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PubMed2007

Double-stranded RNA-dependent protein kinase is involved in 2-methoxyestradiol-mediated cell death of osteosarcoma cells.

UNLABELLED: We studied the involvement of interferon-regulated, PKR on 2-ME-mediated actions in human osteosarcoma cells. Our results show that PKR is activated by 2-ME treatment and is necessary for 2-ME-mediated induction of osteosarcoma cell death. INTRODUCTION: Osteosarcoma is the most common primary bone tumor and most frequently develops during adolescence. 2-Methoxyestradiol (2-ME), a metabolite of 17beta-estradiol, induces interferon gene expression and apoptosis in human osteosarcoma cells. In this report, we studied the role of interferon-regulated double-stranded (ds)RNA-dependent protein kinase (PKR) protein on 2-ME-mediated cell death in human osteosarcoma cells. MATERIALS AND METHODS: Western blot analyses were used to measure PKR protein and phosphorylation levels. Cell survival and apoptosis assays were measured using trypan blue exclusion and Hoechst dye methods, respectively. A transient transfection protocol was used to express the dominant negative PKR mutants. RESULTS AND CONCLUSIONS: PKR was increased in 2-ME-treated MG63 cells, whereas 17beta-estradiol, 4-hydroxyestradiol, and 16alpha-hydroxyestradiol, which do not induce cell death, had no effect on PKR protein levels. Also, 2-ME treatment induced PKR kinase activity as indicated by increased autophosphorylation and phosphorylation of the endogenous substrate, eukaryotic initiation factor (eIF)-2alpha. dsRNA poly (I).poly (C), an activator of PKR protein, increased cell death when osteosarcoma cells were treated with a submaximal concentration of 2-ME. In contrast, a serine-threonine kinase inhibitor SB203580 and a specific PKR inhibitor 2-aminopurine (2-AP) blocked the 2-ME-induced cell death in MG63 cells. A dominant negative PKR mutant protein conferred resistance to 2-ME-induced cell death to MG63 osteosarcoma and 2-ME-mediated PKR regulation did not require interferon gene expression. PKR protein is activated in cell free extracts by 2-ME treatment, resulting in autophosphorylation and in the phosphorylation of the substrate eIF-2alpha. We conclude from these results that PKR is regulated by 2-ME independently of interferon and is essential for 2-ME-mediated cell death in MG63 osteosarcoma cells.

2-Methoxyestradiol↗
PubMed2006

Osteosarcoma in Paget's disease of bone.

Paget's disease of bone (PDB) is a focal disorder of bone metabolism first described by Sir James Paget in 1876. It is presumed benign in nature and mediated by abnormal osteoclast function. The incidence of osteosarcomas complicating PDB is estimated at <1%. These cancers occur mostly in persons with long-standing, polyostotic disease and affect patients in their seventh decade or when osteosarcoma is remarkably rare in the general population. Epidemiological studies suggest that this late peak of osteosarcomas is absent in regions where Paget's is infrequently reported. Whereas PDB has a predilection for the axial skeleton, skull, femurs, and tibias, pagetic osteosarcoma tend to spare the spine, and are reported more commonly in the pelvis, femur, humerus, and skull. A molecular basis for the association of osteosarcoma with Paget's disease is unclear. These osteosarcomas are osteogenic in origin, consistently arise in sites of pagetic bone, and may present as metachronous, multifocal lesions. On histopathology, the lesions are usually osteoblastic, and the tumor phenotype is sometimes characterized as an exaggerated, chaotic form of the accelerated bone remodeling that characterizes PDB. New insights from the biology of adolescent osteosarcomas, VCP and SQSTM1 mutations now defined in patients with Paget's disease, and emerging evidence that stromal lesions are present in patients with Paget's disease are changing the way we think about the pathogenesis of PDB and the rare complication of pagetic osteosarcomas.

Bone Remodeling↗
PubMed2005

Investigation of the effects of deracoxib and piroxicam on the in vitro viability of osteosarcoma cells from dogs.

