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PubMed2003

Overexpression of cadherins suppresses pulmonary metastasis of osteosarcoma in vivo.

Osteosarcoma by nature shows aggressive pulmonary metastasis; however, the underlying molecular mechanisms remain unclear. We previously showed that N-cadherin and cadherin-11 (OB-cadherin), which are highly expressed in normal osteoblasts, are anomalously expressed in human osteosarcoma (Kashima et al., Am J Pathol 1999;155:1549-55). In the present study, we examined the role of cadherins in osteosarcoma metastasis using the mouse osteosarcoma cell line Dunn and its highly metastatic subline LM8. Oligonucleotide array and RT-PCR analyses demonstrated that Dunn and LM8 cells did not express appreciable levels of several members of the cadherin family, and Western blot analysis confirmed that Dunn and LM8 cells did not express P-cadherin, E-cadherin, N-cadherin or cadherin-11 protein. We therefore investigated the functional consequences of cadherin overexpression on cell migration and in vivo metastatic potential of LM8 cells. Several LM8 clones were isolated which expressed exogenous N-cadherin and cadherin-11 localized to the cell membrane and able to bind to beta-catenin. Overexpression of N-cadherin or cadherin-11 in LM8 cells did not affect cell proliferation but caused an inhibitory effect on cell migration in vitro. In vivo analysis showed that N-cadherin- and cadherin-11-overexpressing cells exhibited a marked reduction in their ability to form pulmonary metastases, with significant decreases in lung weight and the number and weight of metastatic lesions, as well as the size and weight of primary lesions at the s.c.-inoculated site. These observations demonstrate that disruption of N-cadherin- and cadherin-11-mediated cell-cell adhesion is critical in the pulmonary metastasis of osteosarcoma.

Animals↗

PubMed1994

Expression of transforming growth factor-beta (TGF-beta) receptors, TGF-beta 1 and TGF-beta 2 production and autocrine growth control in osteosarcoma cells.

Transforming growth factor-beta (TGF-beta) is a polypeptide with multiple physiological functions. Isoforms of this growth factor have important roles in control of the cell cycle, in regulation of cell-cell interactions and in growth and development. Malignant transformation has been shown to be associated with increased expression of TGF-beta. Since bone is the largest storage site and producer of TGF-beta, we speculated on the existence of an autocrine mechanism in osteosarcoma, a malignant bone tumor. Expression of TGF-beta cell surface receptors, effects on growth of TGF-beta and TGF-beta antibodies and production of 2 TGF-beta isoforms were studied in a panel of 7 osteosarcoma cell lines. In contrast to most previous reports on the effects of TGF-beta on osteosarcoma cell growth, we found a mitogenic effect of TGF-beta 1 in 4 of 7 osteosarcoma cell lines. Receptor profiles for TGF-beta were aberrant in 5 of the 7 cell lines tested, and production of TGF-beta 1 and TGF-beta 2 varied among cell lines. Addition of anti-TGF-beta antagonized the effects of endogenous TGF-beta. Our results suggest a potential role of TGF-beta in autocrine growth control of osteosarcoma cells.

Antibodies↗

PubMed1994

Expression of cell growth and bone phenotypic genes during the cell cycle of normal diploid osteoblasts and osteosarcoma cells.

Establishing regulatory mechanisms that mediate proliferation of osteoblasts while restricting expression of genes associated with mature bone cell phenotypic properties to post-proliferative cells is fundamental to understanding skeletal development. To gain insight into relationships between growth control and the developmental expression of genes during osteoblast differentiation, we have examined expression of three classes of genes during the cell cycle of normal diploid rat calvarial-derived osteoblasts and rat osteosarcoma cells (ROS 17/2.8): cell cycle and growth-related genes (e.g., histone), genes that encode major structural proteins (e.g., actin and vimentin), and genes related to the biosynthesis, organization, and mineralization of the bone extracellular matrix (e.g., alkaline phosphatase, collagen I, osteocalcin, and osteopontin). In normal diploid osteoblasts as well as in osteosarcoma cells we found that histone genes, required for cell progression, are selectively expressed during S phase. All other genes studied were constitutively expressed both at the transcriptional and posttranscriptional levels. Alkaline phosphatase, an integral membrane protein in both osteoblasts and osteosarcoma cells, exhibited only minimal changes in activity during the osteoblast and osteosarcoma cell cycles. Our findings clearly indicate that despite the loss of normal proliferation-differentiation interrelationships in osteosarcoma cells, cell cycle regulation or constitutive expression of growth and phenotypic genes is maintained.

