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PubMed2006

Expression of transcription factor Yin Yang 1 in human osteosarcomas.

The transcription factor Yin Yang 1 (YY1) is known to be present in some human cancer cell lines and its expression correlates with immune-mediated apoptosis. By using Western blot analysis, we have shown that the YY1 protein is strongly expressed in human osteosarcoma cells and localised mainly in the nucleus. Moreover, by using immunohistochemistry and RT-PCR techniques, we have analysed the expression of YY1 protein in biopsies from human osteosarcomas. The YY1 protein was not detectable by immunohistochemistry in osteoid tissue. However, its expression was restricted to osteosarcoma tissues. These data were confirmed by densitometric analysis of RT-PCR for YY1 expression. Thus, YY1 gene activation appears to be an early event in the process of osteoblastic transformation and its detection may represent, together with the analysis of other established markers, a useful diagnostic tool in human osteosarcomas.

Adolescent↗
PubMed2006

Potent antiproliferative effects of resveratrol on human osteosarcoma SJSA1 cells: Novel cellular mechanisms involving the ERKs/p53 cascade.

The chemopreventive activity of resveratrol (RSVL) has been demonstrated in several types of cancer. However, its effects and the underling mechanisms remain poorly understood. In this study, we investigated the involvement of the mitogen activated protein kinase (MAPK)/p53 signal transduction mechanism in RSVL-induced growth inhibition using a human osteosarcoma cell line. We demonstrate that RSVL reduces cell viability and growth of SJSA1 osteosarcoma cells. Morphological profiles and 4,6-diamidino-2-phenylindole nuclear staining of RSVL-treated cells indicated marked nuclear fragmentation. Cleavage of the (116-kDa) poly(ADP-ribose) polymerase protein into an 89-kDa fragment (a proapoptotic marker system) was substantially augmented by RSVL treatment. RSVL-dependent growth impairment was preceded by enhanced phosphorylation of extracellular signal-regulated kinase (ERK)1/2 (at Thr202/Tyr204). Likewise, RSVL increased the phosphorylation of p53 tumor suppressor protein (at Ser15). The effects of RSVL on ERKs and on p53 phosphorylation were abrogated by either the MAPK inhibitor PD98059 or the p53 inhibitor pifithrine-alpha. The present study indicates that RSVL antiproliferative effects on osteosarcoma cells are mediated by the activation of the ERKs/p53 signaling pathway and therefore identifies new targets for strategies to treat and/or prevent osteosarcoma.

Blotting, Western↗
PubMed2006

Soft-tissue metastasis of osteosarcoma to the submental vestibule.

A case of metastatic osteosarcoma in the submental vestibule of the oral cavity and the lung is described in an 18-year-old male with primary osteosarcoma occurring in the sacrum. Dissemination of osteosarcoma to other organs, especially early to the lung, is common, but its metastasis to the oral mucosa has been rarely reported. The patient presented 6 years after initial diagnosis, suggesting the need for careful long-term follow-up of patients with osteosarcoma. This case also illustrates that immunohistochemical staining of osteocalcin is useful to confirm the histological diagnosis of oral soft-tissue metastasis.

Adolescent↗
PubMed2004

Surgical management and outcome of osteosarcoma patients with unilateral pulmonary metastases.

PURPOSE: The surgical management of osteosarcoma patients with unilateral pulmonary nodules is controversial. The authors reviewed their institutional experience to evaluate the incidence of occult contralateral metastases. METHODS: Data were obtained retrospectively on all consecutive osteosarcoma patients from 1980 to 2002. Eighty-four patients with pulmonary nodules were identified. Forty-one had bilateral disease, and 43 had unilateral involvement by computed tomography (CT) scan. RESULTS: All 43 patients with unilateral nodules underwent ipsilateral thoracotomies. Fifteen patients had negative exploration findings, and only 1 had pulmonary relapse. Of the 28 patients with metastases confirmed at initial thoracotomies, 14 had extensive pleural or extrapulmonary disease at initial thoracotomy followed by disease progression. The other 14 are separated into early versus late metastases, using 2 years from diagnosis as the cutoff point. Seven of the 9 (78%) patients with early metastases had or subsequently had contralateral disease; 6 were identified at staged contralateral thoracotomy and 1 had relapsed in the unexplored lung a year later. Only 1 of the 5 patients with late unilateral metastases had relapse in the contralateral side. CONCLUSIONS: Our data indicate that there is a high rate of contralateral involvement in osteosarcoma patients with unilateral nodules diagnosed by CT scan. Staged bilateral thoracotomies should be considered in osteosarcoma patients presenting with unilateral pulmonary disease on imaging studies within 2 years of diagnosis.

