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PubMed1998

Heat shock protein 72 expression in osteosarcomas correlates with good response to neoadjuvant chemotherapy.

Although the therapeutic outcome of osteosarcoma patients has improved dramatically within the last 20 years because of combined neoadjuvant chemotherapy and surgery, the problem of drug resistance remains. Thus far, markers that can predict the response to chemotherapy at the time of biopsy are not available. Heat shock proteins (hsp) 60, 72, and 73 have been shown to play a role in tumor immunity, and our study investigated their expression in human osteosarcomas and nonmalignant bone tumors before neoadjuvant chemotherapy. Immunohistochemical evaluations of hsp expression was performed on paraffin-embedded sections of 45 patients (17 female, 28 male, aged 6.5 to 62 years; mean, 19.4 years) with high-grade osteosarcoma at the time of biopsy, before preoperative chemotherapy. These results were correlated to histological response to chemotherapy, tumor size, age, alkaline phosphatase serum levels, and duration of symptoms. Thirty-four patients (15 male, 19 female, mean age 27 years) with osteoblastoma, osteoid-osteoma, or fibrous dysplasia served as nonmalignant controls. Hsp60 was uniformly found in the cytoplasm of both benign and malignant bone tumors. Nuclear hsp73 expression quantitatively increased in osteosarcoma cells. Hsp72 was significantly overexpressed in osteosarcomas (17 of 45, 38%) compared with nonmalignant bone tumors (1 of 34, 2.9%; P < .001). Hsp72-positive osteosarcomas responded better to neoadjuvant chemotherapy than hsp72-negative cases (P < .001), co-express hsp60, and correlate with higher tumor size (P < .005) and location in the distal femur. No differences were observed relative to age, gender, duration of symptoms, alkaline phosphatase levels, or hsp73 expression between hsp72-positive and hsp72-negative tumors. Hsp72 expression seemed to be a predictive immunohistochemical marker for osteosarcoma, because it is the first marker to prospectively correlate to response to neoadjuvant chemotherapy. It therefore, may be of importance in preoperative therapy regimens for nonresponding high-risk patients.

Adolescent↗
PubMed2001

Two unusual osteogenic orbital tumors: presumed parosteal osteosarcomas of the orbit.

OBJECTIVE: To report two cases of suspected parosteal osteosarcoma of the orbit, with dedifferentiation into a high-grade liposarcoma occurring in one patient. DESIGN: Two retrospective case reports. METHODS: The clinical, radiologic, and pathologic records of two patients with suspected orbital parosteal osteosarcoma were retrospectively reviewed. MAIN OUTCOME MEASURES: Histologic evaluation and clinical follow-up were measured. RESULTS: The first patient was a 47-year-old male presenting with a 5-month history of painless right lower lid swelling; excision biopsy suggested a well-differentiated parosteal osteosarcoma of the orbital floor, which recurred 3 years later. Six months after excision of the recurrence, the mass demonstrated accelerated growth, and a lid-sparing exenteration was performed; histologic examination showed a high-grade liposarcoma. The patient remains disease-free at 4 years. The second patient, a 40-year-old male, presented with an 8-year history of proptosis and a right superotemporal orbital mass. The mass was excised completely at lateral orbitotomy; histologic examination suggested a well-differentiated parosteal osteosarcoma. The patient remains well 9 months postoperatively. CONCLUSIONS: Parosteal osteosarcoma is an uncommon tumor, usually affecting long bones, that is extremely rare in the orbit. It is a low-grade sarcoma that tends to recur locally after excision but has a favorable prognosis. Dedifferentiation into a high-grade sarcoma occasionally occurs in parosteal osteosarcoma, but transformation into liposarcoma does not seem to have been previously reported. It is important to recognize dedifferentiated parosteal osteosarcoma, because the prognosis is poor, and radical treatment may be required.

Adult↗
PubMed2003

Activation of the JNK-AP-1 signal transduction pathway is associated with pathogenesis and progression of human osteosarcomas.