OBJECTIVE: To determine whether exposure of canine osteosarcoma cells to deracoxib or piroxicam results in decreased viability, whether the cytotoxic effects of deracoxib and piroxicam involve induction of apoptosis, and whether deracoxib is a more potent inhibitor of osteosarcoma cell growth than piroxicam. SAMPLE POPULATION: 1 fibroblast and 3 osteosarcoma cell lines. PROCEDURE: Cell counts and viability assays were performed using osteosarcoma cells (POS, highly metastatic POS, and canine osteosarcoma cell 31) and fibroblasts after 72 hours of incubation with deracoxib at concentrations of 0.5 microM to 500 microM or piroxicam at concentrations of 1 microM to 1,000 microM. Percentage viability was determined for each concentration. A DNA fragmentation analysis was performed to assess drug-induced apoptosis. RESULTS: Concentration of deracoxib required for 50% inhibition of cell viability (IC50) was reached in all 3 osteosarcoma cell lines and ranged from 70 to 150 microM, whereas the IC50 for piroxicam was only reached in the POS cell line at 500 microM. Neither deracoxib nor piroxicam induced sufficient toxicity in fibroblasts to reach an IC50. Exposure of osteosarcoma cells to cytotoxic concentrations of deracoxib and piroxicam did not result in DNA fragmentation. CONCLUSIONS AND CLINICAL RELEVANCE: Intermediate and high concentrations of deracoxib and high concentrations of piroxicam were cytotoxic to osteosarcoma cells; neither drug inhibited cell viability at typical plasma concentrations in dogs. Deracoxib inhibited viability of cells at concentrations that did not affect fibroblast viability. There was no evidence of apoptosis induction for either drug; however, only 1 cell line was evaluated for apoptosis induction and only for a limited selection of drug concentrations.

Animals↗
PubMed1998

Osteosarcoma of the bones of the foot--an easily misdiagnosed malignant tumor.

OBJECTIVE: To evaluate the frequency of osteosarcoma involving the foot and determine the clinical outcome of affected patients. MATERIAL AND METHODS: We retrospectively reviewed the cases of osteosarcoma encountered between 1911 and 1992 at the Rizzoli Orthopedic Institute. In particular, we analyzed whether common clinical, radiographic, or histologic features could lead to a correct diagnosis of osteosarcoma of the foot. RESULTS: The bones of the foot were the primary site of osteosarcomas in 12 cases--0.6% of the entire series of such tumors at our institution during the study period. The mean age of the patients was 33 years. Initial symptoms were usually pain and swelling. Late diagnosis was common; the mean time interval between the first symptoms and diagnosis was 28 months. Misdiagnoses occurred in 6 of the 12 cases (50%): osteoblastoma, chondroblastoma, chondrosarcoma, osteoid osteoma, desmoid fibroma, and osteomyelitis were, respectively, the initial diagnoses. Histologically, 5 of the 12 tumors (42%) were low-grade lesions. Four of the seven patients with a high-grade tumor died of metastatic disease after a mean survival of 50 months. Eight patients are alive with no evidence of disease after a mean follow-up of 162 months. CONCLUSION: When a painful swelling in a bone of the foot is observed, even if numerous benign conditions (such as fractures, infections, or benign bone tumors) are far more likely to occur, osteosarcoma must be ruled out to avoid delays in the treatment. Osteosarcomas of the foot may easily be misdiagnosed, especially because they almost always occur in adults, in contrast to osteosarcomas in general. High-grade tumors of the foot are as aggressive as other osteosarcomas and should be managed accordingly--with use of a safe-margins surgical procedure and chemotherapy.

Adolescent↗
PubMed2006

Evaluation of Her-2/neu gene status in osteosarcoma by fluorescence in situ hybridization and multiplex and monoplex polymerase chain reactions.

