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1.
Cancer Lett ; 343(1): 24-32, 2014 Feb 01.
Article in English | MEDLINE | ID: mdl-24041865

ABSTRACT

The dual PI3K-mTOR inhibitor BEZ235 was evaluated in preclinical models of nasopharyngeal carcinoma (NPC). The IC50 value of BEZ235 for growth was in the nanomolar range in vitro, induce G1 cycle arrest and apoptosis, and inhibited AKT and mTOR signaling in most NPC cell lines. No synergistic effect was observed when BEZ235 was combined with chemotherapy. BEZ235 increased MAPK activation in vitro but not in vivo. A daily schedule was more effective than a weekly schedule on tumor growth and inhibition of downstream mTOR signaling in vivo. The activity of BEZ235 maybe independent of the PIK3CA amplification and mutation status.


Subject(s)
Gene Expression Regulation, Neoplastic , Imidazoles/pharmacology , Nasopharyngeal Neoplasms/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Quinolines/pharmacology , TOR Serine-Threonine Kinases/metabolism , Animals , Antineoplastic Agents/pharmacology , Carcinoma , Cell Cycle , Cell Line, Tumor , Cell Survival , Cisplatin/pharmacology , Enzyme Activation , Female , Humans , Inhibitory Concentration 50 , MAP Kinase Signaling System , Mice , Mice, Nude , Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms/genetics , Neoplasm Transplantation , Paclitaxel/pharmacology , Phosphoinositide-3 Kinase Inhibitors , TOR Serine-Threonine Kinases/antagonists & inhibitors
2.
Invest New Drugs ; 31(6): 1399-408, 2013 Dec.
Article in English | MEDLINE | ID: mdl-23975511

ABSTRACT

Nasopharyngeal carcinoma (NPC) is common in Southeast Asia and over 40% of NPC tissues have PIK3CA amplification. This study characterized the preclinical activity of a novel potent dual PI3K/mTOR inhibitor, PF-04691502, in five NPC cell lines: CNE-1, HK1, CNE-2, HONE-1 and C666-1, in which all of the cell lines possessed basal and activated expression of Akt and p70S6K. Over 80% inhibition of cell growth in all of these cell lines were achieved after 72 h of PF-04691502 incubation and their IC50 were in hundred nanomolar range. CNE-2, HK1 and HONE-1 were selected to further evaluate the effect of PF-04691502 on cell cycle, apoptosis and Akt downstream signaling. PF-04691502 induced G0/G1 cell cycle arrest and apoptosis at 24 h incubation and it significantly abrogated Akt and its downstream signaling by suppressing the expression of p-mTOR, p-p70S6K, p-Akt(S473, T308), p-S6 and p-4E-BP1, suggesting its effectiveness in inhibition of translation and protein synthesis. Anti-proliferation was also observed in 3D culture system and spheroids formation of NPC cell line HONE-1-EBV was strongly inhibited by PF-04691502. Antitumor activity was observed in CNE-2 xenograft in 2 weeks of 10 mg/kg PF-09641502 treatment to tumor bearing athymic nude mice. Both tumor volume and weight in treatment group were significantly lower than those in vehicle group while no obvious body weight decrease was found, suggesting this working dose was effective and well-tolerated. Additive effects were observed in combination of PF-09641502 with either cisplatin or paclitaxel. There were no synergistic effect observed in drug combination but PF-09641502 alone was effective in treating cisplatin resistant cell lines as compared to its parental control. The beneficial effects of PF-09641502 in both in vitro and in vivo studies for NPC warrant a further investigation.


Subject(s)
Antineoplastic Agents/therapeutic use , Nasopharyngeal Neoplasms/drug therapy , Phosphoinositide-3 Kinase Inhibitors , Protein Kinase Inhibitors/therapeutic use , Pyridones/therapeutic use , Pyrimidines/therapeutic use , TOR Serine-Threonine Kinases/antagonists & inhibitors , Animals , Carcinoma , Cell Line, Tumor , Cisplatin/therapeutic use , Drug Evaluation, Preclinical , Drug Therapy, Combination , Female , Humans , Mice , Mice, Nude , Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms/pathology , Tumor Burden/drug effects
3.
Cancer Chemother Pharmacol ; 71(6): 1417-25, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23546591