Adolescent↗
PubMed2006

Long-term survival after aggressive resection of pulmonary metastases among children and adolescents with osteosarcoma.

PURPOSE: Although survival without resection of pulmonary metastases from osteosarcoma is unlikely, not all surgeons agree on an aggressive surgical approach. We have taken an approach to attempt surgical resection if at all feasible regardless of number of metastases and disease-free interval (DFI). This study presents information on long-term follow-up after this aggressive approach to resection. METHODS: A single-institution retrospective cohort study of osteosarcoma patients younger than 21 years with pulmonary metastases, limited to the contemporary chemotherapeutic period (1980-2000), was conducted. RESULTS: In 137 patients, synchronous (23.4%) or metachronous (76.6%) pulmonary nodules were identified. The median follow-up was 2.0 years (5 days to 20.1 years) for all patients. Overall survival among patients who had pulmonary nodules was 40.2% and 22.6% at 3 and 5 years, respectively. Ninety-nine patients underwent attempted pulmonary metastasectomy (mean survival, 33.6 months; 95% confidence interval, 25.1-42.1) and 38 patients did not (mean survival, 10.1 months; 95% confidence interval, 6.5-13.6; P < .001, t test). Characteristics that were associated with an increased likelihood of 5-year overall survival after pulmonary resection were primary tumor necrosis greater than 98% after neoadjuvant chemotherapy (P < .05) and DFI before developing lung metastases more than 1 year (P < .001). No statistically significant difference in overall survival or disease-free survival was found based on the number of pulmonary metastases resected. Characteristics including primary tumor size, site, or extension; chemotherapy; early vs late metastases; unilateral vs bilateral metastases; and resection margins did not significantly affect survival. CONCLUSIONS: Most patient and tumor characteristics commonly used by surgeons to determine utility of resection of pulmonary metastases among patients with osteosarcoma are not associated with outcome. Biology of the particular tumor (response to preoperative chemotherapy, measured by tumor necrosis percentage, and DFI), as opposed to tumor burden, appears to influence survival more significantly. We would advocate considering repeat pulmonary resection for patients with recurrent metastases from osteosarcoma.

Adolescent↗
PubMed2004

Characterization of the human mandibular osteoblastic osteosarcoma cell line HOSM-2 after long-term culture.

We have been subculturing a human mandible-derived osteosarcoma cell line (HOSM-2) for approximately 15 years, and have compared the characters of early generations, which did not exhibit tumorigenicity, to those in the later generations. The shape and doubling time of the cells did not change during long-term culture. The number of chromosomes, however, changed from 59-81 in the 6th generation (modal number: 70) to 54-59 (modal number: 56 and 57), and the chromosomal structure also changed. In addition, the cell line in the later generations showed tumorigenicity in nude mice, and Codon 306 of the p53 gene was mutated to a stop codon due to a point mutation. HOSM-2 cells expressed osteoblast markers, thus confirming them to be osteoblastic osteosarcoma cells. These results showed that changes in certain genes in the HOSM-2 cells led to tumorigenicity in nude mice following long-term culture. In addition, as a mandible-derived cell line with characteristics different from those of limb-derived osteosarcoma cell lines, HOSM-2 cells may be a valuable model for mandibular osteosarcoma and osteoblasts.

Animals↗
PubMed2005

Free osseous and soft tissue surgical margins as prognostic factors in mandibular osteosarcoma.