CONTEXT: Previous reports suggest that the human epidermal growth factor 2 (HER-2/neu) receptor may be overexpressed in osteosarcoma. OBJECTIVE: To determine whether osteosarcomas have amplifications of the HER-2/neu gene. DESIGN: We studied a series of osteosarcomas by fluorescence in situ hybridization (FISH) and by 2 real-time polymerase chain reaction assays that measure the amount of HER-2/neu DNA relative to a control gene. The HER-2/ neu monoplex and multiplex assays were capable of identifying those cases of breast cancer that were known to overexpress HER-2/neu as assessed by FISH. We initially studied 21 cases of osteosarcoma by FISH analysis (using a technique that included a probe for chromosome 17), 11 of which had their HER-2/neu gene amplification status previously reported. RESULTS: None of these osteosarcoma cases showed HER-2/neu amplification by our FISH analysis and subsequent quantitative (multiplex) polymerase chain reaction. Apparent expression of HER-2/neu protein was observed in several of the cases but the immunoreactivity was localized to the cytoplasm and was not membranous in character. An additional 35 osteosarcoma specimens were subjected to monoplex polymerase chain reaction analysis, and amplifiable DNA was recovered from 19 specimens (54%). None of these samples had HER-2/neu amplification by monoplex PCR analysis and only one case had membranous immunoreactivity graded as 1+. CONCLUSION: Although a small subset of osteosarcomas had weak noncircumferential membranous immunoreactivity for HER-2/neu protein, no osteosarcomas demonstrated positive (2+ or 3+) immunoreactivity for HER-2/ neu protein and none showed HER-2/neu gene amplification by either FISH or polymerase chain reaction.

Bone Neoplasms↗
PubMed1998

[Comparative genomic hybridization (CGH) for detecting a heretofore undescribed amplified chromosomal segment in high-grade medullary osteosarcoma].

Osteosarcoma is one of the most commonly biopsied primary tumor of bone. High-grade osteosarcomas in particular exhibit a wide spectrum of cytogenetic changes. Molecular cytogenetic studies on osteosarcomas have shown that genomic amplification, especially of both the TP53-binding MDM2 gene and the flanking SAS gene, plays an important role in the biology of these tumors. We applied CGH in order to obtain a global view of DNA-sequence losses and gains in osteosarcoma. CGH was performed on 20 high-grade medullary osteosarcomas (13 primary tumors prior to chemotherapy, 5 tumors after chemotherapy, 2 established cell lines [MB63, HOS58]) using genomic DNA of snap-frozen tumor specimens. CGH revealed DNA copy number aberrations, mostly gains, in all the tumors studied with an average of 18.5 aberrations/tumor (range 8-32). High-level amplifications were observed in all cases (average 4.1 amplifications/tumor [range 1-10]). Amplicons affecting at least five tumors were mapped to 1p21-31 (9/20 cases), 3q25-qter (6/20), 6p12-21 (6/20), 8q12-qter (10/20), 12p11-12 (9/20), 12q12-15 (enclosing MDM2 and SAS loci, 7/20). Losses were most frequently seen at 3p, 10q, 11p and 13 (all 10/20). In conclusion, our CGH data indicated that genomic amplification plays an important role in the biology of osteosarcoma. CGH demonstrated the complexity of genetic aberrations in osteosarcomas. The detection of novel non-random DNA amplifications in our study has defined regions for further targeted molecular genetic research aimed at identifying those oncogenes that are characteristic of osteosarcoma development.

Bone Neoplasms↗
PubMed2000

Intracortical osteosarcoma: report of a case.

