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The immunogenic properties of renal cell carcinoma (RCC) on bone osteolysis were investigated. mRNA expression of three proinflammatory cytokines, monocyte chemotactic protein-1 (MCP-1), interleukin-6 (IL-6) and interleukin-8 (IL-8), were determined in a panel of RCC lines (CRBM 1990, ACHN and Caki-1). Moreover proinflammatory cytokine mRNA expression and protein levels of adhesion molecules, intercellular adhesion molecule-1 (ICAM-1) and E-selectin, on human umbilical vein endothelial cells (HUVEC) incubated with the conditioned media from RCC lines were evaluated. RCC express mRNA of MCP-1, IL-6 and IL-8 that may induce a proinflammatory phenotype in endothelial cells. mRNA expression of IL-6, and IL-8 was induced on HUVEC treated with the conditioned media from RCC lines and mRNA and protein levels of ICAM-1 and E-selectin were also increased. This study demonstrates the immunogenic properties of renal cell carcinoma, such as pro-inflammatory cytokine secretion and the induction of adhesion molecules (ICAM-1 and E-Sel) by endothelial cells. ICAM-1 binds lymphocyte function-associated antigen-1 (LFA-1), which is expressed by pre-osteoclasts, so that, the observed proinflammatory phenotype in HUVEC may also favour osteoclast recruitment in bone metastases microenvironment. Osteolysis in bone metastases, mediated by this pathway, may be further potentiated by the pro-angiogenic properties of RCC.

Osteosarcoma (OS) is a highly malignant primary skeletal tumor with a striking tendency to rapidly destroy the surrounding bone and metastasize, since metastases are frequently present at clinical onset. The basis for the aggressiveness of this tumor is largely unknown. However, recent studies in in vivo models indicate that the anti-osteolytic drugs, bisphosphonates, can inhibit the tumor local expansion and the formation of metastases. We further investigated the association between the presence of active osteoclasts and the aggressiveness of OS. We evaluated the presence of osteoclasts and the mRNA of different osteoclast-related genes in tumor biopsies from 16 OS patients and in three OS cell lines and the serum levels of bone resorption markers in the same series and in 28 other patients. Tumor-associated osteoclasts were found in 63 and 75% of cases by histological and mRNA analysis. Among different serum markers, only MMP-9 was significantly higher in OS cases (p=0.0001), whereas TRACP 5b was significantly higher in metastatic patients compared to nonmetastatic patients (p=0.0509). Serum TRACP 5b was significantly correlated to serum NTX (p<0.0001) and cathepsin K mRNA in tumor tissues (p=0.0153). In 8 patients we also analyzed TRACP 5b serum level at follow-up and we verified a significant decrease of TRACP 5b after primary tumor removal (p=0.0117). In conclusion, tumor-infiltrating osteoclasts are frequently found in OS and increased serum TRACP 5b levels and the presence of active osteoclast at primary sites were positively associated with tumor aggressiveness.