Osteosarcomas represent the most common primary malignant bone tumors; however, comprehension of the molecular mechanisms underlying their pathogenesis is far from thorough. Studies in cultured cells have demonstrated that the c-Jun N-terminal kinase (JNK) signal transduction pathway participates in the proliferation, differentiation, and apoptosis of osteoblasts. Phosphorylated JNKs activate the oncoprotein c-Jun, which is known to form the activator protein-1 (AP-1) transcription factor as a homo- or heterodimer. c-Jun's principal dimerization partner is c-Fos, which participates in the differentiation and function of osteoblasts and in the pathogenesis of osteosarcomas. A similar role for the JNK cascade in the malignant transformation of human osteoblasts and in the generation of osteosarcomas has not been documented. Our study addressed the possibility that a functional upregulation of the JNK pathway is implicated in the pathogenesis of osteosarcomas. To this end, we employed immunohistochemistry to examine normal bone and osteosarcoma cells in paraffin-embedded sections from 56 patients with high-grade tumors and 15 patients with low-grade tumors. We assessed the protein levels of the two major JNK isoforms (JNK1 and JNK2); their phosphorylated-hence activated-species, p-JNK; their substrate, c- Jun; its phosphorylated (activated) form, pc-Jun; and c-Jun's heterodimeric partner, c-Fos. We also examined the immunohistochemical profile of the alpha chain of the nascent polypeptide-associated complex (alpha-NAC), an osteoblast-specific AP-1 coactivator that potentiates the transcriptional activity of the c-Jun/c-Jun homodimer. Positive immunostaining for JNK1, JNK2, p-JNK, c-Jun, pc-Jun, c-Fos, and alpha-NAC was observed in 86, 93, 94, 99, 97, 99, and 97.5% of the samples, respectively, whereas normal bone was devoid of these immunoreactivities. The cellular levels of all proteins were significantly correlated to each other (P < 0.001 for each correlation). Moreover, significantly higher expression levels of all proteins were detected in high-grade tumors compared to levels in low-grade ones. The observed expression profile of alpha-NAC implies that the active AP-1 in human osteosarcomas most likely comprises c-Jun/c-Jun homodimers. When cellular levels of the JNK pathway components and c-Fos were evaluated as possible biological markers of tumor grade, high expression of c-Jun and abundant pc-Jun predicted a high-grade tumor. Our findings provide novel evidence that the JNK signaling pathway is functionally operative in the malignant transformation of osteoblasts and the subsequent development and progression of human osteosarcomas. Evaluation of c-Jun expression and JNK-dependent activation may facilitate an improved prediction of the tumor's clinical behavior and potentially be exploited in designing patient-tailored treatment regimens.

Adolescent↗
PubMed1992

Inactivation of p53 gene in human and murine osteosarcoma cells.

We examined structure and expression of the p53 and Rb genes in a C3HOS transplantable mouse model of osteosarcoma. The results were compared to analogous studies conducted with five human osteosarcoma cell lines. The p53 gene was found rearranged in the mouse tumour. The rearrangement mapped to the first intron region of the p53 gene and as a result, no p53 expression could be detected in C3HOS tumours. Using p53 genomic probes, we have detected the same rearrangement in the original radiation-induced tumour and the various clones that were isolated from it. Deletion and rearrangement of the p53 gene were also found in three out of five of the human osteosarcoma cell lines (MG-63, G-292, Saos-2). No p53 expression could be detected in these three cell lines. In the affected human osteosarcoma cell lines, the rearrangement involved the first intron region. In addition, the mouse tumor was analysed for structural and expression changes in the Rb and the c-myc genes. Normal expression of both genes were detected in the murine tumour. Only one (Saos-2) human osteosarcoma cell line exhibited gross structural alteration in the retinoblastoma gene. The results suggest that the inactivation of p53 may be an important step in the development of osteosarcomas, and that a rearrangement affecting the first intron is common in osteosarcomas.

Animals↗
PubMed2003

ErbB2 and bone sialoprotein as markers for metastatic osteosarcoma cells.