Intracortical osteosarcoma is the rarest anatomic variation of osteosarcoma. There have been only 12 cases reported in the English-language literature. We present a case of osteosarcoma in an 18-year-old Taiwanese man that originated within the cortex of the tibial diaphysis. The initial radiograph revealed a lytic mass confined to the cortex, mimicking a benign bone lesion. Histopathologic examination of the biopsy specimen showed an osteoblastic osteosarcoma mingled with some fibroblastic foci. He underwent en bloc resection, and a metallic prosthetic intercalary stem was used to replace the larger bone defect. Adjuvant chemotherapy was administered before and after the operation. He was free of disease during 40 months of follow-up. A review of all reported cases of intracortical osteosarcoma revealed that the initial method of treatment plays an important role in local recurrence and distant metastasis. Local excision and curettage leads to the worst results. The outcomes of more recently reported cases have improved because of early awareness of the possibility of malignancy and advances in chemotherapy. However, whether patients with intracortical osteosarcoma have a different prognosis from those with conventional osteosarcoma cannot be determined, because of the small number of intracortical osteosarcoma cases available for analysis.

Adolescent↗
PubMed2000

[Expression and significance of AR in osteosarcoma].

OBJECTIVES: To determine the relationship between AR and pathological characteristics of osteosarcoma and to investigate the potential role of AR in the pathogenesis of osteosarcoma. METHODS: AR in the samples of the paraffin embedded tissues from 65 cases of osteosarcoma was immunohistochemically detected by streptavidin/peroxidase (SP) method. The pathology of osteosarcoma was classified and graded according to Liu Zijun's Classification. RESULTS: The positive rate of AR was 50.8% (33/65). The positive particles were distributed in the cytoplasm and nucleus. The positive rate of AR in osteosarcoma with higher grade of cell differentiation was lower than that in the tumor with lower one. There was no significant difference in different pathological type of osteosarcoma. CONCLUSION: AR exists in osteosarcoma and its positive rate is related to the cell differentiation of osteosarcoma.

Bone Neoplasms↗
PubMed2004

Tumor blood vessels formation in osteosarcoma: vasculogenesis mimicry.

BACKGROUND: Osteosarcoma is characterized by high neovascularization and a high propensity for metastasis through bloodstream. This study was to examine whether there is evidence for vasculogenic mimicry in osteosarcoma and to illustrate mechanism of tumor blood vessels formation in osteosarcoma. METHODS: Osteosarcoma cell lines (U-2OS) were tested for their ability to form tubular networks in three-dimensional culture containing type I collagen. The structures of the tubular networks were observed with phase contrast microscope and transmission electron microscope (TEM). Morphometric studies using hematoxylin and eosin (HE) stain and CD31 immunohistochemical stain to show tumor-lined channels in human osteosarcoma were also performed. RESULTS: Observation with light microscope and TEM showed that highly aggressive osteosarcoma cell lines (U-2OS) formed networks containing channels when grown in three-dimensional culture containing type I collagen, in the absence of endothelial cells or fibroblasts. Morphometric observation using HE stain and CD31 immunohistochemical stain showed that tumor cell-lined channels were also detected in vivo in osteosarcoma; by comparison, all vascular areas in the pedicle of osteochondroma or outside osteochondroma were endothelial-lined. CONCLUSION: These observations strongly suggest that aggressive osteosarcoma cells may generate vascular channels that facilitate tumor perfusion independent of tumor angiogenesis and have the ability of vasculogenic mimicry.

Bone Neoplasms↗
PubMed2005

Involvement of chemokine receptor 4/stromal cell-derived factor 1 system during osteosarcoma tumor progression.

Despite intensive chemotherapy and surgery treatment, lung and bone metastasis develop in about 30% of patients with osteosarcoma. Mechanisms for this preferential metastatic behavior are largely unknown. We investigated the role of the chemokine receptor 4 (CXCR4)/stromal cell-derived factor 1 (SDF-1) system to drive the homing of osteosarcoma cells. We analyzed the expression of the CXCR4 and SDF-1 proteins on several osteosarcoma cell lines and the effects of SDF-1 on migration, adhesion, and proliferation of these cancer cells. In vitro assays showed that the migration of osteosarcoma cells expressing CXCR4 receptor follows an SDF-1 gradient and that their adhesion to endothelial and bone marrow stromal cells is promoted by SDF-1 treatment. Moreover, the production of matrix metalloproteinase-9 is increased after SDF-1 exposure. We finally proved in a mouse model our hypothesis of the CXCR4/SDF-1 axis involvement in the metastatic process of osteosarcoma cells. Development of lung metastasis after injection of osteosarcoma cells was prevented by the administration of a CXCR4 inhibitor, the T134 peptide. These data show a possible explanation for the preferential osteosarcoma metastatic development into the lung, where SDF-1 concentration is high, and suggest that molecular strategies aimed at inhibiting the CXCR4/SDF-1 pathway, such as small-molecule inhibitors or anti-CXCR4 antibodies, might prevent the dissemination of osteosarcoma cells.

