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)

Chromosome region 9p21 contains a tumor suppressor locus (p16) that may be involved in the genesis of several kinds of malignant tumors. To characterize the role of this gene in the development of soft-tissue tumors (STTs), we investigated the frequency of loss of heterozygosity (LOH) at this locus. DNA was obtained from 77 tumors and the peripheral blood of 23 of the patients with the tumors. Using one microsatellite marker distal to p16(D9S171) and one intragenic sequence-tagged site (STS) marker (c5.1), we observed LOH in only one liposarcoma and one malignant schwannoma (2.6%). Homozygous deletions of the p16 markers were not found. The osteosarcoma cell line MG-63 was used as a control for loss of the p16 gene. Because of the low LOH frequency, we hypothesize that the p16 gene is not essential for STT oncogenesis.
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PMID:Loss of heterozygosity on chromosome 9q21 (p16 gene) uncommon in soft-tissue sarcomas. 904 81

Loss of the p16INK4A gene by homozygous deletions or point mutations is attributed to the development of many types of cancers including leukemia. T cell acute lymphoblastic leukemias (T-ALLs) and B-cell ALLs show a remarkable rate of 75 and 20% homozygous deletion of this gene, respectively. Restoration of p16 expression in p16-deficient solid tumor cell lines results in a dramatic reduction of growth and maligant phenotype. To test the hypothesis that p16INK4A suppresses the growth of p16-deficient leukemias, we utilized a retroviral system to restore wild-type (wt) or mutant p16 protein expression. We tested the efficacy of our system by expressing the wt or mutant p16 genes in the osteosarcoma cell line, U20S, which lacks p16 and retains functional retinoblastoma protein (pRb). The wt p16 protein formed complexes with both cyclin-dependent kinases (CDK) 4 and 6 and inhibited U20S growth by 30-fold. The p16 mutants E120K and R144C formed complexes with CDK4 and CDK6 in cells and inhibited cell growth as effectively as wt p16 (20-fold) while the mutant proteins that did not complex with detectable levels of CDK4 or CDK6 only inhibited growth 0.25- and five-fold (G101W and D141, respectively) or not at all (H83Y and DA4). The COOH-terminal 'tail' of the wt p16 protein (amino acid residues 141-156), missing in mutant D141, enhanced the growth suppressive capability of p16. The amino acid substitutions in mutants G101W and H83Y not only disrupted CDK4 and CDK6 binding, but decreased the protein half-lives by two- and three-fold, respectively, compared to wt p16. The wt, but not mutant p16 genes, effectively inhibited the growth of T cell acute lymphoblastic (CEM) and myeloid leukemia (NB-4 and K562) cell lines that lacked the p16 gene, but retained functional pRb. Growth of the T-ALL cell line, HSB-2, which lacked both p16 and pRb, was not inhibited, indicating the growth suppression involved the pRb pathway. These results define regions critical for the function of p16 and demonstrate that restoration of wt p16 expression in p16-deficient leukemias significantly reverted their transformed phenotype and inhibited their growth.
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PMID:Inhibition of growth of human leukemia cell lines by retrovirally expressed wild-type p16INK4A. 932 88