Osteosarcoma is the most common malignant bone neoplasia occurring in young patients in the first two decades of life, and represents 20% of all primitive malignant bone tumours. At present, treatment of metastatic osteosarcoma is unsatisfactory. High-dose chemotherapy followed by CD34+ leukapheresis rescue may improve these poor results. Neoplastic cells contaminating the apheresis may, however, contribute to relapse. To identify markers suitable for detecting osteosarcoma cells in aphereses we analysed the expression of bone-specific genes (Bone Sialoprotein (BSP) and Osteocalcin) and oncogenes (Met and ErbB2) in 22 patients with metastatic osteosarcoma and six healthy stem cell donors. The expression of these genes in aphereses of patients affected by metastatic osteosarcoma was assessed by RT-PCR and Southern blot analysis. Met and Osteocalcin proved to be not useful markers since they are positive in aphereses of both patients with metastatic osteosarcoma and healthy stem cell donors. On the contrary, BSP was expressed at significant levels in 85% of patients. Moreover, 18% of patients showed a strong and significantly positive (seven to 16 times higher than healthy stem cell donors) ErbB2 expression. In all positive cases, neoplastic tissue also expressed ErbB2. Our data show that ErbB2 can be a useful marker for tumour contamination in aphereses of patients affected by ErbB2-expressing osteosarcomas and that analysis of Bone Sialoprotein expression can be an alternative useful marker.

Adolescent↗
PubMed1998

Integration of SV40 in human osteosarcoma DNA.

Simian virus 40 (SV40) has been demonstrated in several types of tumors, including osteosarcoma, by polymerase chain reaction (PCR). We detected SV40 sequences by PCR, followed by hybridization, in nine of 35 osteosarcoma tumors and one of 11 osteosarcoma explants. PCR can detect fewer than one virus per cell but gives little detail of the gross structure and abundance of the virus. Analysis by Southern blotting of total DNA from ten osteosarcomas, positive for SV40 by PCR, found viral integration in half of these. Analysis showed integration of one to four copies per cell of rearranged SV40. No SV40 was detectable on blots of the remaining five SV40+ osteosarcomas, perhaps because of the lesser sensitivity of direct hybridization. Inactivation of the p53 and Rb tumor suppressors is a key activity of SV40 T-antigen. Unexpectedly, correlation of these findings with our prior studies indicated that five of ten osteosarcomas positive for SV40 DNA had mutations of p53, and two had deleted Rb. Apparently clonal integration with pre-existing alteration of a tumor suppressor gene, suggests that SV40 may play a role in the final conversion to malignant osteosarcoma.

Adolescent↗
PubMed2003

Case of postradiation osteosarcoma with a short latency period of 3 years.

Osteosarcoma is one of the neoplasms that may occur following exposure to radiation. A case of osteosarcoma arising in the craniofacial bone with a short latency period of 3 years after radiotherapy for maxillary squamous cell carcinoma is described. A 64-year-old-man underwent right partial maxillectomy and chemoradiotherapy due to squamous cell carcinoma of his right maxillary sinus. Histologically, the tumor was composed of moderately differentiated squamous cell carcinoma with a component of spindle cell carcinoma. Three years later, osteosarcoma developed in the craniofacial bone within the irradiation field of the first tumor. Detailed histological examination demonstrated that there was no component of osteosarcoma in the first tumor or squamous cell carcinoma in the second tumor. Radiation-induced osteosarcoma usually occurs after a long latency period of more than 10 years after the radiotherapy. In this case, osteosarcoma was possibly a radiation-induced osteosarcoma with a short latency period of 3 years.

Bone Neoplasms↗
PubMed2001

Osteosarcoma of the jaw. The Chaim Sheba Medical Center experience.