Animals↗
PubMed2005

[Prognostic significance of p21(WAF1) expression in osteosarcoma].

OBJECTIVE: To investigate the expression of p21(WAF1) gene in human osteosarcoma and their relationships with clinicopathological parameters and prognostic value. METHODS: The p21(WAF1) gene mRNA and p21 protein expression in 45 osteosarcoma and 10 fibrous dysplasia of bone specimens were analyzed by in situ hybridization and immunohistochemistry respectively. RESULTS: (1) The positive rate of p21 protein expression in osteosarcoma was 17.7% (8/45). (2) The expression rate in high proliferation (4/10) significantly higher than that in low proliferation (4/35) osteosarcoma (chi2 = 4.34, P < 0.05). (3) The positive rate of p21(WAF1) mRNA expression in osteosarcoma was 42.2% (19/45). The expression rate in high proliferation (6/10) significantly higher than that in low proliferation (13/35) osteosarcoma (chi2 = 20.6, P < 0.01). (4) The survival time after operation of the patients with p21(WAF1) mRNA expression were higher than that of the patients with p21(WAF1) mRNA negative expression (P < 0.05). CONCLUSIONS: (1) With the increase in degree of malignancy, the expression of p21(WAF1) mRNA and p21 protein in osteosarcoma tend decrease. (2) The expression of p21(WAF1) mRNA has a definite value in judging prognosis in osteosarcoma.

Adolescent↗
PubMed1988

Osteosarcomas arising on the surfaces of long bones.

Malignant bone-forming tumors that arise from the surfaces of long bones are far less common than those that arise from within bone. These surface osteosarcomas are clinically and radiographically similar, yet histologically they are quite distinct. In reviewing the literature, we classified the tumors according to three subgroups: parosteal (juxtacortical) osteosarcoma, periosteal osteosarcoma, and high-grade surface osteosarcoma. We also studied the clinical, radiographic, and histological findings in eighty patients who had been treated for an osteosarcoma over a forty-four-year period. Adequate follow-up data existed for forty-eight of the eighty patients. The duration of follow-up ranged from two to fifteen years after the initial operation (amputation or resection). Patients who had a parosteal osteosarcoma had the best prognosis; those who had a periosteal osteosarcoma, the next best; and those who had a high-grade surface osteosarcoma, the poorest. Because of these widely varying prognoses, the lesions require different treatment.

Adolescent↗
PubMed1994

An unusual intracranial metastasis of osteosarcoma.

Intracranial metastasis is unusual in osteosarcoma. A case of osteosarcoma was presented with a large intracranial "stone" which was a subdural convexity metastasis. Smaller epidural metastases over other areas were noted also in brain CT scan. Using the radiographs and bone scans, many other lesions at bones, the mediastinum, pleura, perirenal space, and adrenal gland were detected simultaneously. This condition might result from either early metastases or multifocal osteosarcomas. Because many of the above lesion sites were not frequent locations of primary osteosarcoma and had been reported as metastatic targets of osteosarcoma. So the explanation of a very malignant osteosarcoma with early metastases may be more appropriate for this case. The baseball-like tumor in the subdural space with marked compression of the brain surface was grossly totally excised. Histopathologic examination confirmed the diagnosis of osteosarcoma. Postoperatively, the man's condition improved dramatically, though only for two months. He died 5 months later. Reports of such metastatic osteosarcomas are reviewed.