ABSTRACT

PURPOSE: RAD001 targets at the mammalian target of rapamycin (mTOR), while TKI-258 is a potent tyrosine kinase inhibitor targeting at fibroblast growth factor receptor, vascular endothelial growth factor receptor, platelet-derived growth factor receptor and c-kit. We aim to study the activity of combined RAD001 and TKI-258 in cell lines and xenograft model of hepatocellular carcinoma (HCC), with reference to the parallel and upstream pathways of Akt-mTOR axis. METHODS: A panel of 4 human HCC cell lines HepG2, Hep3B, PLC/PRF/5 and Huh7 and the Hep3B-derived xenograft were treated with TKI-258 or/and RAD001, respectively. Related mechanistic studies (including apoptosis and angiogenesis) were conducted. RESULTS: There was an enhanced increase in suppression of cell proliferation with combined TKI-258 and RAD001 compared with either drug alone. The combination could significantly suppress the phosphorylation of mTOR, MEK1/2 and p38 MAPK. Although the addition of the TKI258 only slightly suppressed the phosphorylation of AKT induced by RAD001, the pi-mTOR and its downstream signaling pathways including pi-p70S6K, pi-S6 and pi-4EBP1 were lowered in the combination. In Hep3B-derived xenograft, TKI-258 and RAD001 had shown an enhanced inhibition of tumor growth without impact on the weight of animals. There was a reduction in microvessel density in the xenograft with the combination, which indicated an enhanced inhibition on angiogenesis. Pro-caspases-3 and PARP cleavage were slightly detected at 48 h after treatment, suggesting that the combination mainly increased the cytostatic arrest ability. CONCLUSIONS: The combination of RAD001 and TKI-258 was active in HCC via inhibition of both mTOR-mediated signaling and its parallel pathways.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Carcinoma, Hepatocellular/drug therapy , Liver Neoplasms/drug therapy , Neovascularization, Pathologic/drug therapy , Animals , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Apoptosis/drug effects , Benzimidazoles/administration & dosage , Blotting, Western , Carcinoma, Hepatocellular/blood supply , Carcinoma, Hepatocellular/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Everolimus , Humans , Liver Neoplasms/blood supply , Liver Neoplasms/pathology , Mice , Mice, Nude , Neovascularization, Pathologic/pathology , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Quinolones/administration & dosage , Sirolimus/administration & dosage , Sirolimus/analogs & derivatives , TOR Serine-Threonine Kinases/antagonists & inhibitors , Xenograft Model Antitumor Assays
4.
Invest New Drugs ; 31(1): 30-8, 2013 Feb.
Article in English | MEDLINE | ID: mdl-22565394

ABSTRACT

This study evaluated the preclinical activity of selumetinib (AZD6244, ARRY-142866), an inhibitor of the mitogen-activated protein kinase kinase (MAPKK or MEK1/2) in 6 nasopharyngeal cancer (NPC) cell lines. Selumetinib could achieve up to 90 % inhibition of cell growth with the respective IC(50) values in NPC cell lines as follow: HK1 = 0.04 µM, HK1-LMP1(B95.8) = 0.17 µM, HONE-1-EBV = 0.46 µM, HONE-1 = 1.79 µM, CNE-2 = 2.20 µM and C666-1 > 10 µM. The drug-sensitive cell lines HK1, HK1-LMP1(B95.8) and HONE-1-EBV have higher basal expression of phosphorylated (pi)-MAPK than the less sensitive cell lines. BRAF mutations were not detected in all 6 cell lines. Re-introduction of the EBV genome into HONE-1 cells, generating the HONE-1-EBV cell line, seemed to result in elevated expression of pi-MAPK and sensitivity to selumetinib when compared with the parental HONE-1 cells. At a concentration of 0.5 µM and 5 µM, selumetinib induced apoptosis (as indicated by cleaved PARP expression and caspase 3 induction), and G(0)/G(1) cycle arrest in HONE-1-EBV and HK1-LMP1(B95.8) cells. The combination of selumetinib (at IC(25) concentration) and the EGFR tyrosine kinase inhibitor, gefitinib (at concentrations of 0.1, 3 and 9 µM) resulted in synergistic growth inhibition in HK1-LMP1(B95.8) cells. The combination of selumetinib (at IC(25) concentration) and cisplatin (at concentrations of 0.1, 0.4, 0.8 and 2 µM) resulted in synergistic growth inhibition in HONE-1 and HONE-1-EBV cells. This result suggests that selumetinib alone or in combination with gefitinib or cisplatin maybe a promising strategy against NPC. Further studies are warranted.