Actins↗

PubMed2001

Adjuvant chemotherapy for osteosarcoma may not increase survival after neoadjuvant chemotherapy and surgical resection.

BACKGROUND AND OBJECTIVES: Osteosarcoma is a primary malignancy of bone. Current therapy includes neoadjuvant chemotherapy, surgery, and postoperative (adjuvant) chemotherapy. Prolonged treatment with chemotherapeutic agents may place patients at increased risk for complications including secondary malignancy. The authors have had promising results with neoadjuvant therapy and surgery alone in the treatment of osteosarcoma. This study retrospectively examines neoadjuvant therapy and surgery alone for the treatment of primary osteosarcoma of bone with no evidence of distant metastases. METHODS: Fifty-four patients, with localized osteosarcoma of bone received neoadjuvant therapy followed by definitive surgical resection. Thirty-five patients received chemotherapy after surgery (adjuvant group) and nineteen patients were followed without postoperative chemotherapy (no adjuvant group). RESULTS: Tumor necrosis was predictive of survival. Kaplan-Meier analysis revealed the use of postoperative chemotherapy was not a predictor of improved outcome. Four patients in the adjuvant therapy group died of secondary malignancy compared with none of the no adjuvant therapy group. Patient age, sex, race, and tumor location were not predictive of survival. CONCLUSIONS: The use of adjuvant chemotherapy in the treatment of localized osteosarcoma of bone did not increase survival after neoadjuvant therapy and definitive surgical therapy. Instead, there was an increased incidence of secondary malignancy after its use.

Adolescent↗

PubMed2006

Expression of survivin and correlation with PCNA in osteosarcoma.

BACKGROUND AND OBJECTIVES: Survivin is a new anti-apoptosis gene with reported expression during fetal development and in cancer tissues. Proliferating cell nuclear antigen (PCNA) is essential for the replication of deoxyribonucleic acid (DNA). In this experiment, we examined the expression of survivin and PCNA in human osteosarcoma tissues and investigating whether survivin and PCNA expressions were correlated with histological grades, histological types, and patients' clinical characteristics. METHODS: Sixty-eight osteosarcoma samples were divided into two groups based on the degree of tumor cell differentiation. Immunohistochemical staining was performed to analyze the expression of survinin and PCNA. Four histological types and patients' clinical characteristics were also recorded. RESULTS: There were abundant levels of survivin and PCNA immunoreactivity in the nucleus and/or cytoplasm of the osteosarcoma cells. All cells essentially revealed the cytoplasmic localization and the nuclear signals of survivin in same cases, while PCNA from the majority of cases predominantly showed nuclear expression. Scoring on the percentage of positive cells indicated that survivin expression was significantly associated with the PCNA-labeling index (LI), which was correlated with the histological grades of osteosarcoma (chi2 = 17.86 and chi2 = 23.75, respectively). CONCLUSIONS: The expression of survivin can be used as a useful indicator in grading the malignancy of osteosarcoma.

Adolescent↗

PubMed1993

Correlation between lack of bone Gla protein mRNA expression in rat transplantable osteosarcomas and expression of both c-fos and c-jun proto-oncogenes.

Alkaline phosphatase (AP) activity and expression of bone Gla protein (BGP), c-fos, and c-jun were compared in two transplantable osteosarcomas with high potentials for metastasis to the lung. The original spontaneous osteosarcoma (SOS) gradually became histologically undifferentiated, losing its osteogenic activity during serial transfer, whereas the chemical (4-hydroxyaminoquinoline 1-oxide)-induced osteosarcoma (COS) retained osteogenesis. The two osteosarcomas showed similar doubling times and levels of lung metastasis, and strong AP activity was detected on the cell membranes of both. Northern blot analysis revealed that lack of BGP mRNA expression was associated with expression of both c-fos and c-jun proto-oncogenes in SOS. In contrast, neither c-fos nor c-jun mRNAs were detected but BGP mRNA was expressed in the case of COS. These results suggest that the c-fos and c-jun genes may suppress the expression of BGP mRNA relevant to differentiation and osteoid formation in rat osteosarcomas. However, this does not appear to be directly related to proliferative or metastatic biological behavior.