Our laboratory has developed two cellular models of human prostate cancer progression. The LNCaP prostate cancer progression model is based upon the well-known cellular interaction between human prostate or bone stromal cells and LNCaP cells in vivo. The marginally tumorigenic LNCaP cells acquired tumorigenic and metastatic potential upon cellular interaction with either prostate or bone fibroblasts. A subline termed C4-2 was observed to grow readily in castrated animals and acquired metastatic potential spreading from the primary tumor site to the lymph node, the seminal vesicles, and the axial skeleton, resulting in an intense osteoblastic reaction. The second model is ARCaP, where prostate cancer cells derived from the ascites fluid of a man with metastatic disease exhibited an Androgen- and estrogen-Repressed Prostate Cancer cell growth and tumor formation in either a hormone-deficient or a castrated environment. However, the growth of either the tumor cells in vitro or the tumors in vivo was suppressed by both estrogen and androgen. While the tumor cells expressed low levels of androgen receptor and prostate-specific antigen (PSA), they were highly metastatic when inoculated orthotopically. Distant metastases to a number of organs were detected, including the liver, lung, kidney, and bone. We have employed a human prostate cancer progression model as a system to study the efficacy of gene therapy. Results of the study show that whereas universal promoters, such as Cytomegalovirus (CMV) and Rous Sarcoma Virus (RSV) promoter-driven tumor suppressors (e.g. p53, p21, and p16), were effective in inhibiting prostate tumor growth, the advantages of driving the expression of therapeutic toxic genes using a tissue-specific promoter prostate-specific antigen (PSA) and a tumor--but not tissue-specific promoter, osteocalcin (OC), are preferred. In the case of the PSA promoter, we can achieve cell-kill in PSA-producing human prostate cancer cells. To circumvent the supporting role of bone stroma for prostate cancer epithelial growth, we have recently developed a novel concept where the expression of therapeutic toxic genes is driven by a tumor--but not a tissue-specific OC promoter. Osteocalcin-thymidine kinase (OC-TK) was found to efficiently eradicate the growth of osteosarcoma, prostate, and brain tumors both in vitro and in vivo. We observed that androgen-independent human prostate cancer cells lines expressed OC-TK at higher levels than androgen-dependent human prostate cancer cell lines. We have obtained data to suggest that Ad-OC-TK plus a pro-drug acyclovir (ACV) may be used as an effective therapy to treat prostate cancer bone metastasis in models where the growth of androgen-independent PC-3 and C4-2 tumors in the bone has occurred.
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PMID:Human prostate cancer progression models and therapeutic intervention. 943 28

We constructed an adenoviral vector containing human p16 cDNA in order to evaluate the cytotoxic effects of exogenous p16 expression on cancer cell proliferation and to explore the potential use of p16 in cancer gene therapy. Following infection of human breast (MCF-7, MDA-MB-231, and BT549), osteosarcoma (U-2 OS and Saos-2), cervical (C33a), and lung cancer (H358) cell lines with the recombinant adenovirus Adp16, high levels of p16 expression were observed in all cell lines. Cancer cell lines which were mutant or null for p16 but wild-type for the retinoblastoma gene product (pRb) (MCF-7, MDA-MB-231, BT549 and U-2 OS) were 7-22-fold more sensitive to the cytotoxic effects of Adp16 than to a control virus. In contrast, cancer cell lines which were wild-type for p16 but mutant or null for pRb (Saos-2, C33a and H358) were <threefold more sensitive to Adp16 when compared to a control virus. Analysis of 5-bromodeoxyuridine incorporation into DNA following infection with Adp16 showed a loss of S phase in those cell lines which were null or mutant for p16 but expressed a functional pRb. This cell cycle arrest was associated with binding of the p16 protein to cyclin-dependent kinase 4 and dephosphorylation of pRb. In contrast, human cancer cell lines expressing a wild-type p16 and a mutant pRb or no pRb showed no substantial loss of S phase following Adp16 infection. Based on these studies, we conclude that p16-mediated cytotoxicity is tightly associated with the presence of functional pRb in human cancer cells, and that tumor cells which are mutant or null for p16 are candidates for Adp16 mediated cancer gene therapy.
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PMID:Effects of adenovirus-mediated p16INK4A expression on cell cycle arrest are determined by endogenous p16 and Rb status in human cancer cells. 946 45