Subject(s)
Antineoplastic Agents/administration & dosage , Benzimidazoles/administration & dosage , Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors , Nasopharyngeal Neoplasms/drug therapy , Protein Kinase Inhibitors/administration & dosage , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Cisplatin/pharmacology , Drug Synergism , Gefitinib , Humans , Mitogen-Activated Protein Kinase Kinases/metabolism , Proto-Oncogene Proteins B-raf/genetics , Quinazolines/pharmacology
5.
Invest New Drugs ; 31(3): 567-75, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23143779

ABSTRACT

Nasopharyngeal carcinoma (NPC) is endemic to Asia and over 40 % of NPC tissues harbor PIK3CA amplifications. This study characterized the preclinical activity of MK-2206, an oral allosteric inhibitor of AKT in 6 NPC cell lines: C666-1, HK1, HONE-1-EBV, HONE-1, CNE-2 and HNE-1. Exposure to increasing concentrations of MK-2206 resulted in over 95 % of growth inhibition in all NPC cell lines with IC50 values in the low micromolar range. Further experiments were performed in 3 representative NPC cell lines: CNE-2 (harbor PIK3CA mutation and most sensitive to MK-2206), C666-1 (carries PIK3CA amplification), and HONE-1-EBV (least sensitive to MK-2206). MK-2206 induced G0/G1 cycle arrest in all 3 cell lines, but could induce apoptosis only in CNE-2 cells. MK-2206 significantly abrogated AKT signaling in all 3 cell lines by inhibiting the activation of AKT and its downstream effectors (FKHR, GSK3ß and BAD). MK-2206 also reduced mTOR signaling by reducing activation of mTOR and its downstream 4E-BP1 and p70S6 kinase. MAPK activation was observed in HONE-1 and C666-1 cells, but not in CNE-2 cells following exposure to MK-2206. The addition of MK-2206 to cisplatin (but not with paclitaxel) has a supra-additive inhibitory effect on growth in vitro. In summary, MK-2206 can inhibit growth and abrogate AKT and mTOR signaling in NPC cell lines. This agent is currently being evaluated in a phase II study in metastatic NPC.


Subject(s)
Antineoplastic Agents/administration & dosage , Heterocyclic Compounds, 3-Ring/administration & dosage , Nasopharyngeal Neoplasms/metabolism , Protein Kinase Inhibitors/administration & dosage , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Carcinoma , Cell Line, Tumor , Cell Proliferation/drug effects , Cisplatin/administration & dosage , Humans , Mitogen-Activated Protein Kinases/metabolism , Nasopharyngeal Carcinoma , Paclitaxel/administration & dosage , Proto-Oncogene Proteins c-akt/metabolism , TOR Serine-Threonine Kinases/metabolism
6.
Invest New Drugs ; 29(6): 1123-31, 2011 Dec.
Article in English | MEDLINE | ID: mdl-20467883

