Biomedical subjects

Sheung Tat Fan

Publications and source records attributed to Sheung Tat Fan.

At least 19 recordsLinked to original sources

PubMed2007

Tumor size and operative risks of extended right-sided hepatic resection for hepatocellular carcinoma: implication for preoperative portal vein embolization.

HYPOTHESIS: Major hepatic resection for hepatocellular carcinoma (HCC) is associated with high operative morbidity and mortality, especially in patients with underlying chronic liver disease. The present study evaluated the factors associated with increased operative risks in patients who underwent extended right-sided hepatic resection for HCC. DESIGN: Retrospective study. SETTING: Tertiary referral center. PATIENTS: A retrospective study was performed on 172 patients who underwent extended right-sided hepatic resection of more than 4 Couinaud segments for HCC during a 16-year period (January 1, 1989, to December 31, 2004) to evaluate the clinical factors associated with operative morbidity and mortality. MAIN OUTCOME MEASURE: Risk factors associated with hospital mortality and major operative morbidity. RESULTS: The overall major morbidity and hospital mortality rates were 14.0% and 8.1%, respectively. On multivariate analysis, small tumor size, conventional-approach hepatectomy, Child-Pugh grade B cirrhosis, and preexisting tumor rupture were the independent factors significantly associated with an increased risk of operative mortality. Discriminant analysis showed that a tumor size smaller than 10 cm significantly increased the risk of operative mortality compared with larger tumors (17.2% vs 3.5%; P = .046). CONCLUSIONS: Anterior approach is the preferred technique for extended right-sided hepatic resection for HCC. Increased risk of operative mortality was identified in patients who had a small tumor, which was associated with the resection of a large volume of functioning liver parenchyma. Preoperative portal vein embolization should be considered in this group of patients to enhance atrophy of the right lobe and hypertrophy of the future liver remnant to minimize the operative risk.

Adolescent↗

PubMed2007

Identification of hepatitis B virus-specific lymphocytes in human liver grafts from HBV-immune donors.

Both animal and human studies have demonstrated the adoptive transfer of immunity against hepatitis B virus (HBV) through liver transplantation that may be attributed to the presence of HBV-specific immunocompetent cells of donor origin in liver grafts. In this study, we characterized the resident lymphocytes in 41 human liver grafts by immunohistochemical staining and flow cytometry and directly identified the intragraft HBV-specific lymphocytes in relation to the donor's and subsequent recipient's immunity using enzyme-linked immunospot assay. A significant number of HBV-specific T and B cells were detectable in 59.4% (19/32) and 28.1% (9/32), respectively, of liver grafts from HBV-immune donors. The presence of various HBV-specific lymphocytes was closely associated with each other and with a higher serum titer of antibody against hepatitis B surface antigen (anti-HBs) in donors (P < 0.05). After liver transplantation, 17 of 35 (48.6%) patients with chronic HBV infection showed a spontaneous anti-HBs production, which was significantly associated with a higher number of donor-derived T lymphocytes specific for hepatitis B surface antigen (P = 0.043). In conclusion, the presence of considerable numbers of donor-derived HBV-specific immunocompetent cells in grafts may account for the adoptive transfer of HBV immunity through liver transplantation.

Adult↗

PubMed2007

Effect of side and size of graft on surgical outcomes of adult-to-adult live donor liver transplantation.

