Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0029463 (osteosarcoma)
 16,637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The incidence of osteosarcoma is increased 500-fold in patients who inherit mutations in the RB gene. To understand why the retinoblastoma protein (pRb) is specifically targeted in osteosarcoma, we studied its function in osteogenesis. Loss of pRb but not p107 or p130 blocks late osteoblast differentiation. pRb physically interacts with the osteoblast transcription factor, CBFA1, and associates with osteoblast-specific promoters in vivo in a CBFA1-dependent fashion. Association of pRb with CBFA1 and promoter sequences results in synergistic transactivation of an osteoblast-specific reporter. This transactivation function is lost in tumor-derived pRb mutants, underscoring a potential role in tumor suppression. Thus, pRb functions as a direct transcriptional coactivator promoting osteoblast differentiation, which may contribute to the targeting of pRb in osteosarcoma.
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PMID:The retinoblastoma protein acts as a transcriptional coactivator required for osteogenic differentiation. 1154 33

The retinoblastoma protein (pRb), the gene product of the first reported tumour suppressor gene, is functionally inactivated by the E7 protein of high-risk human papillomavirus (HPV) found in most human cervical cancers. We have, in this study, constructed an adenoviral vector expressing wild-type pRb (Ad5-Rb) and used the constructed Ad5-Rb to transfect the osteosarcoma cell line Saos-2, and three cervical cancer cell lines HeLa, SiHa and C-33A. Our results showed that pRb caused G1 arrest in Saos-2 cells after transfection with Ad5-Rb. The number of colonies formed by the Ad5-Rb-transfected Saos-2 cells in soft agar was also found to be significantly lower (P<0.05) than those transfected with the adenoviral control expressing Escherichia coli beta-galactosidase (Ad5-LacZ). The transfection of Ad5-Rb caused an increase in the population of SiHa and C-33A cells in the G1 phase from 53.0 and 52.9% to 72.4 and 64.3%, respectively, but not in the HeLa cells. However, Ad5-Rb did not show any inhibitory effect on the growth of SiHa, HeLa and C-33A cells, and inhibition of colony formation in soft agar was not observed either. In contrast, flow cytometric analysis showed that Ad5-p53, a p53-expressing adenovirus, induced apoptosis, i.e. the appearance of sub-G1 peak, in all three tested cervical cancer cell lines. Nevertheless, the Ad5-p53-induced apoptosis was partially inhibited when Ad5-Rb was added simultaneously. These findings suggested that pRb may not be a good candidate for cervical cancer gene therapy. Our data also showed that the use of full-length pRb in combination with TP53 might not be a suitable strategy for cancer gene therapy.
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PMID:pRb-expressing adenovirus Ad5-Rb attenuates the p53-induced apoptosis in cervical cancer cell lines. 1172 Aug 46

Effective cell cycle completion requires both Myc and E2F activities. However, whether these two activities interact to regulate cell survival remains to be tested. Here we have analysed survival of inducible c-Myc-overexpressing cell lines derived from U2OS human osteosarcoma cells, which carry wild-type pRb and p53 and are deficient for p16 and ARF expression. Induced U2OS-Myc cells neither underwent apoptosis spontaneously nor upon reconstitution of the ARF-p53 axis and/or serum-starvation. However, they died massively when concomitantly exposed to inhibitors of E2F activity, including a constitutively active pRb (RbDeltacdk) mutant, p16, a stable p27 (p27T187A) mutant, a dominant-negative (dn) CDK2, or dnDP-1. Similar apoptotic effect was observed upon down-modulation of endogenous E2Fs through overexpression of E2F binding site oligonucleotides in U2OS-Myc cells, upon expression of RbDeltacdk or dnDP-1 in the Myc-amplified HL-60 (ARF-; p53-) human leukemia cells, and upon co-transfection of Myc and RbDeltacdk in SAOS-2 (ARF+; p53-) human osteosarcoma cells but not in human primary fibroblasts. Consistent with these results, a dnp53 mutant did not abrogate the Myc-induced apoptotic phenotype, which instead strictly depended on caspase-3-like proteases and on Myc transcriptional activity. Our data indicate that in contrast to normal cells, Myc-overexpressing human cancer cells need E2F activity for their survival, regardless of their ARF and p53 status, a notion that may have important implications for antineoplastic treatment strategies.
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PMID:E2F activity is essential for survival of Myc-overexpressing human cancer cells. 1222 53

