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)

Bone only metastasis in patients with estrogen receptor (ER) positive breast cancer reported to have favorable response to chemotherapy, favorable prognosis, and an "indolent" course. Therefore, we assessed the ability of MG-63 osteoblast-like human osteosarcoma cells (MG-63 cells) and MG-63 conditioned media (CM) to influence adriamycin-cytotoxicity of ER-positive MCF-7 human breast cancer cells. Estradiol (E2; 100 nM) increased the distribution at S and G2/M phases in the cell cycle and stimulated the growth of MCF-7 cells. Adriamycin (100 nM) inhibited the growth and arrested the MCF-7 cells supplemented with or without 100 nM of estradiol [(-E2) and (+E2) MCF-7 cultures] at G2/M phase in the cell cycle. In addition, adriamycin (100 nM) increased the distribution at G1/G0 phase in the cell cycle of (+E2) MCF-7 cultures. Adriamycin (100 nM and 10 microM) did not induce apoptosis of MCF-7 cells as assessed by flow cytometry and analysis of DNA fragmentation on simple agarose gel. Exogenous insulin-like growth factor I (IGF I) stimulated while transforming growth factor beta 1 (TGF beta 1) and MG-63 CM inhibited the growth of MCF-7 cells. Furthermore, MG-63 CM and TGF beta 1 enhanced while exogenous IGF I reversed adriamycin (100 nM)-cytostasis of MCF-7 cells. These data suggested that osteoblastic CM contained growth factors, such as TGF beta 1 capable of enhancing adriamycin-cytostasis, in vitro. Conceivably, these osteoblast-derived "enhancers" of chemotherapy-cytostasis can explain the favorable prognosis and "indolent" course of ER-positive breast cancer patients with bone only metastasis.
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PMID:Osteoblast-derived growth factors enhance adriamycin-cytostasis of MCF-7 human breast cancer cells. 989 70

The results of surgical resection for pulmonary metastases from colorectal, breast, and renal cell carcinomas, soft tissue sarcoma, and osteosarcoma are reviewed. The number of pulmonary metastases, the presence of hilar or mediastinal involvement, and extrapulmonary foci are discussed in terms of surgical treatment. The size of pulmonary tumors or tumor doubling time has no significant effect on survival, while the number of metastatic foci does. Although a slight survival advantage has been noted for patients without hepatic metastases from colorectal cancer before pulmonary metastases occur, the difference in survival rates among patients with and without hepatic metastases is not significant. The role of surgery is less clear in breast cancer patients, and therefore further prospective study is considered essential. Higher relapse rates have been reported in patients with soft tissue sarcoma and osteosarcoma, although patients with these metastases can achieve long-term survival after a second metastasectomy. VATS is not be recommended for metastatic cancer surgery, because intraoperative identification of metastatic foci is often difficult.
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PMID:[Surgical management of pulmonary metastases]. 1006 99

Bone metastases are a common complication in prostate and breast cancer patients. It leads to extensive morbidity and eventually mortality. Matrix metalloproteinases (MMPs) are known to be involved in the metastatic process. MMP activity can be down-regulated by transforming growth factor beta1 (TGF-beta1), a growth-modulating factor, found in high concentrations in the bone. TGF-beta1 acts through the TGF-beta1 inhibitory element (TIE) element, a cis-acting element found in the promoter region of most MMP genes, with the exception of MMP-2. We used three human cell lines relevant for bone metastases, namely prostate adenocarcinoma PC-3, breast adenocarcinoma MDA-MB-231, and adenocarcinoma cells of unknown origin, Hs696, and one human osteosarcoma cell line, SAOS-2, and showed that in these cell lines TGF-beta1 partially lost its repressing action on MMP expression. TGF-beta1 was able to induce MMP-9 activity and protein expression in all three bone-metastatic tumour cell types, whereas MMP-9 protein levels were repressed in SAOS-2 cells. In PC-3 cells, TGF-beta1 repressed MMP-1 expression, whereas in MDA-MB-231 and SAOS-2 cells, an increase in the expression of MMP-1 protein was detected. Additionally, an increase in MMP-3 expression was observed in Hs696 cells. Expression and activity of the tissue inhibitors of matrix metalloproteinases, TIMP-1 and TIMP-2, were found increased in both PC-3 and MDA-MB-231 cells. With respect to cell proliferation, TGF-beta1 was able to induce a dose-dependent growth inhibition of up to 50% in primary human mammary epithelial cells. However, in none of the tumour cell lines was TGF-beta1 able to suppress growth substantially. Data presented in this paper support the hypothesis that TGF-beta1 can potentially disrupt the balance existing between osteoclast- and osteoblast-derived MMP activity by inducing altered expression of matrix metalloproteinases and their tissue inhibitors derived from bone-metastasizing cancer cells. This could eventually lead to skeletal destruction in patients with advanced metastatic disease.
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PMID:Transforming growth factor beta1 acts as an inducer of matrix metalloproteinase expression and activity in human bone-metastasizing cancer cells. 1039 Jan 44