Alkaline Phosphatase↗

PubMed2004

Interferon-gamma sensitizes osteosarcoma cells to Fas-induced apoptosis by up-regulating Fas receptors and caspase-8.

BACKGROUND: Osteosarcoma is the third most frequent neoplasm in adolescents. Although chemotherapy, frequently used in pre- and post-operative settings, has resulted in significant improvement in disease-free survival, some patients show little sensitivity to chemotherapy and alternative therapeutic strategies are needed. Because the Fas ligand/Fas receptor (CD95, APO-1) apoptosis pathway is a potential therapeutic target in osteosarcomas, we examined the effect of IFN-gamma on Fas-induced apoptosis in four osteosarcoma cell lines. PROCEDURE AND RESULTS: As measured by flow cytometry, all cell lines expressed cell surface IFN-gamma receptors, and when cultured for 2 days in the presence of IFN-gamma, all cell lines exhibited a significant increase in expression of Fas receptors. By flow cytometric detection of intracellular fragmented DNA as a marker of apoptosis, all cell lines cultured with either IFN-gamma or anti-Fas antibody (clone CH-11) alone showed only moderate apoptosis, whereas significantly high levels of apoptosis occurred in cells cultured with both IFN-gamma and CH-11. Western blotting analysis also revealed that IFN-gamma caused up-regulation of caspase-8 in all cell lines, but no change in Fas-associated death domain protein (FADD/MORT1) or caspase-3. Both caspase-8 and caspase-3 were activated when apoptosis was induced with both IFN-gamma and CH-11. Addition to cultures of z-IETD-fmk, an inhibitor of caspase-8, significantly blocked this apoptosis. CONCLUSIONS: IFN-gamma sensitizes osteosarcoma cells to Fas-induced apoptosis through up-regulation of Fas receptor and caspase-8. Combined immunotherapy with IFN-gamma and either anti-Fas monoclonal antibody or cytotoxic T cells that bear Fas ligand might be a useful adjunctive therapy for patients with osteosarcoma.

Adaptor Proteins, Signal Transducing↗

PubMed1994

Primary osteosarcoma of the uterus: report of a case with immunohistochemical analysis.

Primary osteosarcoma of the uterus is an extremely rare neoplasm, and its immunohistochemical characteristic is unknown. We report a case of osteosarcoma occurring primarily in the uterine corpus of a 67-year-old woman with lower abdominal pain. The excised tumor showed bony inconsistency and histologically displayed a "pure" osteosarcoma of the uterus. Immunocytochemically, the tumor cells were positive for vimentin but negative for epithelial markers. The patient died 4 months after surgery because of developed local recurrence and pulmonary metastases. In conclusion, uterine osteosarcoma differs from malignant mixed Müllerian tumor (MMMT) in biological behavior, macroscopic and histologic features, and immunohistochemical profile. Osteosarcoma shows more aggressive behavior than MMMT, and displays nonpolypoid feature in appearance and no evidence of epithelial differentiation.

Aged↗

PubMed1980

The biology, pathology and immunology of a virus induced rat osteosarcoma. II. Immunological studies.