Osteosarcoma is an infrequent, locally aggressive neoplasm in the head and neck region. To date, surgery is the mainstay of treatment. However, patients with mandibular osteosarcomas usually have a locally advanced disease at diagnosis and therefore represent a therapeutic challenge because surgical margins are difficult to obtain due to aesthetic and functional concerns. To evaluate possible prognostic factors implicated in recurrence, persistence or relapse in osteosarcoma of the mandible, with special reference to the soft tissue and bone surgical margins. A series of 20 patients with mandibular osteosarcomas treated at the Instituto Nacional de Cancerología (México) from 1985 to 1999 are reviewed. There were 14 female and 6 male patients. Twelve cases were treated with surgery alone, 3 patients with surgery and adjuvant radiotherapy, 1 had neoadjuvant chemotherapy followed by surgery, 1 had neoadjuvant chemotherapy, surgery and postoperative radiotherapy, 1 with surgery and adjuvant chemotherapy, 1 with surgery followed by adjuvant chemotherapy and radiotherapy and one patient rejected treatment. Between 1985 and 1992 these neoplasms were treated by means of total mandibulectomy, independently of tumor size, but between 1993 and 1999 the policy was to practice smaller resections but long enough to obtain macroscopic surgical free margins. In the first period the relationship between mandibular size resection and tumor size was 1.9, meanwhile in the second period the relation was 1.5. There was not significant difference between both periods in terms of tumor size (6.0 cm vs. 6.02 cm at the time of surgery) nor in local control and survival. Soft tissue involvement as reported by histological study was strongly associated with recurrence (p = 0.0024). Overall 5-year survival was 20%. A policy of total mandibulectomy is not associated with a better local control or survival. Extent of resection must be tailored with tumor size. Extent of margins in soft tissue is the limiting factor for local control.

Adolescent↗
PubMed2005

Low-grade central osteosarcoma of the skull.

A case of low-grade central osteosarcoma of the skull in a 36-year-old male is described. A 10cm mass of the left temporo-occipital bone, which was incidentally found 6 years previously on the occasion of a head trauma, was osteolytic and osteoplastic, affecting soft tissues and the subdural space. The patient was treated with intralesional curettage. Histologically, the tumor was characterized by spindle cell proliferation with woven and lamellar bone formation, resembling fibrous dysplasia, parosteal osteosarcoma, low-grade fibrosarcoma, or desmoplastic fibroma. The spindle cells were fairly uniform with mild atypia and low-mitotic activity (3 per 50 high power fields), and cellularity varied from low to high. Clinicians and pathologists should be aware of this type of low-grade osteosarcoma of the skull and distinguish it from its mimics, including fibrous dysplasia, parosteal osteosarcoma, and low-grade fibrosarcoma. Careful microscopic correlation with radiographic findings is the clue to the correct diagnosis.

Adult↗
PubMed2004

Characterisation of three novel canine osteosarcoma cell lines producing high levels of matrix metalloproteinases.

Three canine osteosarcoma cell lines were established from spontaneous pelvic and radial osteosarcomas. The cell populations cultured exhibited characteristics of malignancy and consisted of adherent, pleomorphic, mostly large spindle-shaped or polyhedral cells, characterised by the presence of numerous cytoplasmic granules and vacuoles. The main ultrastructural features included the presence of abundant rough endoplasmic reticulum and numerous cytoplasmic vesicles, deposit vacuoles and small cytoplasmic protrusions. Zymography showed that the cell lines produce high levels of MMP-2 and MMP-9, enzymes directly involved in crucial aspects of the metastatic process. Consistent with their osteoblastic lineage and malignant phenotype, all cell lines were immunoreactive to vimentin, osteopontin, PCNA, p53, MMP-2 and MMP-9, while they were negative for cytokeratin, desmin, SMA, Factor VIII, NSE, GFAP, Rb and p21 protein. No retroviral particles or RNA were detected ultrastructurally or with RT-PCR, although the possibility of viral involvement in osteosarcoma cannot be excluded. The new cell lines provide excellent in vitro models that may allow further studies on the pathobiology of canine osteosarcoma to be undertaken.

Alkaline Phosphatase↗
PubMed2004

Differential susceptibility of osteosarcoma cells and primary osteoblasts to cell detachment caused by snake venom metalloproteinase protein.