Osteosarcomas often suffer mutations of the RB (retinoblastoma) gene, with resultant inactivation of the pRb protein. pRb is one component in a cell-cycle control pathway that includes the p16 (encoded by the CDKN2A gene) and cyclin-dependent kinase 4 (cdk4, encoded by the CDK4 gene) proteins. We therefore sought to determine whether the CDKN2A and CDK4 genes were altered in those osteosarcomas that lacked RB inactivation. Twenty-one osteosarcomas (2 low-grade and 19 high-grade) were evaluated for homozygous deletion of the CDKN2A gene, CDK4 amplification, and allelic loss of the RB gene, as well as for expression of p16 and pRb proteins. Five high-grade osteosarcomas showed loss of p16 expression; four of these had homozygous CDKN2A deletions, and the fifth had a probable deletion obscured by numerous nonneoplastic, p16-immunopositive multinucleated giant cells. Thus, p16 immunohistochemistry may provide a sensitive means for assessing CDKN2A status. Twelve tumors (including the two low-grade osteosarcomas) were immunopositive for pRb, and nine tumors were immunonegative for pRb. Of the five cases with CDKN2A/p16 alterations, none had allelic loss of the RB gene and all expressed pRb, suggesting that each of these tumors had an intact RB gene. None of the tumors showed CDK4 amplification. No alterations were detected in the two low-grade osteosarcomas. This study suggests that CDKN2A is a tumor suppressor inactivated in osteosarcomas that lack RB mutations and that the p16-pRb cell-cycle control pathway is deregulated in a large number of high-grade osteosarcomas.
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PMID:CDKN2A gene deletions and loss of p16 expression occur in osteosarcomas that lack RB alterations. 966 76

The retinoblastoma tumor suppressor gene product (pRb) is involved in controlling cell cycle progression from G1 into S. pRb functions, in part, by regulating the activities of several transcription factors, making pRb involved in the transcriptional control of cellular genes. Transient-transfection assays have implicated pRb in the transcription of several genes, including c-fos, the interleukin-6 gene, c-myc, cdc-2, c-neu, and the transforming growth factor beta2 gene. However, these assays place the promoter in an artificial context and exclude the effects of far 5' upstream regions and chromosomal architecture on gene transcription. In these experiments, we have studied the role of pRb in the control of cell cycle-related genes within a chromosomal context and within the context of the G1 phase of the cell cycle. We have used adenovirus vectors to overexpress pRb in human osteosarcoma cells and breast cells synchronized in early G1. By RNase protection assays, we have assayed the effects of this virus-produced pRb on gene expression in these cells. These results indicate that pRb is involved in the transcriptional downregulation of the E2F-1, E2F-2, dihydrofolate reductase, thymidine kinase, c-myc, proliferating-cell nuclear antigen, p107, and p21/Cip1 genes. However, it has no effect on the transcription of the E2F-3, E2F-4, E2F-5, DP-1, DP-2, or p16/Ink4 genes. The results are consistent with the notion that pRb controls the transcription of genes involved in S-phase promotion. They also suggest that pRb negatively regulates the transcription of two of the transcription factors whose activity it also represses, E2F-1 and E2F-2, and that it plays a role in downregulating the immediate-early gene response to serum stimulation.
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PMID:Regulation of cellular genes in a chromosomal context by the retinoblastoma tumor suppressor protein. 967 66

At the histological level, the differential diagnosis of osteoblastic bone tumors is characterized by several problems that cannot be solved by conventional histological methods including immunohistology. Differentiating aneurysmal bone cyst from telangiectatic osteosarcoma or giant cell tumor from giant cell-containing highly malignant osteosarcoma are only two examples reflecting the complexity of this field. To develop a new approach to these diagnostic problems, we analyzed the genetic instability in a large number of bone-forming tumor-like lesions as well as in benign and malignant osteoblastic tumors. Our research concentrated on genetic alterations in cell cycle regulator genes: mutations in the p53 gene and ras gene, loss of heterozygosity at the p53, p16 and Rb-locus, and amplification of the mdm2-gene and the c-myc-gene. In addition to cell cycle regulators, the telomerase activity has also been analyzed. The results show that the number of genetic alterations increases with the malignancy of the tumors. The highest number of genetic alterations could thus be found in conventional intraosseous osteosarcoma. In tumor-like lesions, genetic alterations have rarely been observed. The results of this study show that analyzing the genetic instability probably contributes to an improvement in the differential diagnosis of osteoblastic tumors.
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PMID:Genetic instability in osteoblastic tumors of the skeletal system. 982 Aug 62