OBJECTIVE: The purpose of this article is to present 14 cases of osteosarcoma of the jaw treated at our medical center from 1989 to 1998. These cases are discussed in the light of a comprehensive review of 774 cases reported in the English literature over the past 3 decades. Differences between osteosarcoma of the jaws and osteosarcoma of the long bones are examined. SUBJECTS AND METHODS: The patients ranged in age from 8 to 78 years, the mean age being 33 years. Each patient had a histopathologically established diagnosis of osteosarcoma of the jaw. Records were reviewed for epidemiologic data, treatment modalities, and survival. RESULTS: Of the 14 patients, 6 (42%) had tumors in the mandible and 8 (58%) had tumors in the maxilla. Of the mandibular tumors, 5 occurred in the body of the mandible; all maxillary tumors originated in the alveolar ridge and involved the maxillary sinus. The chief complaint was an intraoral or extraoral painless swelling. Histopathologic types included chondroblastic, osteoblastic, fibroblastic, and malignant fibrous histiocytoma-like. Pathologic grade was determined to be high (3 or 4) in 13 cases and low (1) in only 1 mandibular case. All patients underwent surgical resection and immediate reconstruction. Adjuvant therapy included postoperative radiation (5 patients), postoperative chemotherapy (2 patients), and preoperative chemotherapy and postoperative radiation (1 patient). CONCLUSIONS: The results of the present study support the literature indicating that osteosarcoma of the jaw differs from osteosarcoma of the long bones in its biological behavior even though they have the same histologic appearance. Because of differences in tumor characteristics, the introduction of chemotherapy did not dramatically alter the prognosis of osteosarcoma of the jaw. Early diagnosis and radical surgery are the keys to high survival rates.

Adolescent↗
PubMed2001

Osteosarcoma following retinoblastoma: age at onset and latency period.

In order to assess the role of genetic predisposition in the induction of radiation-induced tumors, we performed statistical analysis on data from the literature and from our own Institute with regard to the age at onset and the latency period of osteosarcoma as the second primary tumor for retinoblastoma with or without subsequent radiotherapy. In retinoblastoma survivors who subsequently developed osteosarcoma, the age at onset of retinoblastoma was young (average of 12 months) in both unilateral and bilateral forms. This suggests that all or almost all of the patients were genetically predisposed by a mutation of one allele of the RB1 gene. For retinoblastoma patients, osteosarcomas occurred 1.2 years earlier inside than outside the radiation field. The latency period between radiotherapy and osteosarcoma onset was 1.3 years shorter inside than outside the radiation field. Interestingly, a bimodal distribution of latency periods was observed for osteosarcomas arising inside, but not outside the radiation field: 40% occurred after a short latency, while the latency of the remaining 60% was comparable to that of osteosarcoma occurring outside the radiation field. This suggests that different mechanisms may be involved in radiocarcinogenesis. A radiation-induced mutation of the second RB1 allele may be the cause of osteosarcomas occurring after a short delay, while other genes may be affected in those occurring after a longer delay.

Adolescent↗
PubMedDate not supplied

Intracranial manifestation of osteosarcoma.

Involvement of the central nervous system in osteosarcoma is uncommon. These neoplasms are most often located at the metaphyses of tubular bones and rarely in flat bones of vertebra, ribs, pelvis, facial bones, or skull. Tumors of the latter bones may obviously spread into the cerebrum. Osteosarcomas primarily metastasize hematogenously to the lungs. Bone, lymph node, or brain metastases are mostly seen following or concomitantly with pulmonary metastatic disease. However, there are single cases of primary osteosarcoma of the brain parenchyma without bone association or tumor manifestation at other locations. Three illustrative cases highlight the diversity of the clinical presentation of cerebral osteosarcoma: a 22-year-old man with multiple brain metastases following late pulmonary relapse of an osteosarcoma of the tibia, a 31-year-old woman with an osteosarcoma of the left anterior cranial fossa arising from the skull base, and a 78-year-old man presenting with primary osteogenic sarcoma of the left frontal cerebral hemisphere. According to the current literature, 10-15% of all osteosarcoma patients experiencing relapse may beat risk for central nervous system metastases. To the authors' best knowledge, there are 11 cases of primary intracerebral or meningeal osteogenic sarcoma, including this case report, without any skeletal attachment.

Adult↗
PubMed2003

Association between osteosarcoma and deleterious mutations in the RECQL4 gene in Rothmund-Thomson syndrome.