A novel mRNA isoform (meprin beta') of the cell-surface protease subunit meprin beta was previously identified in human colon cancer cells. The study reported here revealed that this mRNA isoform was identical within the protein coding region and at the 3' end to the beta isoform of normal intestine but that it contained an extended 5' untranslated region. Meprin beta' mRNA was expressed in the human breast cancer cell lines MCF-7 and SK-BR-3, in the human osteosarcoma cell line U2 Os, and in the human pancreatic cancer cell line BxPC-3. Meprin beta mRNA, but not beta' mRNA, was expressed in human fetal kidney cells. We cloned and sequenced genomic DNA encoding portions of the promoter region of the meprin beta gene. The unique sequences present in the beta' mRNA were present in the human genomic DNA immediately upstream of the transcription start site for the beta mRNA. The human meprin promoter sequence was searched for potential transcription-factor binding sites, and putative activator protein-1, polyoma enhancer activator 3 (PEA3), CCAAT enhancer-binding protein beta, and estrogen-receptor binding sites were identified along with binding sites for the intestine-specific cdx-2 transcription factor. The activity of meprin promoter/luciferase reporter gene constructs transfected into U2 Os cells was highest with constructs containing 83 and 639 bp of promoter DNA. These regions of the promoter each contain a putative PEA3 element. Treatment of the human colon adenocarcinoma cell line HT29-18C1 with 50 or 100 ng/mL phorbol myristal acetate for 8 h increased meprin beta' mRNA levels. Likewise, U2 Os cells transfected with the -639/luciferase or -1800/luciferase constructs showed a phorbol myristal acetate-inducible increase in reporter gene activity, indicating that the PEA3 element within the -639 construct or other elements further upstream respond to phorbol ester.
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PMID:Expression and regulation of the meprin beta gene in human cancer cells. 1041 Nov 43

Bone sialoprotein (BSP) and osteopontin (OPN) are secreted glycoproteins with a conserved Arg-Gly-Asp (RGD) integrin-binding motif and are expressed predominantly in bone. The RGD tripeptide is commonly present in extracellular attachment proteins and has been shown to mediate the attachment of osteosarcoma cells and osteoclasts. To determine the origin and incidence of BSP and OPN mRNA expression in primary tumor, a cohort of archival, primary invasive breast carcinoma specimens was analyzed. BSP transcripts were detected in 65% and OPN transcripts in 77% of breast cancers examined. In general, BSP and OPN transcripts were detected in both invasive and in situ carcinoma components. The transcripts were not detected in surrounding stromal cells or in peritumoral macrophages. Despite its abundance in carcinomas, BSP expression was not detected in a panel of 11 human breast cancer cell lines (MCF-7, T47D, SK-Br-3, MDA-MB-453, MDA-MB-231, MDA-MB-436, BT549, MCF-7ADR, Hs578T, MDA-MB-435, and LCC15-MB) and OPN expression was detected only in two of these (MDA-MB-435 and LCC15-MB). To examine the possibility that expression of these genes was down-regulated in cell culture, several cell lines were grown as nude mouse xenografts in vivo; however, these tumors also failed to express BSP. OPN expression was identified in all cell lines grown as nude mouse xenografts. Our data suggest that in human primary breast tumors, the origin of BSP and OPN mRNA is predominantly the breast cancer cells and that expression of these transcripts is influenced by the tumor environment.
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PMID:Tumor cells are the source of osteopontin and bone sialoprotein expression in human breast cancer. 1041 27

ImmTher, a liposome-encapsulated lipophilic disaccharide tripeptide derivative of muramyl dipeptide, previously showed activity against liver and lung colorectal metastases in a phase I trial. The purpose of the current studies was to investigate whether ImmTher could up-regulate specific cytokine gene expression and protein production, as well as activate the tumoricidal or cytostatic activity of human monocytes. ImmTher induced the expression and production of interleukin(IL)-1alpha IL-1beta, IL-6, IL-8, IL-12, macrophage chemotactic and activating factor, and tumor necrosis factor alpha but not IL-2 or IL-10. Cytostatic or cytotoxic monocyte activity was stimulated against human Ewing's sarcoma, osteosarcoma, and melanoma cells but not breast cancer cells. Production and secretion of these cytokine proteins may play a role in the antitumor activity of ImmTher.
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PMID:ImmTher, a lipophilic disaccharide derivative of muramyl dipeptide, up-regulates specific monocyte cytokine genes and activates monocyte-mediated tumoricidal activity. 1047 6