By virtue of size, the right liver graft has become the workhorse of adult-to-adult live donor liver transplantation (ALDLT). Although favorable results of left liver ALDLT have also been reported, a head-to-head comparison of these 2 graft types both containing the middle hepatic vein had not been made. In this study, we compared the outcomes of 29 right liver and 16 left liver ALDLTs of comparable graft weight to recipient estimated standard liver volume ratio (GW/ESLV, 36.9% and 36.4%, respectively). All liver grafts contained the middle hepatic vein. The Model for End-Stage Liver Disease (MELD) score and urgency for transplantation of both groups were similar. Postoperatively, left liver donors had significantly lower international normalized ratios and serum total bilirubin levels and no complications. Although the rate of return of international normalized ratios for recipients of both groups were comparable, left liver recipients had significantly higher serum total bilirubin and serum aminotransferase levels. Intensive care unit stay of the left liver recipients was longer than that of the right liver recipients (8.5 days versus 4 days, P = 0.007). Hospital mortality was 6.9% (2/29) for the right liver group and 18.8% (3/16) for the left liver group (P = 0.330). Safety profile of donor left hepatectomy was higher. However, despite similar GW/ESLV, the more arduous recovery and higher mortality rate of left liver recipients raise the caution of assuming the gram-to-gram equivalence of right and left liver grafts.

Adult↗

PubMed2007

Atypical localization of membrane type 1-matrix metalloproteinase in the nucleus is associated with aggressive features of hepatocellular carcinoma.

Membrane type 1-matrix metalloproteinase (MT1-MMP) is a versatile proteinase and recent studies indicated it could be internalized. Our earlier study found that it is overexpressed in hepatocellular carcinoma (HCC) and could promote intrahepatic metastasis. The present study was conducted to examine its subcellular localization and its clinicopathological significance in HCC after curative partial hepatectomy. Localization of MT1-MMP in 101 pairs of HCCs and their adjacent liver tissues, and 8 normal liver tissues was examined by the immunohistochemical method. MT1-MMP protein was localized at membrane and cytoplasm of hepatocytes in the normal and tumor adjacent liver tissues. In contrast, the HCCs were highly heterogeneous with variable degrees of membrane, cytoplasmic, and even nuclear staining. Interestingly, patients with presence of nuclear MT1-MMP were associated with poor overall survival (log-rank test, P=0.043) and large tumor size (>5 cm) (Fisher's exact test, P=0.031). Subcellular distribution was further demonstrated by Western blotting and immunofluorescence with Hep3B stable transfectant overexpressing MT1-MMP. Western blot analyses of subcellular fractions confirmed a differential partitioning of various post-translationally modified MT1-MMP in these fractions. Different antibodies corroborated the presence of MT1-MMP in the nuclear fraction. Concomitant nuclear presence of MMP2 with MT1-MMP further indicated its potential involvement in the nuclear functions. MT1-MMP co-localized with caveolin-1 at the perinuclear region, suggesting nuclear translocation of MT1-MMP via caveolae-mediated endocytosis. In summary, the association of nuclear MT1-MMP with aggressive tumor features including poor prognosis and large tumor expands its functional repertoire and further indicates a new functional role of MMPs within nuclei of tumor cells.

Adolescent↗

PubMed2007

Toward current standards of donor right hepatectomy for adult-to-adult live donor liver transplantation through the experience of 200 cases.

OBJECTIVE: To define the current standards of donor right hepatectomy, including the middle hepatic vein for adult-to-adult live donor liver transplantation. SUMMARY BACKGROUND DATA: Donor morbidity and mortality are inevitable given the ultra-major nature of the donor operation. Results from a matured center could define the true impact of this donor procedure most accurately. PATIENTS AND METHODS: From May 9, 1996 to April 13, 2005, 200 consecutive donors underwent donor right hepatectomy at the University of Hong Kong Medical Center. All right liver grafts except one included the middle hepatic vein. Donor characteristics, operation time, blood loss, hospital stay, laboratory results, and complications graded by Clavien's classification divided into four eras (each consecutive 50 cases) were compared. RESULTS: Donor characteristics of the four eras were generally comparable. Operative outcomes improved progressively through the four eras. From era 1 to era 4, operation time decreased from 598 minutes (range, 378-932 minutes) to 391 minutes (range, 304-635 minutes). Blood loss also decreased from 500 mL (200-1600 mL) of era 1 to 251 mL (range, 95-595 mL) of era 4. Overall complication rate was 20.5% (41 of 200). Complications rates from eras 1 to 4 were 34%, 16%, 16%, and 16%, respectively. The most common complications were of grade I (24 of 41, 58.5%). A late donor death occurred in era 4 from the development of a duodenocaval fistula 10 weeks postoperation, giving a donor mortality of 0.5% (1 of 200). CONCLUSIONS: This study validated the estimated morbidity and mortality of donor right hepatectomy of 20% and 0.5%, respectively. The data provide reference for counseling potential donors and setting the standards of donor right hepatectomy in the current era.