ABSTRACT

PURPOSE: Sunitinib is a multi-target receptor tyrosine kinase (RTK) inhibitor against vascular endothelial growth factor receptors, platelet-derived growth factor receptors (PDGFR), c-kit and RET. Several of these RTKs are known to be involved in the progression of nasopharyngeal carcinoma (NPC). Here, we evaluated the preclinical activities of sunitinib in NPC. METHOD: We determined the basal level of total and phosphorylated PDGFR, c-kit and RET by immunoblotting in a panel of five NPC cell lines. The effect of sunitinib on NPC cell proliferation was evaluated by MTT assay. We further studied the effect of sunitinib on NPC cell cycle progression and apoptosis. We investigated the in vitro and in vivo activities of sunitinib as single agent and in combination with cisplatin or docetaxel in NPC cell lines and tumor xenografts. RESULTS: Sunitinib exhibited dose-dependent growth inhibition in all NPC cell lines tested with IC(50) between 2-7.5 µM and maximum inhibition of over 97%. Sunitinib induced apoptosis and cell cycle arrest at G(0)/G(1) phase. In vitro, sunitinib moderately enhanced the growth inhibition of cisplatin or docetaxel. Single agent sunitinib demonstrated significant growth inhibition, reduced microvessel density and caused extensive tumor necrosis in a NPC xenograft model. However, concurrent administration of sunitinib and docetaxel induced severe toxicity in mice without enhanced antitumor effect. CONCLUSIONS: Single agent sunitinib demonstrated potent in vitro and in vivo growth inhibition in NPC. When combined with chemotherapy, sequential instead of concurrent administration schedule should be further explored.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Indoles/pharmacology , Nasopharyngeal Neoplasms/drug therapy , Protein Kinase Inhibitors/pharmacology , Pyrroles/pharmacology , Animals , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cisplatin/administration & dosage , Docetaxel , Dose-Response Relationship, Drug , Female , Humans , Indoles/administration & dosage , Mice , Mice, Nude , Nasopharyngeal Neoplasms/pathology , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/toxicity , Pyrroles/administration & dosage , Sunitinib , Taxoids/administration & dosage , Xenograft Model Antitumor Assays
7.
Invest New Drugs ; 28(4): 413-20, 2010 Aug.
Article in English | MEDLINE | ID: mdl-19471857

ABSTRACT

Phosphorylated (pi-) protein kinase B (AKT) is commonly expressed in nasopharyngeal carcinoma (NPC) cell lines and tissues, suggesting the involvement of AKT-mammalian target of rapamycin (mTOR) signaling in NPC carcinogenesis. This study evaluated the activity of an mTOR inhibitor, RAD001 (Everolimus, Novartis Pharma AG, Switzerland), in 5 NPC cell lines (HK1, HONE-1, CNE-1, CNE-2, C666-1), 2 cisplatin-resistant NPC cell lines and their respective parental cell lines (HK1-LMP1, HONE-1-EBV). RAD001 inhibited cell growth in a dose-dependent manner at nanomolar concentrations in all cell lines. HONE-1 was most sensitive to RAD001 (IC(50) = 0.63 nM, 60% maximal inhibition), while Het-1A (a normal esophageal epithelial cell line) was relatively resistant. No consistent relationship between sensitivity to RAD001 and basal expression of pi-mTOR and pi-p70S6 Kinase-1 (p70S6K) was found. Exposure to RAD001 at picomolar concentrations for 48 h resulted in reduction of pi-mTOR and pi-p70S6K1 expression, but increase in pi-AKT (Ser473) expression in HONE-1 and CNE-1 cell lines. RAD001 significantly induced apoptosis in HONE-1 cells, but has no effect on cell cycle progression. RAD001 exerted an additive to synergistic effect on cisplatin-induced growth inhibition in CNE-1 and HONE-1 cells, and could inhibit the growth of both cisplatin-resistant and cisplatin-sensitive NPC cell lines. In summary, combination of RAD001 and cisplatin maybe a useful therapeutic strategy in NPC. AKT upregulation following RAD001 treatment suggests the presence of a feedback loop on AKT signaling in NPC which warrants further investigation.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Cisplatin/pharmacology , Drug Resistance, Neoplasm/drug effects , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Nasopharyngeal Neoplasms/drug therapy , Protein Serine-Threonine Kinases/antagonists & inhibitors , Sirolimus/analogs & derivatives , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Cisplatin/therapeutic use , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor/methods , Drug Synergism , Everolimus , Humans , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Ribosomal Protein S6 Kinases, 70-kDa/metabolism , Sirolimus/pharmacology , Sirolimus/therapeutic use , TOR Serine-Threonine Kinases
8.
Carcinogenesis ; 30(12): 2085-94, 2009 Dec.
Article in English | MEDLINE | ID: mdl-19843642