Fine-needle aspiration (FNA) is a reliable, safe, and cost-effective procedure with a well-established role in the diagnosis of various solid tissue neoplasms. The role of FNA in the diagnosis of primary bone tumors, including osteosarcoma (OGS), is controversial and has yet to be established. We reviewed our experience with the use of FNA as a diagnostic technique over the past 8 yr at our institution. Diagnosis was conclusive in 26 (65%) of 40 patients, 18 of whom went to neoadjuvant therapy and/or resection based solely on the FNA interpretation of either "high grade sarcoma" or "osteosarcoma." Of the remaining 14 (25%) patients, 12 had inconclusive diagnosis and two (5%) were false-negatives. An inconclusive diagnosis was most likely to be an inadequate or paucicellular aspirate, seen in six (15%) patients. An additional six patients had variants of osteosarcoma (four chondroid, one "giant cell rich," one parosteal) that made definitive diagnosis impossible. The two that were incorrectly classified were diagnosed as fracture callus and plasmacytoma. FNA is an accurate and cost-effective tool for the initial diagnosis of primary osteosarcoma with a sensitivity of 65% and accuracy of 95%. Inconclusive diagnoses are likely to be due to insufficient sample cellularity or the presence of OGS variant. In our experience, FNA is sufficient to provide the diagnosis of OGS prior to definitive treatment when interpreted in conjunction with imaging studies and clinical findings. In those cases where FNA fails to yield a diagnostic sample, a traditional biopsy can be performed.
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PMID:Utility of fine-needle aspiration in the diagnosis of primary osteosarcoma. 1245 65

Mechanisms underlying multidrug resistance (MDR), one of the major causes of cancer treatment failure, are still poorly understood. We selected the osteosarcoma MDR HosDXR150 cell line by culturing Hos cells in the presence of increasing doxorubicin doses and showed that it is crossresistant to vinblastine. Similarly to the Hos parental cell line, HosDXR150 cells present mutated p53, functionally inactivated pRb/p105 and wild-type pRb2/p130. Owing to p53 mutation, MDR-1 gene, codifying for P-glycoprotein, is upregulated. Evasion of apoptosis in HosDXR150 cells is only partially explained by drug extrusion because of P-glycoprotein overexpression. Analysis of gene expression level profiles showed that parental cell line undergoes apoptosis through an E2F1/p73-dependent pathway while its resistant variant evades it. This result can be explained by the presence of distinct E2Fs-pRb2/p130 complexes on the p73 promoter. Namely, in Hos p73 transcription is activated by E2F1-Rb2/p130-p300 complexes, while in HosDXR150 it is kept repressed by E2F4-Rb2/p130-HDAC1 complexes.
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PMID:Triggering of p73-dependent apoptosis in osteosarcoma is under the control of E2Fs-pRb2/p130 complexes. 1278 60

This study demonstrates that in human osteosarcoma cells treatment with 3-aminobenzamide (3-AB), a potent inhibitor of poly(ADP-ribose) polymerase (PARP), induces morphological and biochemical features of differentiation, the duration of which depends on whether or not the normal RB gene is expressed. In Saos-2 cells expressing a non-functional Rb protein, 3-AB treatment induced the formation of transient, short dendritic-like protrusions. In RB-transfected-Saos-2 cells (a clone previously generated in our laboratory that shows stable expression of wild-type Rb protein), 3-AB induced marked and prolonged changes with the formation of long dendritic-like protrusions and the appearance of stellate (osteocyte-like) cells. In MG-63 cells producing a wild-type Rb protein, 3-AB treatment had more marked effects, with a larger number of cells assuming the stellate appearance of osteocytes, which were connected to each other via junctions resembling small channels. Regardless of cell type, at some point after 3-AB treatment the differentiative attempt failed and the cells died. Death was apoptotic, as demonstrated by chromatin condensation and fragmentation, specific cleavage of PARP and Lamin-B, processing of caspase-3 and the appearance of Bax immunoreactive species. Enzymatic assay and RT-PCR of alkaline phosphatase (ALP) - an enzyme whose levels markedly decrease when osteoblasts undergo terminal differentiation into osteocytes - showed that 3-AB treatment markedly lowered ALP expression. Simultaneously, 3-AB treatment markedly increased the expression of CD44, a transmembrane multifunctional adhesion molecule and sensitive marker of osteocytic differentiation. This study hypothesizes a cross-talk between pRb and PARP and suggests that PARP may be a useful target for anticancer drugs.
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PMID:The effect of 3-aminobenzamide, inhibitor of poly(ADP-ribose) polymerase, on human osteosarcoma cells. 1461 22

Alterations of the retinoblastoma (RB1) tumor suppressor gene are not only associated with retinoblastoma but also with several other malignancies including osteosarcoma. Besides direct sequence alterations, hypermethylation of a CpG island in the promoter region can cause inactivation of the RB1 gene as it has been shown in retinoblastomas. We examined the methylation status of the RB1 gene in 25 osteosarcoma specimens by using the methylation-sensitive restriction enzymes SacII and SmaI. The restriction fragments were hybridized with clone p123, which is a 1.8-kb genomic subclone that spans the RB1 CpG island including the promoter region and exon 1. Whereas we reconfirmed hypermethylation of the RB1 gene in a sporadic retinoblastoma, no hypermethylation could be detected in the 25 osteosarcoma specimens, suggesting that hypermethylation of the RB1 promoter is not of major importance during osteosarcoma genesis.
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PMID:Methylation status of the retinoblastoma gene (RB1) in osteosarcoma: no evidence for hypermethylation. 1466 Mar 7