The interaction of extracellular matrix with cells plays a key role in the regulation of cell adhesion, migration, proliferation as well as differentiation. Transformed cells express a different profile of adhesion molecules, which may mediate metastasis under specific matrix microenvironment. We here found that ROS 17/2.8 osteosarcoma cells and osteoblasts have different expression of alpha5 integrin, executing different fibronectin fibrillogenesis. As compared with ROS 17/2.8 cells, osteoblasts have higher expression of fibronectin, collagen, alpha5, beta1, alpha2 integrins and focal adhesion kinase as examined by immunostaining and flow cytometry. Crovidisin, a PIII snake venom metalloproteinase (SVMP) purified from venom of Crotalus viridis, exhibits collagen-binding activity and matrix metalloproteinase activity. Crovidisin selectively caused the detachment of ROS 17/2.8 osteosarcoma cells but not of primary cultured osteoblasts. On the other hand, triflavin, an RGD-dependent disintegrin purified from venom of Trimeresurus flavoviridis, did not cause the detachment of both osteoblasts and ROS 17/2.8 cells. Although ROS 17/2.8 cells detached from substratum after crovidisin treatment for 24 h, the loss of mitochondrial membrane potential was not observed unless a prolonged treatment for longer than 36 h. These results suggest that cultured primary rat osteoblasts and ROS 17/2.8 osteosarcoma cells possess different expression of integrins and matrix environment, and ROS 17/2.8 is much more susceptible to be detached by crovidisin. The matrix degradation by crovidisin may be responsible for the preferential detachment of ROS 17/2.8 osteosarcoma cells.

Animals↗
PubMed1997

Human osteosarcoma cell susceptibility to natural killer cell lysis depends on CD54 and increases after TNF alpha incubation.

Osteosarcoma cell lines vary widely in their susceptibility to natural killer (NK) cell lysis in vitro although it is still unclear why this occurs. In this study we investigated the expression of some cell adhesion molecules on osteosarcomas to determine which of these can modify the susceptibility to NK lysis and we also attempted to modulate the cytolytic susceptibility of these targets with TNF alpha. We found that osteosarcoma lysis induced by NK cells correlates with different expression of the CD54 adhesion molecule on osteosarcomas and the increased susceptibility after TNF alpha treatment mostly depends on the expression of CD54 molecules on target cells.

Adult↗
PubMed1982

Improved survival in children with osteosarcoma following resection of pulmonary metastases.

Despite the effectiveness of improved chemotherapy and radiotherapy, surgical resection of all gross metatastic disease from the lung appears to improve the survival of children with osteosarcoma. At Children's Orthopedic Hospital and Medical Center (COHMC), from 1952 through 1980, 55 patients were treated for osteosarcoma. Twenty-eight of these patients (4 with active disease) were surviving in January 1981. Six patients had pulmonary metastases at diagnosis and 28 patients developed pulmonary metastases after diagnosis. From 1964 through 1980, 17 patients had 34 thoracotomies for resection of metastases. Seven of these 17 patients (41%) are surviving and remain free of disease. The disease was often bilateral, and in most patients more than one thoracotomy was required to erradicate recurrent disease. No patient who developed pulmonary metastases from osteosarcoma survived without surgical resection of all gross disease. An aggressive surgical approach to the treatment of osteosarcoma metastatic to the lung in children appears worthwhile.

Adolescent↗
PubMed2003

Inhibition of matrix metalloproteinase-14 in osteosarcoma cells by clodronate.

BACKGROUND: Bisphosphonates reduce the bone metastasis formation and angiogenesis but the exact molecular mechanisms involved are unclear. Progelatinase A (proMMP-2; 78 KDa) is activated up during the tumor spread and metastasis by a cell surface-associated matrix metalloproteinase (membrane-type matrix metalloproteinase [MT1-MMP] or MMP-14). MATERIAL AND METHODS: We evaluated the effects of a bisphosphonate (clodronate) on MT1-MMP mRNA expression and protein production, catalytic activity and proteolytic activation of proMMP-2 by cultured human MG-63 osteosarcoma cells. RESULTS: Clodronate, at therapeutically attainable noncytotoxic concentrations, dose-dependently inhibited phorbol myristic acetate (PMA)-induced proteolytic activation of proMMP-2 by human MG-63 osteosarcoma cells. Clodronate also downregulated the PMA-induced expression of MT1-MMP mRNA and protein production in human MG-63 osteosarcoma cells, as evidenced by Northern analysis and fluorescent immunohistochemistry. Furthermore, clodronate inhibited directly and dose-dependently MT1-MMP activity, and the MT1-MMP inhibition by clodronate was reduced in the presence of an increased (5 mM) Ca(2+) concentrations when compared to physiological (1 mM) Ca(2+) concentrations. CONCLUSION: We conclude that (1) the extracellular/cell-associated mechanism of bisphosphonate involves inhibition of MT1-MMP catalytic activity eventually by chelation, and that (2) intracellular mechanism involves downregulation of induced MT1-MMP mRNA and protein expression. The inhibition and downregulation of MT1-MMP by clodronate can be related to their ability to reduce MG-63 osteosarcoma cell invasion and spread. These findings may, at least in part, explain at molecular level the antitumor and antibone resorption activities of clodronate observed in clinical studies.