ABSTRACT

Nasopharyngeal carcinoma (NPC) is an Asian-prevalent head and neck cancer with high invasiveness. Although several important risk factors for NPC development have been identified, there is currently no preventive strategy for NPC, even in endemic regions. Signal transducer and activator of transcription 3 (STAT3) has been implicated in NPC carcinogenesis, which may serve as a potential target for cancer prevention. Here, we examined the chemopreventive potential of Cucurbitacin I, a natural-occurring selective inhibitor of JAK/STAT3, in NPC models. We hypothesized that Cucurbitacin I would prevent NPC invasion and tumor formation. Our data demonstrated that brief exposure of NPC cells to Cucurbitacin I was sufficient to significantly reduce the in vitro clonogenicity and in vivo tumorigenicity of NPC cells. The chemopreventive potential of Cucurbitacin I was further demonstrated by pre-dosing of the animals with Cucurbitacin I prior to tumor inoculation, which was found to be able to suppress tumor growth up to 7 days post-inoculation. The anti-proliferation activity of Cucurbitacin I was accompanied by downregulation of phospho-STAT3 and STAT3 target gene expression (e.g. cyclin D1 and Mcl-1). Cucurbitacin I also reduced the invasiveness of invasive NPC cell lines with elevated STAT3 activation. Furthermore, our data demonstrated for the first time that Cucurbitacin I harbored potent anoikis-sensitization activity (i.e. sensitizing cancer cells to detachment-induced cell death) against human cancer. Taken together, our results suggested that Cucurbitacin I may be a potent chemopreventive agent for NPC with anti-invasion and anoikis-sensitizing activities.


Subject(s)
Anoikis , Carcinoma/metabolism , Carcinoma/pathology , Nasopharyngeal Neoplasms/metabolism , Nasopharyngeal Neoplasms/pathology , Triterpenes/metabolism , Animals , Carcinoma/drug therapy , Cell Line, Tumor , Cell Survival , Collagen/chemistry , Drug Combinations , Female , Humans , Laminin/chemistry , Mice , Mice, Nude , Nasopharyngeal Neoplasms/drug therapy , Neoplasm Invasiveness , Neoplasm Transplantation , Proteoglycans/chemistry , STAT3 Transcription Factor/metabolism , Triterpenes/pharmacology
9.
World J Gastroenterol ; 11(13): 1896-902, 2005 Apr 07.
Article in English | MEDLINE | ID: mdl-15800977

ABSTRACT

AIM: Recent studies suggested that cyclooxygenase-2 (COX-2) enhances tumor angiogenesis via upregulation of vascular endothelial growth factor (VEGF). Although COX-2 expression has been demonstrated in hepatocellular carcinoma (HCC), the significance of COX-2 in progression of HCC remains unclear. This study evaluated the clinico-pathological correlation of COX-2 level and its relationship with VEGF level in HCC. METHODS: Fresh tumor tissues were obtained from 100 patients who underwent resection of HCC. COX-2 protein expression was examined by immunohistochemistry, and quantitatively by an enzyme immunometric assay (EIA) of tumor cytosolic COX-2 levels. Tumor cytosolic VEGF levels were measured by an ELISA. RESULTS: Immunostaining showed expression of COX-2 in tumor cells. Tumor cytosolic COX-2 levels correlated with VEGF levels (r = 0.469, P<0.001). Correlation with clinicopathological features showed significantly higher tumor cytosolic COX-2 levels in the presence of multiple tumors (P = 0.027), venous invasion (P = 0.030), microsatellite lesions (P = 0.037) and advanced tumor stage (P = 0.008). Higher tumor cytosolic COX-2 levels were associated with worse patient survival. CONCLUSION: This study shows that elevated tumor COX-2 levels correlate with elevated VEGF levels and invasiveness in HCC, suggesting that COX-2 plays a significant role in the progression of HCC.


Subject(s)
Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Prostaglandin-Endoperoxide Synthases/metabolism , Adolescent , Adult , Aged , Biomarkers, Tumor/metabolism , Cyclooxygenase 2 , Cytosol/enzymology , Female , Humans , Male , Membrane Proteins , Middle Aged , Neoplasm Invasiveness , Prognosis , Vascular Endothelial Growth Factor A/metabolism
10.
Radiology ; 235(2): 478-86, 2005 May.
Article in English | MEDLINE | ID: mdl-15798156