Adolescent↗

PubMed2007

Difference in tumor invasiveness in cirrhotic patients with hepatocellular carcinoma fulfilling the Milan criteria treated by resection and transplantation: impact on long-term survival.

SUMMARY BACKGROUND DATA: Some previous studies demonstrated better survival after transplantation for small hepatocellular carcinoma (HCC) compared with resection, but the influence of differences in tumor invasiveness between transplanted and resected patients has not been studied. This study compared the tumor characteristics of patients with HCC within the Milan criteria treated by resection or transplantation, and elucidated their impact on long-term survival. PATIENTS AND METHODS: Tumor characteristics and long-term survival of 204 cirrhotic patients with resection and 43 cirrhotic patients with transplantation for HCC within the Milan criteria were compared. A multivariate analysis was performed to determine the prognostic factors of survival in all patients with resection or transplantation. RESULTS: Tumors in the transplanted group were associated with lower incidence of high-grade tumors, microscopic venous invasion, and microsatellite nodules. The overall 5-year survival was better in the transplantation group than the resection group (81% vs. 68%, P = 0.017). However, there were no significant differences in survival between the two groups when stratified according to presence or absence of venous invasion. Multivariate analysis showed that hepatitis C virus serology, tumor size, tumor number, and microscopic venous invasion, but not resection or transplantation, were of prognostic significance. CONCLUSIONS: There were significant differences in tumor invasiveness in HCC treated by transplantation and resection as a result of selection bias, even in patients with the tumors fulfilling the Milan criteria. When the different tumor invasiveness was taken into account, there was no significant difference in the long-term survival after resection or transplantation.

Adolescent↗

PubMed2007

Marked suppression of tumor growth by FTY720 in a rat liver tumor model: the significance of down-regulation of cell survival Akt pathway.

We aim to investigate the anticancer effect of a novel immunomodulator FTY720 on a rat orthotopic liver tumor model. A buffalo rat orthotopic liver tumor model was established by injection of a buffalo hepatoma cell line MH7777 into the right portal vein. FTY720 was administered by intraperitoneal injection starting at 10 days after tumor cell injection at a dosage of 5 mg/kg/day. FTY720 markedly suppressed tumor growth and inhibited tumor progression by selective induction of apoptosis of tumor cells via down-regulation of phospho-Akt(ser473) and up-regulation of cleaved caspase-3, together with decrease of focal adhesion kinase. Moreover, the proliferation index of tumor cells was significantly reduced to 15.92+/-5.03% by FTY720 compared with that of 42.92+/-4.47% in the control group (p<0.001). In addition, we confirmed that FTY720 caused no effect on infiltrated lymphocyte in tumor tissue. We conclude that FTY720 is an effective anticancer agent for liver tumor in a rat model without affecting the immune system of the host.

Animals↗

PubMed2006

Radiofrequency ablation for hepatocellular carcinoma and metastatic liver tumors: a comparative study.