The immunogenicity of a virus-induced rat osteosarcoma was studied utilizing the lymphocyte microcytoxicity test. Lymphocytes from "progressor" animals (in which the tumour progressed and metastasized) demonstrated an ability to kill osteosarcoma cells in vitro, while serum from these animals abrogated or blocked the cell-mediated cytotoxicity. Lymphocytes from "regressor" animals (in which tumours failed to develop or regressed spontaneously) also showed cytolytic activity against osteosarcoma cells in vitro, but their serum failed to block the lymphocyte-mediated cytolysis. Both progressor and regressor animals demonstrated the presence of humoral cytotoxic antibodies to tumour antigens on the basis of the ability of their serum to kill tumour cells in vitro. In an attempt to alter the fatal course of the disease in progressor animals, immunoprophylaxis and immunotherapy of the osteosarcoma in F1 hybrid rats war carried out by injecting them with parentalor, third party, allogeneic lymphoid cells. Injection of parental spleen lymphocytes into F1 hybrids produced a transient graft versus host reaction (GVHR), and prolonged the survival of the animals when lymphocytes were injected three days before, seven days after and on the day of tumour induction. Injection of allogeneic, third party lymphoid cells produced no detectable GVHR and prolonged the survival of F1 hybrids with osteosarcoma only when injected on the day of tumour induction. The prolonged survival of the groups treated with parental lymphoid cells was a result of stimulation of the host's immunological mechanisms during a transient GVHR, whereas the prolongation of survival in the group given allogeneic cells was most likely the result of a direct action of the donor lymphocytes on tumour cells, and not connected to a GVHR.

Animals↗

PubMed1994

Primary osteosarcoma of the cerebrum with immunohistochemical and ultrastructural studies: report of a case.

A 57-year-old woman with primary intracerebral osteosarcoma is reported. The tumor was identified by computed tomography as a mass with hemorrhage in the right parietal lobe. The surgical and pathological examinations confirmed an osteosarcoma of intracerebral origin. She suffered from repeated local recurrence of the tumor and died about 1 year after the onset. The pathological findings showed features of osteoblastic osteosarcoma with numerous osteoclast-like multinucleated giant cells. Immunohistochemically, tumor cells were positive for vimentin, and partially for actin. Multinucleated giant cells were reactive with vimentin and CD68 antibodies. Ultrastructurally, tumor cells were rich with rough endoplasmic reticulum. These findings are consistent with the histological features of skeletal or extraskeletal osteosarcoma. This is the third case of primary intracerebral osteosarcoma reported in the literature and the first one analyzed ultrastructurally.

Brain Neoplasms↗

PubMed1982

Purely lytic osteosarcoma.

The radiographic features of 42 purely lytic osteosarcomas are presented. Purely lytic osteosarcoma is identified as a lytic lesion of bone with no demonstrable osteoid matrix by conventional radiographic modalities. Purely lytic osteosarcoma represented 13.7% of a group of 305 osteosarcomas. The most common presentation was that of a lytic ill-defined lesion with a moderate to large extraosseous mass component. Nine lesions presented with benign radiographic features. The differential diagnosis is outlined. The need for awareness of this type of presentation of osteosarcoma is stressed.

Adolescent↗

PubMed1986

Synthesis, antitumor activity, distribution and toxicity of 4-[4-[bis(2-chloroethyl)amino]phenyl]-1-hydroxybutane-1 1-bisphosphonic acid (BAD), a new lost derivative with increased accumulation in rat osteosarcoma.

The aim of this study was to investigate whether the newly synthesized bisphosphonic acid-linked N-Lost derivative BAD retains bone-seeking and cytostatic properties. The paper describes experiments on mutagenicity in vitro and on toxicity in vivo. BAD is characterized by very low mutagenic activity toward histidine auxotrophic Salmonella typhimurium strains. Cytotoxic effects were tested in rat osteosarcoma and in Walker carcinosarcoma 256B. The LD50 of i.v. injected BAD was 146 mg/kg. Acute toxicity is probably caused by calcium complexing of the bisphosphonate part of the molecule. Labeling experiments showed moderate accumulation in bone and osteosarcoma, as well as in lung metastases. BAD effected high tumor growth inhibition in osteosarcoma and Walker carcinosarcoma-bearing rats and marked prolongation of survival; histologic and radiographic examination revealed rapid calcification of osteosarcoma and lung metastases. BAD-pretreatment produced protective effects against osteolysis induced by intratibially implanted Walker carcinosarcoma ascites cells. The cytostatic efficacy of equitoxic doses of BAD in rat osteosarcoma is comparable to that of dacarbazine and in Walker carcinosarcoma to that of melphalan.

Animals↗

PubMed1987

Cytostatic effects in osteosarcomas as detected by flow cytometric DNA analysis after preoperative chemotherapy according to the COSS 80/82 protocol.

