Levels of angiogenesis and expression of angiogenesis‐related genes are prognostic for organ‐specific metastasis of renal cell carcinoma

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Abstract
BACKGROUND To identify organ‐specific, metastasis‐related factors that can be used to predict the development and location of metastasis of clear cell renal cell carcinoma (CRCC), the authors assessed the angiogenesis and the expression of angiogenesis‐related genes in primary and metastatic tumors. METHODS They evaluated intratumoral microvessel density (MVD) by immunohistochemical staining, assessed the expression of angiogenesis‐related genes by mRNA in situ hybridization, and determined the clinicopathologic characteristics of 92 archival specimens of primary and metastatic CRCCs from 54 patients. All 38 metastatic tumor specimens were resected from 24 patients. RESULTS The pathologic stage (P = 0.026) of the primary tumor specimen was an important predictor for metastasis, as were MVD (P = 0.000025) and the ratio of matrix metalloproteinases (MMPs) to E‐cadherin (M/E ratio; P = 0.000041). In addition, primary tumor specimens resected from patients with metastatic CRCCs had high MVD, high levels of MMP‐2 expression, and a high M/E ratio (P < 0.05). Relative to the primary tumors, the metastatic tumors also had high MVD, overexpression of basic fibroblast growth factor, vascular endothelial growth factor, interleukin‐8, MMPs, and a high M/E ratio (P < 0.05). Multivariate analysis revealed that MVD and the M/E ratio in the primary tumor were independent prognostic factors for metastasis (P = 0.049 and P = 0.001, respectively). Furthermore, the M/E ratio in metastatic tumor specimens resected from the lung and lymph node was an independent prognostic factor for metastasis (P = 0.01823 and P = 0.03950, respectively). CONCLUSIONS The current study indicated that angiogenesis and M/E ratio were specific predictors for metastases of RCC, especially to the lung or lymph node. Therefore, MMPs and E‐cadherin could be relevant targets for novel therapeutic strategies to control or prevent the metastasis of RCC. Cancer 2005. © 2005 American Cancer Society.