Adult↗
PubMed1993

MDM2 gene amplification in metastatic osteosarcoma.

The human homologue of the murine double minute 2 gene (MDM2), a p53-binding protein which may act as a regulator of p53 protein function, has recently been cloned. Initial studies of this gene in a variety of human tumors have shown frequent gene amplification in most types of sarcomas, including osteosarcomas. Amplification of the MDM2 gene may produce a functional inactivation of the p53 protein. To examine possible clinical or pathological correlates of MDM2 gene amplification in osteosarcoma, we studied 28 specimens on 26 patients with high grade osteosarcoma (16 primary, 11 metastatic, and 1 local recurrence) for MDM2 gene amplification by Southern blot analysis, using two MDM2 complementary DNA probes isolated by polymerase chain reaction. Four specimens (14%) showed amplification, including 3 metastases and 1 local recurrence. None of the primary osteosarcoma specimens had detectable MDM2 gene amplification. None of the specimens tested showed MDM2 gene rearrangement. In the present series, MDM2 gene amplification was detected significantly more frequently in metastatic or recurrent osteosarcomas than it was in primary osteosarcomas (P = 0.02). Our data suggest that MDM2 gene amplification may be associated with tumor progression and metastasis in osteosarcoma. Further investigation is warranted on the potential clinicopathological correlates of MDM2 gene amplification in osteosarcoma.

Adolescent↗
PubMed1998

Matrix metalloproteinase-9 (MMP-9) expression in childhood osseous osteosarcoma.

BACKGROUND: Over 80% of patients with osteosarcoma treated with excision alone develop pulmonary metastases, suggesting that the majority of patients with this disease harbor "micrometastases" at diagnosis. There are no histologic or molecular variables which can predict the presence or absence of micrometastasis. Matrix metalloproteinases (MMPs) are a class of matrix- and basement membrane-degrading enzymes whose expression is associated with tumor cell invasive and metastatic behavior. One of these enzymes, MMP-9 or gelatinase B, is expressed in developing and remodeling bone and in osteosarcoma cell lines. We speculated that MMP-9 expression might be associated with the micrometastatic behavior of osteosarcoma. PROCEDURE: We examined a series of pediatric primary osseous osteosarcomas and metastases for the expression of MMP-9, using a monoclonal antibody. RESULTS: We found intense MMP-9 immunostaining in most tumor cells in all samples of pretreatment osteosarcomas. In all postchemotherapy resection samples, tumor cells stained similarly, but there were fewer positively staining cells overall. In 4 of 5 metastastic lesions examined, intense immunostaining for MMP-9 was detected. CONCLUSIONS: These results suggest that MMP-9 expression is common in osteosarcoma, and that further study of the role of MMP-9 in pediatric osteosarcoma behavior is warranted.

Bone Neoplasms↗
PubMed1996

ErbB-2 expression is correlated with poor prognosis for patients with osteosarcoma.