Binding Sites↗
PubMed1997

Analysis of p53 expression in osteosarcoma of the jaw: correlation with clinicopathologic and DNA ploidy findings.

The objective of this study was to determine whether p53 expression correlated with clinicopathological and DNA ploidy in osteosarcoma of the jaw, a particular subtype of osteosarcoma associated with an older age at presentation, longer median survival, rare metastasis, and death due to uncontrolled local recurrence. Seventeen cases of osteosarcoma of the jaw were stained for p53 using CM1 antibody (Novocastra). Eight cases (47.5%) showed nuclear staining in more than 10% of the neoplastic nuclei. Ploidy analysis showed 13 aneuploid (eight p53+) and three diploid (none p53+) tumors. No significant relationship was found between p53 positivity and clinicomorphological features, DNA ploidy or survival. p53-positive cases were, however, more commonly associated with aneuploidy and chondroblastic differentiation. These results indicate that p53 immunostaining does not seem to provide prognostic information in osteosarcoma of the jaw.

Adolescent↗
PubMed1997

Osteosarcoma of the jaw bones.

Osteosarcoma of the jaw bone is comparatively rare and accounts for about 6.5% of all osteosarcomas. We treated eight cases of osteosarcoma of the jaw bone involving the mandible and maxilla in equal proportions between 1986-1992. The median age was 31 years and male: female ratio was 5:3. Swelling and bony expansion were the most common presentations. Radiologically six patients had lytic lesions, and histopathologically they were osteoblastic (n = 4), chondroblastic (n = 3) and fibroblastic (n = 1). Three patients, two with mandibular and one with maxillary osteosarcoma underwent radical surgery and six courses of cisplatinum-based chemotherapy. All were alive and disease free 24, 30, and 54 months after treatment. Histologically all three were chondroblastic. Five patients had incomplete or palliative treatment. All patients died of progressive or locally recurrent disease within 2 years.

Adult↗
PubMed1997

p53 mutation and absence of mdm2 amplification and Ki-ras mutation in 4-hydroxyamino quinoline 1-oxide induced transplantable osteosarcomas in rats.

Previously, we reported the establishment of two transplantable osteosarcomas, one induced by local application of a carcinogen, 4-hydroxyamino quinoline 1-oxide(4-HAQO), and another which developed spontaneously in rats, and their subdivision into four lines with high and low metastatic potential to the lung. In the present study, mutations of p53 and Ki-ras genes were investigated by PCR and SSCP followed by direct sequencing, and the amplification of the mdm2 gene was assessed by Southern blot analysis. Mutations of p53 in exon 7 were detected in 4-HAQO-induced transplantable osteosarcomas, but not their spontaneous counterparts, irrespective of the metastatic potentials. Direct sequencing revealed a CGC to CAC transition with an amino acid change of Arg to His, at codon 246. Neither Ki-ras mutations nor mdm2 amplification were detected in any of the transplantable tumors. The results suggest that while p53 mutations occurred during osteosarcoma development by 4-HAQO without mdm2 amplification and Ki-ras mutation does not contribute to osteosarcoma development in rats.

4-Hydroxyaminoquinoline-1-oxide↗
PubMed1997

Increased telomerase activity is not directly related to metastatic potential in rat transplantable osteosarcomas.

Previously, we reported the establishment of two transplantable osteosarcomas in rats, one induced by local application of a carcinogen, 4-hydroxyamino quinoline 1-oxide (4-HAQO), and another which developed spontaneously, and their subdivision into four lines with high and low metastatic potential to the lung. In the present study, activation of telomerase was investigated by the telomeric repeat amplification protocol (TRAP) assay followed by densitometric quantification. Telomerase activity was found to be elevated in all four lines without any link to the metastatic potential. Thus the spontaneous osteosarcoma (SOS) and derived metastatic lesions (S-SLM) demonstrated a 20.1-23.5-fold increase and the chemical carcinogen (4HAQO)-induced osteosarcoma (COS) and metastatic lesions (C-SLM) were 18.4-19.1-fold elevated as compared to the value for abdominal muscle. The results suggest that activation of telomerase occurs in rat osteosarcomas but that it is not directly involved in determining their metastatic potential.

Animals↗