BACKGROUND: This study compared the effectiveness of radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) and liver metastases. METHODS: We compared the outcomes of 240 patients with HCC and 44 patients with liver metastases treated with RFA. Data were prospectively collected and retrospectively analyzed. Effects of different variables on recurrences were studied. RESULTS: A total of 406 tumor nodules were treated. The median size of the largest ablated tumor was 2.5 cm, and the median tumor number was 1. Complete tumor ablation was achieved in 91.2%. Local recurrence rate was 15.4% after a median follow-up of 24.5 months. There was no significant impact of tumor pathology on local recurrence. However, patients with liver metastasis had higher extrahepatic recurrence rate (P = 0.019) and shorter disease-free survival (P = 0.007). Patients with multiple tumors had higher local (P = 0.047) and extrahepatic (P = 0.019) recurrence rates than those with a solitary tumor. Tumor size had an impact on local recurrence rate only in patients with liver metastasis with a higher rate in those with tumor > 2.5 cm in diameter (P = 0.028). CONCLUSIONS: Tumor pathology does not appear to have a significant impact on local recurrence rates. RFA is effective in local tumor control for both HCC and liver metastasis.

Adolescent↗

PubMed2006

Regulation of angiogenesis by Id-1 through hypoxia-inducible factor-1alpha-mediated vascular endothelial growth factor up-regulation in hepatocellular carcinoma.

PURPOSE: Metastasis is commonly associated with poor prognosis of hepatocellular carcinoma (HCC). Being an important angiogenic factor, vascular endothelial growth factor (VEGF) plays a central role in HCC growth and metastasis. Recently, Id-1 (inhibitor of differentiation/DNA synthesis) has been suggested to be a key factor in cancer progression but the molecular mechanism remains unknown. EXPERIMENTAL DESIGN: We first showed that overexpression of Id-1 was correlated with HCC metastasis (P < 0.001) and its expression was significantly correlated with VEGF expression by tissue microarray. By ectopic transfection of Id-1 into HCC cells, Id-1 was able to induce VEGF secretion through activation of VEGF transcription. RESULTS: Increased VEGF secretion in Id-1 transfectants induced morphologic change and proliferation of human umbilical vascular endothelial cell resulting in promotion of angiogenesis. Id-1 induced transcriptional activation of VEGF by stabilizing hypoxia-inducible factor-1alpha protein. Down-regulation of Id-1 by antisense approach led to suppression of hypoxia-inducible factor-1alpha-mediated VEGF production. In addition, Id-1 suppression resulted in retardation of cell invasion through down-regulation of VEGF. CONCLUSIONS: Id-1 is a novel angiogenic factor for HCC metastasis and down-regulation of Id-1 may be a novel target to inhibit HCC metastasis through suppression of angiogenesis.

Animals↗

PubMed2006

Signal transducers and activators of transcription 5b activation enhances hepatocellular carcinoma aggressiveness through induction of epithelial-mesenchymal transition.

Poor prognosis of hepatocellular carcinoma (HCC) is associated with a high potential of vascular invasion and metastasis. Epithelial-mesenchymal transition (EMT) is a key event in the tumor invasion process. Recently, signal transducers and activators of transcription 5 (STAT5) has been linked to tumor progression by EMT induction. However, the precise roles of STAT5 genes (STAT5a and STAT5b) in human epithelial cancers have not been elucidated clearly. The aim of this study is to analyze the roles of STAT5 isoforms in HCC progression using HCC clinical samples. We showed that activation of STAT5b, but not STAT5a, was found in HCC clinical samples and its expression was significantly associated with younger age (P = 0.037), advanced tumor stages (P = 0.003), venous infiltration (P = 0.016), microsatellite formation (P = 0.024), multiple tumor nodules (P = 0.02), and poor patient survival. To specifically investigate the mechanism underlying constitutive activation of STAT5b in HCC, EGFP-HBX was introduced into Huh-7 cells. STAT5b activation in HCC is at least partially mediated by HBX activation. Ectopic STAT5b transfection conferred increased HCC cell motility and invasiveness by induction of EMT changes. In conclusion, STAT5b activation enhanced HCC aggressiveness by induction of EMT, which was possibly mediated by HBX activation. STAT5b could serve as a novel molecular target for HCC treatment.

Adolescent↗

PubMed2006

Live donor liver transplantation in adults.