In the histological differential diagnosis of osteoblastic bone tumors, several problems could not have been solved by conventional histological methods including immunohistology. Some well-known examples are the differential diagnosis between aneurysmal bone cyst and telangiectatic osteosarcoma and giant cell tumor versus giant cell-containing highly malignant osteosarcoma. As a new approach to these diagnostic problems, we analyzed the genetic instability in a larger number of bone-forming tumor-like lesions, benign and malignant osteoblastic tumors. Analysis focused on genetic alterations in cell cycle regulator genes: Mutations in the p53 gene and ras gene, loss of heterozygosity at the p53, p16 and Rb-locus, and amplification of the mdm2 gene and the c-myc-gene. In addition to cell cycle regulators, the telomerase activity has also been analyzed. The results show that the number of genetic alterations increases with the malignancy of the tumors. The highest number of genetic alterations could thus be found in conventional intraosseous osteosarcoma. In tumor-like lesions, genetic alterations have rarely been observed. The results of this study show that the analysis of genetic instability will probably contribute to an improved differential diagnosis of osteoblastic tumors.
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PMID:[Genetic instability in osteoblastic tumors of the skeletal system]. 1009 25

The tumor suppressor p16(INK4a) inhibits cyclin-dependent kinases 4 and 6. This activates the retinoblastoma protein (pRB) and, through incompletely understood events, arrests the cell division cycle. To permit biochemical analysis of the arrest, we generated U2-OS osteogenic sarcoma cell clones in which p16 transcription could be induced. In these clones, binding of p16 to cdk4 and cdk6 abrogated binding of cyclin D1, p27(KIP1), and p21(WAF1/CIP1). Concomitantly, the total cellular level of p21 increased severalfold via a posttranscriptional mechanism. Most cyclin E-cdk2 complexes associated with p21 and became inactive, expression of cyclin A was curtailed, and DNA synthesis was strongly inhibited. Induction of p21 alone, in a sibling clone, to the level observed during p16 induction substantially reproduced these effects. Overexpression of either cyclin E or A prevented p16 from mediating arrest. We then extended these studies to HCT 116 colorectal carcinoma cells and a p21-null clone derived by homologous recombination. In the parental cells, p16 expression also augmented total cellular and cdk2-bound p21. Moreover, p16 strongly inhibited DNA synthesis in the parental cells but not in the p21-null derivative. These findings indicate that p21-mediated inhibition of cdk2 contributes to the cell cycle arrest imposed by p16 and is a potential point of cooperation between the p16/pRB and p14(ARF)/p53 tumor suppressor pathways.
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PMID:Induction of p21(WAF1/CIP1) and inhibition of Cdk2 mediated by the tumor suppressor p16(INK4a). 1020 15

We report on a 26-year-old Caucasian woman who was referred to the Department of Surgery complaining of general malaise, feeling of fullness with occasional vomiting and intermittent jaundice. The patient had previously suffered from tibial osteosarcoma of the left leg which was resected 13 years ago and subsequently treated with radiation and chemotherapy. During clinical investigations a 12 x 12 x 6.5 cm large mass was found in the left lobe of the liver. This was resected, and subsequently shown to be a sporadic hepatic angiomyolipoma. In order to investigate a possible link between the two tumours, we investigated mutations in the p53-gene, loss of heterozygosity (LOH) at p53, Rb and p16, c-Myc expression, and the telomerase activity of the angiomyolipoma and the osteosarcoma. Whilst the tibial osteosarcoma showed LOH at p16, no genetic alterations or increased telomerase activity were found in the angiomyolipoma. The occurrence of both these tumours in this patient is therefore probably a coincidence.
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PMID:Hepatic angiomyolipoma in a 26-year-old Caucasian woman with a history of tibial osteosarcoma. 1060 97


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