A total of 20 highly malignant osteosarcomas were studied by DNA flow cytometry after preoperative chemotherapy according to the COSS 80/82 protocol to assess their nuclear DNA content and the impact of chemotherapy on DNA ploidy and proliferation. Of the cases studied, 70% revealed aneuploid DNA stem lines with a median value of 1.67, and a median S-phase proportion of 16.1%. These data differed substantially from the results of a preceding study on untreated osteosarcomas revealing a higher frequency of DNA aneuploidy, higher DNA indices, and higher proportions of cells in S-phase. The pretreated tumors also showed a distinct relation between DNA content and the grade of tumor regression. No aneuploid DNA stem line was found in the responder group-I, whereas group-V (osteosarcomas with more than 50% viable tumor tissue) consisted almost completely of aneuploid DNA populations; all tumors with more than 2 DNA aneuploids were found in the latter group. All populations with a DNA index (DI) over 2.0 were found in the nonresponder groups IV and V, where all DNA aneuploids had an S-phase above 12%. No differences in DNA ploidy or proliferation were found in the various histological subtypes of pretreated osteosarcomas. These data indicate that flow cytometric DNA measurement in osteosarcoma may not only serve as a tumor marker, but also support the evaluation of morphologically established regression grades, thereby verifying the patient's prognosis: a high DI (over 2.0), a high number of DNA aneuploids (more than 2), and a high proliferation (S-phase above 12%) seemed to indicate a poor regression of the primary lesion, which may offer a pretherapeutic way of prognostic evaluation.

Adolescent↗

PubMed1992

Effect of chemotherapy combined with caffeine for osteosarcoma.

Nine patients with osteosarcoma were treated by chemotherapy combined with caffeine and surgery. All primary tumors showed complete histological response to preoperative chemotherapy consisting of three intraarterial infusions of cisplatin and caffeine without/with doxorubicin and two systemic high-dose methotrexate combined with vincristine. Limb-salvage surgery was performed in eight patients with marginal procedure, which led to the preservation of good limb function. Below-knee amputation was done in one patient with calcaneal osteosarcoma. There has been neither local recurrence nor lung metastasis in seven patients with conventional osteosarcoma during a median follow-up period of 28 months. Lung metastases leading to death were observed in one patient with small-cell osteosarcoma despite complete destruction of the primary tumor by preoperative chemotherapy. Chemotherapy combined with caffeine administration deserves further extensive and large-scale study in osteosarcoma.

Adolescent↗

PubMed1989

Immunohistochemical and biochemical studies on the collagenous proteins of human osteosarcomas.

The distribution of type I, II, III, IV, V and VI collagens in 20 cases of osteosarcoma was demonstrated immunohistochemically using monospecific antibodies to different collagen types. In addition, biochemical analysis was made on collagenous proteins synthesized by tumor cells in short-term cultures obtained from seven representative cases and compared with dermal fibroblasts. In osteoblastic areas, most of the tumor osteoid consisted exclusively of type I collagen. Type V collagen was associated in some of them. Type III and type VI collagens were mainly localized in the perivascular fibrous stroma. Cultured tumor cells from osteoblastic osteosarcomas produced type I collagen exclusively and small amount of type V collagen constantly, while the synthetic activity of type III collagen was extremely low. In contrast, fibroblastic areas were characterized by the codistribution of type I, III, VI collagens and chondroblastic areas by type I, V, VI collagens as well as type II. Furthermore, type IV collagen was demonstrated in the stroma, other than the basement membrane region of blood vessels, in fibroblastic, intramedullary well-differentiated and telangiectatic osteosarcomas. In vitro, the production of variable amounts of type IV collagen, which was not detected in cultured dermal fibroblasts, was also recognized in the osteoblastic, fibroblastic, undifferentiated and intramedullary well-differentiated osteosarcomas examined. These findings suggest that the immunohistochemical approach using monospecific antibodies to different collagen types is useful not only in identifying some specific organoid components, such as tumor osteoid, but also in disclosing the biological properties of osteosarcoma cells with diverse differentiation.