BACKGROUND: It has been reported that the c-erbB-2 protooncogene is frequently amplified and overexpressed in many types of cancers, except sarcomas and hematological malignancies. METHODS: Expression of ErbB-2 in the tumors of 26 patients with conventional osteosarcoma was evaluated by immunoblotting. DNA from osteosarcoma tissues that expressed ErbB-2 were analyzed by Southern blot hybridization to examine gross rearrangement of the gene. The DNA was also surveyed for the presence of genetic mutation in the transmembrane domain of ErbB-2 by polymerase chain reaction-single-stranded DNA conformation polymorphism analysis. In addition, possible correlation of ErbB-2 expression with gender, age, histopathologic subtype, and response to chemotherapy was analyzed. Survival analysis was performed by the Kaplan-Meier test using the approximate chi-square statistic for the log-rank test. RESULTS: The ErbB-2 protein was detected in 11 of 26 osteosarcoma tissues (42%) by immunoblot analysis. Expression of ErbB-2 was confirmed by immunohistochemical studies using specific anti-ErbB-2 monoclonal antibody. However, neither amplification of the c-erbB-2 gene nor evidence of significant genetic mutation was found in these osteosarcomas. Expression of ErbB-2 examined by immunoblotting was most strongly correlated with early pulmonary metastases (P < 0.05). Among the entire group of 26 patients in this study, Kaplan-Meier life table survival of the patients with apparent ErbB-2 expression was significantly worse than that of the patients with little ErbB-2 expression (P < 0.01). CONCLUSIONS: In 42% of the osteosarcomas, the tumor cells expressed ErbB-2. Expression of ErbB-2 was strongly correlated with early pulmonary metastasis and poor survival rate for the patient. These data suggest that ErbB-2 plays a significant role in aggressive tumor growth and in the promotion of metastatic potential in osteosarcomas. ErbB-2 in the osteosarcoma tissues would be a useful prognostic marker for patients.

Adolescent↗
PubMed1998

Radiation dose, chemotherapy and risk of osteosarcoma after solid tumours during childhood.

Osteosarcoma is the most frequent second primary cancer occurring during the first 20 years following treatment for a solid cancer in childhood. Using a cohort study of children treated for a solid cancer, we investigated the incidence and etiology of osteosarcoma as a second malignant neoplasm after childhood cancer in a cohort and a case-control study. We analysed the relationship between the local dose of radiation and the risk of osteosarcoma, taking into account chemotherapy received. A cohort study of 4,400 3-year survivors of a first solid cancer during childhood diagnosed in France or the United Kingdom, between 1942 and 1986, revealed 32 subsequent osteosarcomas. In a nested case-control study, we matched 32 cases and 160 controls for sex, type of first cancer, age at first cancer and the duration of follow-up. Parameters studied were the incidence of osteosarcoma, the cumulative local dose of irradiation and the cumulative dose of chemotherapy received by cases and controls. The risk of a osteosarcoma was found to be a linear function of the local dose of radiation (excess relative risk per gray=1.8), and was found to increase with the number of moles of electrophilic agents per square meter but not with other drugs. No interaction was noted between radiotherapy and chemotherapy. Bilateral retinoblastoma, Ewing's sarcoma and soft tissue sarcoma were found to render patients susceptible to a higher risk of developing an osteosarcoma as a second malignant neoplasm. We recommend long-term surveillance of patients who were treated during childhood for bilateral retinoblastoma, Ewing's sarcoma, soft tissue sarcoma, as well as other first cancer treated with radiotherapy plus high doses of chemotherapy, without focusing exclusively on the radiation field.

Adolescent↗
PubMed1999

Redundancy of autocrine loops in human osteosarcoma cells.

With the aim of identifying innovative therapeutic strategies for osteosarcoma patients who are refractory to conventional chemotherapy, we analyzed the in vitro effects of the blockage of autocrine circuits. Since the insulin-like growth factor-I receptor (IGF-IR)-mediated loop is relevant to the growth of osteosarcoma, we analyzed the activity of the IGF-IR-blocking antibody alphaIR3 in both sensitive and multidrug-resistant osteosarcoma cell lines. Only limited effects, however, were observed, suggesting the simultaneous existence of other autocrine circuits. Indeed, in a representative panel of 12 human osteosarcoma cell lines, in addition to the IGF-IR-mediated circuit, we demonstrated also a loop mediated by epidermal growth factor receptor as well as the presence of nerve growth factor, low-affinity nerve growth factor receptor as well as tyrosine receptor kinase A in the great majority of osteosarcomas. Therapies based on the inhibition of single circuits may have only limited effects in osteosarcoma, whereas the use of suramin, a drug which, besides other activities, non-selectively interferes with the binding of growth factors to their receptors, appears as a promising alternative, in both sensitive and drug-resistant osteosarcoma cells.

Antineoplastic Agents↗