Live donor liver transplantation (LDLT) was initiated in 1988 for children recipients. Its application to adult recipients was limited by graft size until the first right liver LDLT was performed in Hong Kong in 1996. Since then, right liver graft has become the major graft type. Despite rapid adoption of LDLT by many centers, many controversies on donor selection, indications, techniques, and ethics exist. With the recent known 11 donor deaths around the world, transplant surgeons are even more cautious than the past in the evaluation and selection of donors. The need for routine liver biopsy in donor evaluation is arguable but more and more centers opt for a policy of liberal liver biopsy. Donation of the middle hepatic vein (MHV) in the right liver graft was considered unsafe but now data indicate that the outcome of donors with or without MHV donation is about equal. Right liver LDLT has been shown to improve the overall survival rate of patients with chronic liver disease, acute or acute-on-chronic liver failure and hepatocellular carcinoma waiting for liver transplantation. The outcome of LDLT is equivalent to deceased donor liver transplantation despite a smaller graft size and higher technical complexity.

Adult↗

PubMed2006

Increased expression of glycosyl-phosphatidylinositol anchor attachment protein 1 (GPAA1) is associated with gene amplification in hepatocellular carcinoma.

Glycosyl-phosphatidylinositol (GPI) anchor attachment protein 1 (GPAA1) transcript level was frequently up-regulated in our earlier study on gene expression profile. We therefore analyzed the potential involvement of GPAA1 in hepatocellular carcinoma (HCC) as GPAA1 gene locates at chromosome 8q24.3 which chromosome region is frequently amplified in HCCs. In this study, we observed that GPAA1 transcript in the HCCs (n = 93) showed a significantly higher expression level compared with their paralleled adjacent nontumor liver tissues, cirrhosis (n = 15) and normal (n = 16) liver tissues using real-time quantitative RT-PCR (p < 0.005). We also demonstrated that GPAA1 protein up-regulation was common in HCCs (90%, 9/10), and GPAA1 gene was frequently amplified (73%, 11/15) using quantitative microsatellite analysis. Increased GPAA1 expression was significantly associated with HCCs poor cellular differentiation (p = 0.011) and poor prognosis (p = 0.010). We then modulated the GPAA1 expression level in HCC cells (Hep3B) by transfection experiments, which was shown to positively regulate cell adhesion ability (p = 0.004) and proliferation rate (p = 0.037). Our data revealed GPAA1 gene amplification with overexpression of RNA and protein in HCC. GPAA1 is a potential amplification target of chromosome 8q and responsible to regulate tumor cells behavior.

Aged↗

PubMed2006

Twist overexpression correlates with hepatocellular carcinoma metastasis through induction of epithelial-mesenchymal transition.

PURPOSE: Hepatocellular carcinoma (HCC) is a rapidly growing tumor associated with a high propensity for vascular invasion and metastasis. Epithelial-mesenchymal transition (EMT) is a key event in the tumor invasion process. Recently, Twist has been identified to play an important role in EMT-mediated metastasis through the regulation of E-cadherin expression. However, the actual role of Twist in tumor invasiveness remains unclear. The purpose of this study is to investigate the expression and possible role of Twist in HCC. EXPERIMENTAL DESIGN: We evaluated Twist and E-cadherin expression in HCC tissue microarray of paired primary and metastatic HCC by immunohistochemical staining. The role of Twist in EMT-mediated invasiveness was also evaluated in vitro in HCC cell lines. RESULTS: We first showed that overexpression of Twist was correlated with HCC metastasis (P=0.001) and its expression was negatively correlated with E-cadherin expression (P=0.001, r=-0.443) by tissue microarray. A significant increase of Twist at the mRNA level was also found in metastatic HCC cell lines MHCC-97H, MHCC-97L, and H2M when compared with nonmetastatic Huh-7, H2P, and PLC cell lines. The MHCC-97H cell line, which has a higher metastatic ability, was found to have a higher level of Twist than MHCC-97L. Accompanied with increased Twist expression in the metastatic HCC cell lines when compared with the nonmetastatic primary ones, we found decreased E-cadherin mRNA expression in the metastatic HCC cell lines. By ectopic transfection of Twist into PLC cells, Twist was able to suppress E-cadherin expression and induce EMT changes, which was correlated with increased HCC cell invasiveness. CONCLUSION: This study shows that Twist overexpression was correlated with HCC metastasis through induction of EMT changes and HCC cell invasiveness.

