osteoprotegerin and Skin-Neoplasms

Melanoma represents one of the most aggressive forms of cancer. With the rapid increases in the incidence of melanoma in the United States, Australia and Europe over the last decades, melanoma has been considered an epidemic cancer in these areas. The aim of our study was to evaluate the utility of osteoprotegerin (OPG), osteopontin (OPN), epidermal growth factor (EGF) and vascular endothelial growth factor VEGF for the diagnosis and prognosis of melanoma.. Overall, 322 individuals were assessed: 183 melanoma patients and 139 healthy individuals. Melanoma patients were divided into four subgroups according to the Breslow score. OPN, OPG, EGF, and VEGF were determined in each plasma sample.. The serum levels of the following biomarkers were statistically significantly higher in the melanoma group compared to the control group: OPG and, OPN (p<0.0001), EGF (p=0.0379). In the first stage, OPG (p=0.0236) and OPN (p=0.0327) showed a statistically significant increase. Concerning positive and negative sentinel node metastases a statistically significant change was observed in: OPN (p<0.0001), EGF (p=0.0114), VEGF (p=0.0114).. OPG and OPN are promising biomarkers of early-stage melanoma. EGF and VEGF appear to be prognostic biomarkers.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Epidermal Growth Factor; Female; Humans; Lymphatic Metastasis; Male; Melanoma; Melanoma, Cutaneous Malignant; Middle Aged; Neoplasm Staging; Osteopontin; Osteoprotegerin; Prognosis; Skin Neoplasms; Vascular Endothelial Growth Factor A; Young Adult

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family, which preferentially induces apoptosis in cells that have undergone malignant transformation. In humans, non-neoplastic cells are normally protected from the effects of TRAIL by expressing decoy receptors, lacking death domains. In contrast, neoplastic cells tend to downregulate their decoy receptor expression, increasing their susceptibility to the pro-apoptotic effects of TRAIL, via the functional TRAIL receptors. The aim of the current study was to investigate the effect of TRAIL on the canine C2 mastocytoma cell line to determine whether this agent might be a suitable treatment for mast cell tumors in dogs. C2 and MDCK cells were cultured with recombinant human TRAIL. Apoptosis was assessed using a Caspase 3 and 7 chemiluminescence assay and flow cytometry following Annexin V:FITC labelling. Cell metabolism was assessed using a colorimetric MTT-based assay. C2 cells demonstrated greater sensitivity to TRAIL-induced apoptosis compared to MDCK cells by all assessment methods. The dog genome assembly was searched for orthologs of TRAIL and its receptors using published sequences from other species for reference. Although a canine ortholog for TRAIL was identified, only one TRAIL receptor ortholog (TNFRSF11B) could be found. C2, but not MDCK, cells expressed mRNA for TNFRSF11B, detected by RT-PCR. In other species, TNFRSF11B is a decoy receptor, as even though it has a death domain it is secreted due to its lack of a transmembrane domain. The effect of TRAIL on the C2 cell line suggests that this cytokine might be suitable for treatment of mast cell tumors in dogs.

Topics: Animals; Apoptosis; Caspase 3; Caspase 7; Cell Line, Tumor; Cell Survival; Dog Diseases; Dogs; Flow Cytometry; Mastocytoma; Osteoprotegerin; Polymerase Chain Reaction; Recombinant Proteins; Skin Neoplasms; TNF-Related Apoptosis-Inducing Ligand

The cellular and humoral mechanisms accounting for osteolysis in skeletal metastases of malignant melanoma are uncertain. Osteoclasts, the specialised multinucleated cells that carry out bone resorption, are derived from monocyte/macrophage precursors. We isolated tumour-associated macrophages (TAMs) from metastatic (lymph node/skin) melanomas and cultured them in the presence and absence of osteoclastogenic cytokines and growth factors. The effect of tumour-derived fibroblasts and melanoma cells on osteoclast formation and resorption was also analysed. Melanoma TAMs (CD14+/CD51-) differentiated into osteoclasts (CD14-/CD51+) in the presence of receptor activator for nuclear factor kappaB ligand (RANKL) and macrophage-colony stimulating factor. Tumour-associated macrophage-osteoclast differentiation also occurred via a RANKL-independent pathway when TAMs were cultured with tumour necrosis factor-alpha and interleukin (IL)-1alpha. RT-PCR showed that fibroblasts isolated from metastatic melanomas expressed RANKL messenger RNA and the conditioned medium of cultured melanoma fibroblasts was found to be capable of inducing osteoclast formation in the absence of RANKL; this effect was inhibited by the addition of osteoprotegerin (OPG). We also found that cultured human SK-Mel-29 melanoma cells produce a soluble factor that induces osteoclast differentiation; this effect was not inhibited by OPG. Our findings indicate that TAMs in metastatic melanomas can differentiate into osteoclasts and that melanoma fibroblasts and melanoma tumour cells can induce osteoclast formation by RANKL-dependent and RANKL-independent mechanisms, respectively.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Bone Resorption; Carrier Proteins; Cell Differentiation; Cells, Cultured; Culture Media, Conditioned; Female; Fibroblasts; Glycoproteins; Humans; Interleukin-1; Lymphatic Metastasis; Macrophages; Male; Melanoma; Membrane Glycoproteins; Middle Aged; Osteoclasts; Osteolysis; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Reverse Transcriptase Polymerase Chain Reaction; Skin Neoplasms; Tumor Necrosis Factor-alpha