expression of individual genes varied less than 30% in metastases taken from different mice irrespective of the organ system assessed. Expression of VEGF and MMP-2, and –9 was increased 45%, 70% and 85%, respectively, in the liver compared to the kidney. VEGF was overexpressed up to 60% in the lung compared to the kidney. SN2-PM6 growing indifferent murine organs was then treated with antiangiogenic doses of interferon-alpha (20,000 U s.c. daily). Differences in tumor weights/number metastases and gene expression were compared between mice treated with interferon-alpha and those treated with saline. The greatest effect of interferon-alpha was seen in the lungs (65% reduction in number of metastases), kidney (40% reduction in kidney weight), and bone (27% reduction in tumor weight). Interferon-alpha had little effect on liver and subcutis tumors (<20% reduction). Expression of MMP-9 and bFGF were reduced by 50% in the lung and kidney tumors, 40% in the bone tumors and less than10% in liver and subcutis tumors. These results suggest that this orthotopic murine model of RCC may aid us in the understanding of organ-specific effects on gene expression. The effect of interferon-alpha on tumor growth and expression of MMP-9 and bFGF occurs in an organ-dependent manner with the greatest reductions seen in the lung. The mechanism responsible for these phenomena remains to be elucidated.

[Proc Amer Assoc Cancer Res, Volume 45, 2004]