Intact interferon signaling in peripheral blood leukocytes of high-grade osteosarcoma patients

High-grade osteosarcoma has a poor prognosis with an overall survival rate of about 60 percent. The recently closed European and American Osteosarcoma Study Group (EURAMOS)-1 trial investigates the efficacy of adjuvant chemotherapy with or without interferon-α. It is however unknown whether the interferon-signaling pathways in immune cells of osteosarcoma patients are functional. We studied the molecular and functional effects of interferon treatment on peripheral blood lymphocytes and monocytes of osteosarcoma patients, both in vivo and ex vivo. In contrast to other tumor types, in osteosarcoma, interferon signaling as determined by the phosphorylation of signal transducer and activator of transcription (STAT)1 at residue 701 was intact in immune cell subsets of 33 osteosarcoma patients as compared to 19 healthy controls. Also, cytolytic activity of interferon-α stimulated natural killer cells against allogeneic (n = 7 patients) and autologous target cells (n = 3 patients) was not impaired. Longitudinal monitoring of three osteosarcoma patients on interferon-α monotherapy revealed a relative increase in the CD16-positive subpopulation of monocytes during treatment. Since interferon signaling is intact in immune cells of osteosarcoma patients, there is a potential for indirect immunological effects of interferon-α treatment in osteosarcoma

Current Therapeutic Strategies and Novel Approaches in Osteosarcoma

Osteosarcoma is the most frequent malignant primary bone tumor and a main cause of cancer-related death in children and adolescents. Although long-term survival in localized osteosarcoma has improved to about 60% during the 1960s and 1970s, long-term survival in both localized and metastatic osteosarcoma has stagnated in the past several decades. Thus, current conventional therapy consists of multi-agent chemotherapy, surgery and radiation, which is not fully adequate for osteosarcoma treatment. Innovative drugs and approaches are needed to further improve outcome in osteosarcoma patients. This review describes the current management of osteosarcoma as well as potential new therapies

Interferon effects on osteoinduction.

Xenografts of human osteosarcoma growing in athymic mice are inhibited in growth rate by human interferon-alpha (IFN-alpha) treatment. In addition, differentiation of trabecular bone occurs external to the osteosarcomatous tissue and this is entirely dependent on IFN treatment. We have used species-specific anticollagens and antivimentin antibodies to determine the species origins of this trabecular bone. By using immunohistochemical procedures, it was found that this bone is host-derived. These results suggest that IFN provoked the production of a bone-inducing agent by the human osteosarcomas

Tiling resolution array comparative genomic hybridization analysis of a fibrosarcoma of bone.

Fibrosarcoma of bone is a rare malignant tumor accounting for less than 5% of all primary malignant bone neoplasms. There is very limited knowledge regarding the molecular genetics of this tumor, and there are no cytogenetic data available. In the present study, a fibrosarcoma deriving from the left iliac bone of a 10-year-old girl was characterized using cytogenetics, fluorescence in situ hybridization (FISH), and whole genome tiling resolution array comparative genomic hybridization (CGH). Cytogenetic and FISH analyses revealed a ring chromosome 6 as the sole acquired aberration, a finding corroborated by array CGH. The ring formation, however, did not result in any gain of genetic material. Nor did the breakpoints in 6p25 and 6q14 seem to affect any known gene loci in such a way that the ring formation could have resulted in the creation of a fusion gene or in the exchange of regulatory sequences. Thus, a reasonable interpretation of the pathogenetic significance of the ring formation would be that it resulted in the loss of one or more putative tumor suppressor gene loci distal to the two breakpoints

Interferon effects on osteoinduction.

Xenografts of human osteosarcoma growing in athymic mice are inhibited in growth rate by human interferon-alpha (IFN-alpha) treatment. In addition, differentiation of trabecular bone occurs external to the osteosarcomatous tissue and this is entirely dependent on IFN treatment. We have used species-specific anticollagens and antivimentin antibodies to determine the species origins of this trabecular bone. By using immunohistochemical procedures, it was found that this bone is host-derived. These results suggest that IFN provoked the production of a bone-inducing agent by the human osteosarcomas