BACKGROUND: Rothmund-Thomson syndrome (RTS) is an autosomal recessive disorder associated with an increased predisposition to osteosarcoma. Children with RTS typically present with a characteristic skin rash (poikiloderma), small stature, and skeletal dysplasias. Mutations in the RECQL4 gene, which encodes a RecQ DNA helicase, have been reported in a few RTS patients. We examined whether a predisposition to developing osteosarcoma among an international cohort of RTS patients was associated with a distinctive pattern of mutations in the RECQL4 gene. METHODS: We obtained clinical information about and biologic samples from 33 RTS patients (age range = 1-30 years). Eleven patients were diagnosed with osteosarcoma. All 21 exons and 13 short introns of the RECQL4 gene were sequenced from the genomic DNA of all subjects. Kaplan-Meier survival analysis was used to estimate the incidence of osteosarcoma among patients with and without mutations predicted to produce a truncated RECQL4 protein. RESULTS: Twenty-three RTS patients, including all 11 osteosarcoma patients, carried at least one of 19 truncating mutations in their RECQL4 genes. The incidence of osteosarcoma was 0.00 per year in truncating mutation-negative patients (100 person-years of observation) and 0.05 per year in truncating mutation-positive patients (230 person-years of observation) (P =.037; two-sided log-rank test). CONCLUSIONS: Mutations predicted to result in the loss of RECQL4 protein function occurred in approximately two-thirds of RTS patients and are associated with risk of osteosarcoma. Molecular diagnosis has the potential to identify those children with RTS who are at high risk of this cancer.

Adenosine Triphosphatases↗
PubMed2000

Osteosarcomas and other cancers of bone.

The results of several studies suggest that alterations in various cell cycle regulatory genes are involved in the pathogenesis of osteosarcomas. Experiments in animal models provide preliminary data on the feasibility of gene therapy in osteosarcoma and chondrosarcoma. Prediction of response to chemotherapy remains a major focus of imaging research. Several clinicopathologic studies have explored the mechanisms underlying multidrug resistance in osteosarcoma patients receiving neoadjuvant chemotherapy. HER2/erbB2 expression, linked to poor prognosis, has been proposed as a therapeutic target in osteosarcoma. In clinical studies of osteosarcoma, further data confirm the activity of ifosfamide and carboplatin but provide little support for the use of immunotherapy. A retrospective analysis showed no value for dose intensification of doxorubicin/cisplatin, but the results of a prospective trial should be more informative. Recent evidence confirms that secondary osteosarcomas and malignant fibrous histiocytomas of bone should be treated with aggressive chemotherapy regimens, similar to those used for osteosarcomas.

Bone Neoplasms↗
PubMed2000

P-glycoprotein levels predict poor outcome in patients with osteosarcoma.

To evaluate the relationship between the expression of P-glycoprotein by osteosarcomas and the rate of metastasis and death, a retrospective review of 172 patients who were diagnosed with osteosarcoma between 1987 and 1992 was performed. Forty patients had P-glycoprotein levels available. The majority of the osteosarcomas were Stage II-B (33 patients), with the remaining seven being Stage III. Tumor sites included 25 femurs, seven humeri, five tibias, and one each of pelvis, radius, and fibula. The patients with Stage III disease at presentation were treated differently from the time of diagnosis and therefore, these seven patients with Stage III osteosarcoma were excluded from additional analyses. The expression of P-glycoprotein by cultured tumor cells from biopsy specimens was determined using immunofluorescent microscopy. In the 33 patients with Stage IIB osteosarcoma with detectable P-glycoprotein, 67% (10 of 15) had metastases develop as compared with 28% (five of 18) of patients with undetectable P-glycoprotein. Similarly, 53% (eight of 15) of patients with tumors expressing P-glycoprotein died of disease compared with 11% (two of 18) with no detectable P-glycoprotein. Expression of P-glycoprotein by tumor cells seems to be associated with an estimated ninefold increase in the odds of death and a fivefold increase in the odds of metastases in patients with Stage IIB osteosarcoma. Kaplan-Meier survivorship analysis revealed that patients with detectable P-glycoprotein fared worse in terms of survival time and metastasis-free survival. Adjusting for covariates in the Cox proportional hazards model, expression of P-glycoprotein and its level were significantly predictive of time to death in patients with Stage IIB osteosarcoma.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1990

Induction of lymphoma and osteosarcoma in mice by single and protracted low alpha doses.