Cadherins↗

PubMed2006

Rac activation is associated with hepatocellular carcinoma metastasis by up-regulation of vascular endothelial growth factor expression.

PURPOSE: Hepatocellular carcinoma (HCC) is associated with a propensity for vascular invasion and metastasis, which contribute to poor prognosis. Angiogenesis is a crucial process contributing to tumor growth and metastasis. Recently, Rac has been suggested to play a role in angiogenesis. However, the actual role of Rac in HCC angiogenesis remains unclear. Given that vascular endothelial growth factor (VEGF) is an important angiogenic factor in HCC, the purpose of this study was to evaluate the possible correlation between Rac activation and VEGF expression in HCC tumor samples, as well as the mechanism involved in Rac-induced HCC angiogenesis. EXPERIMENTAL DESIGN: We evaluated Rac and VEGF expression in the HCC tissue microarray of paired primary and metastatic HCC samples using immunohistochemical staining. The role of Rac-induced HCC angiogenesis was also evaluated in vitro in HCC cell lines. RESULTS: We first showed that activation of Rac was correlated with HCC metastasis (P<0.001), and its expression was significantly correlated with VEGF expression by tissue microarray. Ectopic Rac-dominant active transfection in Hep3B cells increased VEGF secretion, which induced the morphologic change and proliferation of human umbilical vein endothelial cells, resulting in the promotion of angiogenesis. Rac induced the transcriptional activation of VEGF by direct interaction with hypoxia-inducible factor-1alpha (HIF-1alpha) expression. In hypoxic conditions, Rac promoted angiogenesis through an increase in HIF-1alpha stabilization. CONCLUSION: This study shows that Rac is a novel angiogenic factor for HCC through the enhancement of HIF-1alpha protein stability, which provides a possible therapeutic target in the development of inhibitors of angiogenesis.

Carcinoma, Hepatocellular↗

PubMed2006

Liver intestine-cadherin (CDH17) haplotype is associated with increased risk of hepatocellular carcinoma.

PURPOSE: Hepatocellular carcinoma (HCC), the most common form of liver cancer, is a leading cause of cancer death worldwide. We previously showed that aberrant mRNA splicing of the liver intestine-cadherin gene CDH17 in liver tissues was triggered by the specific constellation of two CDH17 single nucleotide polymorphisms (651T and IVS6+35G). CDH17 aberrant splicing was highly associated with tumor dissemination and shorter survival of HCC patients. Consequently, it is highly relevant to assess whether the presence of these single nucleotide polymorphisms in the general population represents a risk to the development of HCC. EXPERIMENTAL DESIGN: We conducted a case-control study including 164 HCC and 99 cirrhosis patients and 293 healthy controls. Genotyping was done by PCR and direct sequencing. Odds ratio (OR) and chi2 analysis were used to analyze genotypes and haplotypes. RESULTS: Genotypes 651TT [OR, 2.62; 95% confidence interval (95% CI), 1.34-5.03] and IVS6+35 GG (OR, 1.95; 95% CI, 1.04-3.62) were highly associated with HCC disease. The 651T (C>T) and IVS6+35G (A>G) alleles were also overrepresented in HCC patients and, in particular, the T-G haplotype was the most prevalent in HCC patients when compared with healthy controls (OR, 1.57; 95% CI, 1.167-2.109; P=0.004), which was in agreement with the aberrant splicing observed in tumor tissues. There was no significant difference in genotype and allele frequencies between cirrhosis patients and controls. CONCLUSION: The functional T-G haplotype of CDH17 (651 C>T and IVS6+35A>G) is a genetic susceptibility factor for the development of HCC in a Chinese population.