ABSTRACT

PURPOSE: To evaluate morphologic characteristics and cell viability of radiofrequency ablation zones in porcine liver. MATERIALS AND METHODS: Approval of the study protocol was obtained from the Ethics Committee on Use of Live Animals for Teaching and Research at University of Hong Kong. Internally cooled electrodes were used to produce 120 ablated zones ex vivo and 60 ablated zones in vivo with single electrodes (1-, 2-, and 3-cm exposed lengths) or clustered electrodes (1.0-, 2.0-, and 2.5-cm exposed lengths) at 4, 8, 12, and 16 minutes of ablation (ex vivo) and 8 and 12 minutes of ablation (in vivo). Morphologic measurements of each ablated zone were performed. Cell viability in each ablated zone was assessed qualitatively with histochemical staining and quantitatively with measurement of intracellular adenosine 5'-triphosphate (ATP) concentration. RESULTS: Exposed length of electrode (coefficient = 0.79, standard error = 0.04, P < .001), duration of ablation (coefficient = 0.14, standard error = 0.01, P < .001), and clustered electrode design (coefficient = 1.21, standard error = 0.05, P < .001) were independent factors that affected minimal transverse diameter and volume of ablated zone in ex vivo study. Similar morphologic characteristics existed among ablated zones in in vivo study. Mean distance of ablation beyond the electrode tip remained constant (ex vivo, 1.0 cm +/- 0.08 [standard deviation]; in vivo, 0.5 cm +/- 0.05) regardless of different ablation conditions. Histochemical staining revealed no viable hepatocytes from center to margins of white zone in each ablated area. Mean intracellular ATP concentration in margins of white zone (9.5 x 10(-12) mol/microg DNA +/- 1.43) was lower than that in red zone (4088 x 10(-12) mol/microg DNA +/- 65.97, P < .001) and in adjacent normal liver (4528 x 10(-12) mol/microg DNA +/- 52.74, P < .001). CONCLUSION: Distance of ablation beyond the tip of the electrode remained constant (ex vivo, 1.0 cm; in vivo, 0.5 cm) with different conditions of ablation. Complete and uniform cellular destruction was achieved in the white zone of ablated area.


Subject(s)
Catheter Ablation/instrumentation , Cell Survival/physiology , Electrodes , Liver/surgery , Adenosine Triphosphate/analysis , Animals , Catheter Ablation/methods , Equipment Design , Liver/pathology , Organ Culture Techniques , Swine , Temperature , Tissue Culture Techniques , Treatment Outcome
11.
Clin Cancer Res ; 10(12 Pt 1): 4150-7, 2004 Jun 15.
Article in English | MEDLINE | ID: mdl-15217952

ABSTRACT

PURPOSE: Thrombospondin 1 (THBS 1) is a matricellular protein capable of modulating angiogenesis. However, the actual role of THBS 1 in angiogenesis and tumor progression remains controversial. Hepatocellular carcinoma (HCC) is a hypervascular tumor characterized by neovascularization. The significance of THBS 1 in HCC remains unknown. In this study, the significance of THBS 1 in HCC was evaluated by correlating its expression with clinicopathological data. The possible role of THBS 1 in the angiogenesis of HCC was also studied by correlating its expression with vascular endothelial growth factor (VEGF) expression. EXPERIMENTAL DESIGN: Sixty HCC patients were recruited in this study. THBS 1 and VEGF protein expression in tumorous livers were localized by immunohistochemical staining and quantified by ELISA. THBS 1 mRNA was quantified by quantitative reverse transcription-PCR. RESULTS: Immunohistochemical staining of THBS 1 was positive in HCC cells in 51.7% of patients and in stromal cells in 65% of patients. Tumor THBS 1 protein level was significantly correlated with its mRNA expression (P = 0.001) and was significantly correlated with tumor VEGF protein levels (P = 0.001). Its expression was significantly associated with the presence of venous invasion (P = 0.008) and advanced tumor stage (P = 0.049). High THBS 1 expression was also a prognostic marker of poor survival in HCC patients. CONCLUSIONS: This study shows that high expression of THBS 1 is associated with tumor invasiveness and progression in HCC. THBS 1 appears to be a proangiogenic factor that stimulates angiogenesis in HCC in view of its positive correlation with VEGF expression.


Subject(s)
Carcinoma, Hepatocellular/metabolism , Liver Neoplasms/metabolism , Thrombospondin 1/biosynthesis , Aged , Enzyme-Linked Immunosorbent Assay , Female , Humans , Immunohistochemistry , Male , Middle Aged , Neovascularization, Pathologic , Prognosis , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Time Factors , Treatment Outcome , Vascular Endothelial Growth Factor A/biosynthesis
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