Polycyclic aromatic hydrocarbons (PAHs) have been known as a kind of xenoestrogen. Benzo[a]pyrene, a PAH present in tobacco smoke and tar, has been implicated in the induction of cell proliferation as well as tumors including osteosarcoma. Nevertheless, the literature about the action of benzo[a]pyrene on the bone system is rare. It has been identified that osteoblasts owned the estrogen receptors and estrogen could modulate the osteoblast proliferation. In this study, we found that benzo[a]pyrene was capable of increasing the cell proliferation in cultured rat osteoblasts, human osteosarcoma cell line (MG-63), and estrogen sensitive human cell line (MCF-7) but not in the human estrogen receptor negative cell line (MDA-MB-231). This benzo[a]pyrene-induced osteoblast proliferation could be inhibited by the estrogen receptor antagonist ICI182780 and tamoxifen, PD98059 [extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) inhibitor], and LY294002 [phosphatidylinositol 3-kinase (PI3K) inhibitor] but not alpha-naphthoflavone (aryl hydrocarbon receptor antagonist) and SB203580 (p38 MAPK inhibitor). Western blot analysis showed that benzo[a]pyrene could induce the phosphorylation of ERK1/2 and Akt (PI3K downstream effector) in osteoblasts. The proliferating cell nuclear antigen protein levels in nuclear fraction of osteoblasts were also increased by benzo[a]pyrene. Moreover, cyclooxygenase-2 (COX-2), but not COX-1, expression could be induced in osteoblasts under benzo[a]pyrene treatment. Its upregulation was associated with the induction of prostaglandin E(2) (PGE(2)). COX-2 inhibitors NS398 and aspirin are capable of inhibiting the benzo[a]pyrene-induced osteoblast proliferation. These results indicate that benzo[a]pyrene may modulate the osteoblast proliferation through activation of COX-2 protein.
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PMID:Benzo[a]pyrene regulates osteoblast proliferation through an estrogen receptor-related cyclooxygenase-2 pathway. 1514 25

The molecular basis for the inverse relationship between differentiation and tumorigenesis is unknown. The function of runx2, a master regulator of osteoblast differentiation belonging to the runt family of tumor suppressor genes, is consistently disrupted in osteosarcoma cell lines. Ectopic expression of runx2 induces p27KIP1, thereby inhibiting the activity of S-phase cyclin complexes and leading to the dephosphorylation of the retinoblastoma tumor suppressor protein (pRb) and a G1 cell cycle arrest. Runx2 physically interacts with the hypophosphorylated form of pRb, a known coactivator of runx2, thereby completing a feed-forward loop in which progressive cell cycle exit promotes increased expression of the osteoblast phenotype. Loss of p27KIP1 perturbs transient and terminal cell cycle exit in osteoblasts. Consistent with the incompatibility of malignant transformation and permanent cell cycle exit, loss of p27KIP1 expression correlates with dedifferentiation in high-grade human osteosarcomas. Physiologic coupling of osteoblast differentiation to cell cycle withdrawal is mediated through runx2 and p27KIP1, and these processes are disrupted in osteosarcoma.
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PMID:Terminal osteoblast differentiation, mediated by runx2 and p27KIP1, is disrupted in osteosarcoma. 1558 32

Mice lacking both p18(Ink4c) and p27(Kip1) develop a tumor spectrum similar to pRb(+/-) mice, and loss of p53 function accelerates tumorigenesis in pRb(+/-) mice. We hypothesized that codeletion of either p18 or p27 in conjunction with p53 deletion will also accelerate tumorigenesis. Mice lacking both p18 and p53 develop several tumors not reported in either single null genotype, including hepatocellular carcinoma, testicular choriocarcinoma, hemangiosarcoma, leiomyosarcoma, fibrosarcoma, and osteosarcoma. Mice lacking both p27 and p53 exhibit a decreased lifespan and develop unique tumors, including papillary carcinoma of the colon, hemangiosarcoma, and leiomyosarcoma. In both p18/p53 and p27/p53 double null genotypes, the incidence and spectra of tissues that develop lymphoma are also increased, as compared to the single null genotypes. The development of p27/p53 double null colon tumors correlates with secondary changes in cell-cycle protein expression and CDK (cyclin-dependent kinase) activity, perhaps contributing to the progression of colorectal cancer. We concluded that p18 and p27 can, not only functionally collaborate with one another, but also can independently collaborate with p53 to modulate the cell cycle and suppress tumorigenesis in a tissue-specific manner.
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PMID:Tumorigenesis in p27/p53- and p18/p53-double null mice: functional collaboration between the pRb and p53 pathways. 1558 24


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