Alleles↗

PubMed2006

Suppression of hypoxia inducible factor-1alpha (HIF-1alpha) by YC-1 is dependent on murine double minute 2 (Mdm2).

Inhibition of HIF-1alpha activity provides an important strategy for the treatment of cancer. Recently, 3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole (YC-1) has been identified as an anti-HIF-1alpha drug in cancer therapy with unclear molecular mechanism. In the present study, we aimed to investigate the effect and mechanism of YC-1 on HIF-1alpha in a hepatocellular carcinoma cell line under hypoxic condition, which was generated by incubating cells with 0.1% O(2). The phenotypic and molecular changes of cells were determined by cell proliferation assay, apoptosis assay, luciferase promoter assay, and Western blot analysis. YC-1 arrested tumor cell growth in a dose-dependent manner, whereas it did not induce cell apoptosis. Hypoxia-induced upregulation of HIF-1alpha was suppressed by YC-1 administration. YC-1 inhibited HIF-1alpha protein synthesis under normoxia and affected protein stability under hypoxia. YC-1 suppressed the expression of total and phosphorylated forms of murine double minute 2 (Mdm2), whereas this inhibitory effect was blocked by overexpression of Mdm2. In conclusion, YC-1 suppressed both protein synthesis and stability of HIF-1alpha in HCC cells, and its inhibitory effects on HIF-1alpha were dependent on Mdm2.

Antineoplastic Agents↗

PubMed2006

Blockage of epidermal growth factor receptor by quinazoline tyrosine kinase inhibitors suppresses growth of human hepatocellular carcinoma.

Epidermal growth factor receptor (EGFR) is highly expressed in many human tumors including hepatocellular carcinoma (HCC). Therefore, inhibition of EGF receptors could be a potential target for anticancer therapy. In this study, we investigated the effects of two EGFR tyrosine kinase inhibitors, PD153035 and its analogue 4-[[3-chloro-4-fluorophenyl]amino]-6,7-dimethoxyquinazoline hydrochloride (ANAPD) on human HCC cell lines by cell proliferation assay, flow cytometry and Western blot. Our results demonstrated that both EGFR inhibitors inhibited tumor cell growth in a dose-dependent manner, but ANAPD was more potent than PD153035. These specific inhibitors not only blocked EGF-stimulated EGFR autophosphorylation but also targeted EGFR signaling including MAPK and Akt pathways. Furthermore, EGFR inhibitors induced a delay in cell cycle progression and a G(1) arrest together with a partial G(2)/M block. EGFR inhibitors also induced tumor cells to undergo apoptosis. In conclusion, this study demonstrated that both PD153035 and ANAPD inhibit tumor cell growth in HCC through inhibition of EGFR signaling pathway, and ANAPD is a more potent inhibitor than PD153035. This suggested that blockage of EGF receptors may provide an effective therapeutic approach for human HCC and ANAPD could be a potential drug candidate for the treatment of HCC.

Apoptosis↗

PubMed2006

Platelet activation during tumor development, the potential role of BDNF-TrkB autocrine loop.

Platelets are an important place for the storage of angiogenic factors, such as vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF). The present study aims to investigate the interaction between BDNF-TrkB pathway and platelet activation during tumor development. In an orthotopic hepatocellular carcinoma (HCC) model, increased levels of serum and plasma BDNF were detected with tumor progression. Higher numbers of CD62P+ and TrkB+ platelets were found in the tumor-bearing rats. In the in vitro setting, tumor-conditioned-medium (TCM) and BDNF recombinant protein stimulated CD62P upregulation and subsequent BDNF release in the freshly isolated platelets, whereas this effect could be inhibited by TrkB blockade. TCM and BDNF culture augmented the expression of heat shock protein 90 (Hsp90) in the platelets, which could be reversed by TrkB blockade. In conclusion, this study suggested the presence of BDNF-TrkB autocrine loop in platelets and its importance in regulating platelet activation during tumor development.

Animals↗