Adolescent↗

PubMed1981

Tumor cell types in osteosarcoma as revealed by electron microscopy. Implications for histogenesis and subclassification.

Ultrastructural studies in 26 osteosarcomas of high grade malignancy which were in diverse locations and of varied histological types revealed seven different tumor cell types. They were characterized by their features as follows: 1) anaplastic cells of malignant blast structure: 2) osteoblastic cells -- some of them with dot-like intranuclear bodies; 3) osteocyte-like cells surrounded by mineralized matrix; 4) fibroblast-like cells; 5) cells of myofibroblastic differentiation; 6) chondroblast-like cells in chondroblastic areas, and even 7) angioblastic cells that may be differentiated from the angioblastic and endothelial structures of capillaries. Histogenetically, osteosarcoma may be derived from stromal mesenchymal cells with a potential for differentiation into these seven tumor cell types, any tumor including, however, the osteoblastic and the osteocyte-like cells with tumor osteoid. This matrix serves as the specific criterion for identifying a tumor as "osteosarcoma", but almost every osteosarcoma of high grade malignancy will show these seven tumor cell types. The predominance of one or the other cell in the population may provide the basic information for achieving a cytologic subclassification of osteosarcoma in order to obtain relevant morphologic criteria in terms of prognosis.

Adolescent↗

PubMed2004

Human osteosarcoma xenografts and their sensitivity to chemotherapy.

Despite the increased survival rates of osteosarcoma patients attributed to adjuvant chemotherapy, at least one third of the patients still die due to their disease. Further improvements in the management of osteosarcoma may rely on a more individualised treatment strategy, as well as on the introduction of new drugs. To aid in the preclinical evaluation of new candidate substances against osteosarcoma, we have established 11 human osteosarcoma xenograft lines and characterised them with regard to response to five different reference drugs. Doxorubicin, cisplatin methotrexate, ifosfamide and lomustine were effective in 3/11, 3/11, 1/10, 5/11 and 4/11 of the xenografts, respectively. Five xenografts were resistant to all compounds tested. We also assessed the mRNA expression levels of the xenografts for the O(6)-Methylguanine DNA Methyltransferase (MGMT), DNA topoisomerase II- (Topo II)-alpha, Gluthathione-S-transferase (GST)-pi, Multidrug-resistance related protein (MRP) 1 and Multidrug-resistance (MDR) 1 genes. There was an inverse correlation between the transcript levels of GST-pi and doxorubicin growth inhibition (r=-0.66; p<0.05), and between the transcript levels of MGMT and the effect of lomustine (r=-0.72; p<0.01), whereas the expression of MRP1 and cisplatin growth inhibition was positively correlated (r=0.82; p<0.005). This panel of xenografts should constitute a good tool for pharmacological and molecular studies in osteosarcoma.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2005

Segmental cement extraction system (SEG-CES) and the Ilizarov method in limb salvage procedure after total knee cemented prosthesis removal in a former osteosarcoma patient.

Survival of osteosarcoma has greatly improved in the past few decades. Knee prosthesis is a well-recognized limb salvage procedure for osteosarcoma of the distal end of the femur. One drawback is that prostheses have a limited life and prosthetic failure with the inherent high rate of reoperations remains a serious long-term problem for former osteosarcoma patients. The segmental cement extraction system (SEG-CES) is a technique to remove cement in arthroplasty revision, based on a cement-bone interface with a lower strength compared to the old cement-new cement interface. We report the case of a 32-year-old former osteosarcoma patient in whom the SEG-CES was applied to remove a long-stemmed total knee cemented prosthesis. The prosthesis was placed 17 years before for a recurrent telangiectatic osteosarcoma of the left femur. Thirteen years after the prosthesis implantation, the patient complained of knee instability, pain, and complete failure of the extensor apparatus. The extraction of the prosthesis was performed using cylindrical batters of diameter corresponding to the diameter of the axle, two hammer extractors clamping the prosthesis components between two jaws. Extraction of the periprosthetic cement in the femoral and tibial components was done using the SEG-CES technique. The successful prosthesis removal performed in this patient allowed us to perform an external fixation with bone lengthening and reconstruction by the Ilizarov method.

Adult↗