Internal doses from the short-lived alpha-emitter 22Ra were given to 4-wk-old female NMRI mice. One group of about 300 animals received a single injection of 18.5 kBq 22Ra kg-1 body weight, corresponding to a mean skeletal alpha dose of 0.15 Gy. A second group of about 300 animals received the same total amount of 224Ra in the form of 72 fractions of 257 Bq kg-1 each, applied twice weekly during 36 wk. The fractionated group received the same final mean total skeletal dose of 0.15 Gy as the single injected group, but with a mean skeletal dose rate of 1 mGy d-1. A rather high incidence, 13.5% (40/296), of early malignant lymphomas was observed in the fractionated group during and shortly after the injection period, followed by a 7% incidence (21/296) of osteosarcomas during the second half of the animals' lifetime. The group with a single injection did not develop early lymphomas but did develop osteosarcomas later with an incidence of 5.8% (17/295). The occurrence of osteosarcomas was similar up to day 800 in the two experimental groups. Surprisingly, however, after this period no additional case of osteosarcoma was observed in the single-injected group, whereas one-third of all osteosarcomas occurred after day 800 in the protracted group. The additional later occurrence of osteosarcomas occurred after indicates a longer lasting induction effect on osteosarcomas, or a promoting effect in older age, for this kind of treatment.

Alpha Particles↗
PubMed2001

Sacral radiculopathy secondary to multicentric osteosarcoma.

STUDY DESIGN: A case of multicentric osteosarcoma presenting with sacral radiculopathy is reported. OBJECTIVE: To present unusual clinical and radiologic findings of multicentric osteosarcoma. SUMMARY OF BACKGROUND DATA: Multicentric osteosarcoma is a rare variant of osteosarcoma. To the authors' knowledge, no cases of multicentric osteosarcoma presenting as sacral radiculopathy have been reported previously. METHODS: A 14-year-old boy had a large sacral tumor extending into the spinal canal, which was found to account for the initial symptoms, which mimicked those of herniated nucleus pulposus. At diagnosis, a bone survey showed multiple foci of osteosarcoma in the long bones. RESULTS: The patient was treated with chemotherapy, but died of the disease 8 months after the initial presentation. CONCLUSION: Multicentric osteosarcoma should be considered in the differential diagnosis for a pediatric patient with low back pain and sciatica.

Adolescent↗
PubMed2007

Osteosarcoma and osteoblastic differentiation: a new perspective on oncogenesis.

In addition to changes in cellular pathways, loss of differentiation is a notable feature of osteosarcoma. We hypothesized that blocks to normal differentiation may be a common feature of osteosarcoma, and may be one of many critical events that occur during oncogenesis in osteosarcoma. Furthermore, therapies that restore normal programs of differentiation may be attractive new treatment strategies for chemo-therapy and/or chemoprevention. We exposed an osteosarcoma cell line to two highly osteogenic bone morphogenetic proteins and noted increased tumor volume and no evidence of osteoinduction in vivo. We then used expression profile analysis to identify downstream targets of the osteogenic bone morphogenetic proteins, revealing up-regulation of the inhibitor of differentiation genes 1, 2, and 3, and the nuclear receptor, peroxisome proliferator activated receptor gamma. We then evaluated the use of nuclear receptor agonists, including peroxisome proliferator activated receptor gamma, to circumvent the apparent block to bone morphogenetic protein-induced differentiation in osteosarcoma cell lines. The peroxisome proliferator activated receptor gamma/retinoid X receptor agonists induced terminal differentiation in all four osteosarcoma cell lines and were synergistic when combined. In osteosarcoma cells, there are inherent blocks to normal bone morphogenetic protein-induced differentiation; however, they do not prevent nuclear receptor agonists from inducing terminal differentiation.

Animals↗
PubMed2001

Loss of ErbB2 expression in pulmonary metastatic lesions in osteosarcoma.