The transcription factor YB-1 is expressed in a wide range of cell types and has been implicated in the regulation of various genes involved in cell proliferation. Nuclear expression of YB-1 is correlated with MDR-1 gene expression in breast cancer and osteosarcoma. In this study, we asked whether YB-1 expression is enhanced in human colorectral carcinoma and if it is associated with the expression of target genes such as MDR-1, DNA topoisomerase II alpha and PCNA. YB-1, DNA topoisomerase II alpha, PCNA and MDR-1 expression were assessed by Western blotting, Northern blotting and immunohistochemistry in 26 human colorectal carcinomas. The involvement of YB-1 in DNA topoisomerase II alpha gene expression was examined by transient DNA transfection assays. YB-1 was overexpressed in almost all cancerous lesions in comparison with normal mucosa in surgically resected colorectal carcinomas of 26 patients. YB-1 expression correlated well with both DNA topoisomerase II alpha and PCNA expression. In contrast, no correlation was observed between YB-1 and MDR-1 expression. We also found that a transient co-transfection with a DNA topoisomerase II alpha promoter-luciferase plasmid and an antisense YB-1 expression construct resulted in a significant reduction of the promoter activity in KM12C human colon cancer cells. YB-1 may be an excellent proliferation-associated marker and may be a transcription factor regulating DNA topoisomerase II alpha gene expression in human colorectal carcinoma.
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PMID:Enhanced coexpression of YB-1 and DNA topoisomerase II alpha genes in human colorectal carcinomas. 1059 87

Autoantibodies to the heat shock protein 90 (Hsp 90) have been reported as prognostic marker in breast cancer patients. Sera from 20 high-grade osteosarcoma patients were tested at the time of diagnosis by enzyme-linked immunosorbent assay. Presence of anti-Hsp90 antibodies correlated with a better response to neoadjuvant chemotherapy (P < 0.01), whereas the absence correlated with development of metastases. These data suggest that anti-Hsp90 antibodies might be of predictive value in human osteosarcoma.
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PMID:Antibodies to heat shock protein 90 in osteosarcoma patients correlate with response to neoadjuvant chemotherapy. 1063 71

Polyhalogenated aromatic hydrocarbons, of which 2,3,7, 8-tetrachloro-p-dioxin (TCDD) is the prototype compound, elicit a variety of toxic, teratogenic, and carcinogenic responses in exposed animals and in humans. In cultured cells, TCDD shows marked effects on the regulation of cell cycle progression, including thymocyte apoptosis, induction of keratinocyte proliferation and terminal differentiation, and inhibition of estrogen-dependent proliferation in breast cancer cells. The presence of an LXCXE domain in the dioxin aromatic hydrocarbon receptor (AHR), suggested that the effects of TCDD on cell cycle regulation might be mediated by protein-protein interactions between AHR and the retinoblastoma protein (RB). Using the yeast two-hybrid system, AHR and RB were in fact shown to bind to each other. In vitro pull-down experiments with truncated AHR peptides indicated that at least two separate AHR domains form independent complexes with hypophosphorylated RB. Coimmunoprecipitation of whole cell lysates from human breast carcinoma MCF-7 cells, which express both proteins endogenously, revealed that AHR associates with RB in vivo only after receptor transformation and nuclear translocation. However, the AHR nuclear translocator and transcriptional heterodimerization partner, is not required for (nor is it a part of) the AHR.RB complexes detected in vitro. Ectopic expression of AHR and RB in human osteosarcoma SAOS-2 cells, which lack endogenous expression of both proteins, showed that AHR synergizes with RB to repress E2F-dependent transcription and to induce cell cycle arrest. Furthermore, AHR partly blocked T-antigen-mediated reversal of RB-dependent transcriptional repression. These results uncover a potential function for the AHR in cell cycle regulation and suggest that this function may be that of serving as an environmental sensor that signals cell cycle arrest when cells are exposed to certain environmental toxicants.
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PMID:Aromatic hydrocarbon receptor interaction with the retinoblastoma protein potentiates repression of E2F-dependent transcription and cell cycle arrest. 1064 64

Inheritance of a mutant allele of the breast cancer susceptibility gene BRCA1 confers increased risk of developing breast and ovarian cancers. Likewise, inheritance of a mutant allele of the retinoblastoma susceptibility gene (RB1) results in the development of retinoblastoma and/or osteosarcoma, and both alleles are often mutated or inactivated in sporadic forms of these and other cancers. We now demonstrate that the product of the RB1 gene, Rb, regulates the expression of the murine Brca1 and human BRCA1 genes through its ability to modulate E2F transcriptional activity. The Brca1 gene is identified as an in vivo target of E2F1 in a transgenic mouse model. The Brca1 promoter contains E2F DNA-binding sites that mediate transcriptional activation by E2F1 and repression by Rb. Moreover, ectopic expression of cyclin D1 and Cdk4 can stimulate the Brca1 promoter in an E2F-dependent manner, and this is inhibited by coexpression of the p16(INK4a) cyclin-dependent kinase inhibitor. The human BRCA1 promoter also contains a conserved E2F site and is similarly regulated by E2F1 and Rb. This functional link between the BRCA1 and Rb tumor suppressors may provide insight into the mechanism by which BRCA1 inactivation contributes to cancer development.
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PMID:Regulation of BRCA1 expression by the Rb-E2F pathway. 1066 Jun 29


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