OBJECTIVES: The c-erbB2 protooncogene is located on human chromosome 17 and encodes a 185-kilodalton transmembrane glycoprotein (ErbB2). Elevated ErbB2 expression or gene amplification has been shown to be associated with a poor prognosis in many cancers. Recently, it has been demonstrated that overexpression of the ErbB2 protein in osteosarcoma is associated with the presence of pulmonary metastasis and decreased survival. To further investigate the role of ErbB2 overexpression in pulmonary metastasis of osteosarcoma, its expression in the primary and metastatic lesions of the same osteosarcoma patients was compared. METHODS: We compared the expression levels of ErbB2 receptor protein between the biopsy samples and pulmonary metastatic lesions in each of 19 patients with osteosarcoma who had not presented with metastasis at diagnosis. All archival materials from patients were retrieved and stained with monoclonal antibody CB11 to detect ErbB2 protein. RESULTS: The rate of overexpression was significantly lower in the pulmonary metastatic tumors than in the biopsy samples (11 versus 42%; p = 0.03). Among 8 patients who had shown increased levels of ErbB2 in the biopsy samples, 7 exhibited complete absence of ErbB2 in the pulmonary metastatic lesions. Overall loss of ErbB2 expression was noted in 14 of 19 patients as the initial tumor became metastatic. CONCLUSIONS: It is suggested that overexpression of ErbB2 decreases within individual osteosarcomas as they become metastatic. Overexpression of ErbB2 may not play an important role in the development of pulmonary metastases of osteosarcoma. Further data are needed before ErbB2 can be used in making clinical decisions for osteosarcoma patients.

Adolescent↗
PubMed2004

Downregulation of osteoblast markers and induction of the glial fibrillary acidic protein by oncostatin M in osteosarcoma cells require PKCdelta and STAT3.

UNLABELLED: The effects of OSM on proliferation and differentiation of osteosarcoma and nontransformed osteoblasts were analyzed. OSM downregulates osteoblast markers but induces the glial fibrillary acidic protein by the combined activation of PKCdelta and STAT3, offering new lines of therapeutic investigations. INTRODUCTION: Oncostatin M (OSM) is a multifunctional cytokine of the interleukin-6 family implicated in embryonic development, differentiation, inflammation, and regeneration of various tissues, mainly the liver, bone, and the central nervous and hematopoietic systems. One particularity of OSM relies on its growth inhibitory and pro-differentiating effects on a variety of tumor cell lines such as melanoma, providing arguments for a therapeutic application of OSM. The objective of this study was to analyze the effects of OSM on osteosarcoma cell lines proliferation and differentiation. MATERIALS AND METHODS: Proliferation was analyzed by 3H thymidine incorporation. Differentiation was analyzed by semiquantitative RT-PCR and immunocytochemistry for various markers. Alizarin red S staining was used to evaluate bone nodule formation. Morphological changes were studied by confocal and electron microscopy. Western blotting, kinases inhibitors, and dominant negative STAT3 were used to identified the signaling pathways implicated. RESULTS: OSM inhibits the growth of rat osteosarcoma cell lines as well as normal osteoblasts, in correlation with induction of the cyclin-dependent kinases inhibitor p21WAF1. However, OSM reduces osteoblast markers such as alkaline phosphatase, osteocalcin, and bone sialoprotein, leading to strong inhibition of mineralized nodule formation. This inhibitory effect is restricted to mature osteoblasts and differentiated osteosarcoma because OSM effectively stimulates osteoblast markers and bone nodule formation in early, but not late, bone marrow mesenchymal stem cell (BMSC) cultures. In osteosarcoma cells or BMSC, OSM induces expression of the glial fibrillary acidic protein (GFAP) as well as morphological and ultrastructural changes, for example, elongated shape and bundles of microfilaments in cell processes. Rottlerin (PKCdelta inhibitor), and to a lesser degree UO126 (MEK/ERK inhibitor), prevents the loss of osteoblastic markers by OSM, whereas dominant negative STAT3 prevents GFAP induction. CONCLUSIONS: These results highlight the particular gene expression profile of OSM-treated osteosarcoma cells and BMSCs, suggesting either a osteocytic or a glial-like phenotype. Together with the implication of PKCdelta, ERK1/2, and STAT3, these results offer new lines of investigations for neural cell transplantation and osteosarcoma therapy.

Alkaline Phosphatase↗