Gallbladder Cancer Metastasis Research Articles

Metastatic Gallbladder Cancer Masquerading as Primary Colon Malignancy

We report a 69-year-old female with personal history of gallbladder cancer who was referred to our institution with a circumferential obstructing intra-luminal colonic mass that possessed pathological features common to both primary colorectal as well as gallbladder cancer, which posed a significant diagnostic and treatment challenge. This case reviews the method and rationale for arriving at the final diagnosis of gallbladder cancer metastasis and highlights the importance of modern molecular diagnostics as well as close communication between the pathologist and surgeon in its process. demonstrated findings consistent with adenocarcinoma, low- grade invasion into peri-muscular soft tissue, and was positive for lymphovascular and perineural invasion. No lymph nodes were obtained. For reasons unclear to the authors, she did not undergo repeat laparotomy for radical resection given her stage II disease (T2NxMx) and was instead followed clinically. Seven months later, she was found to have developed a 1.6cm enhancing lesion in the left hepatic lobe and was started on systemic chemotherapy with gemcitabine and capecitabine for 1.5 years without biopsy confirmation. She did well on this treatment with radiographic resolution of the liver lesion until 1 month prior to presentation, when she developed abdominal pain. A colonoscopy was performed that revealed a clearly intra-luminal, large circumferential friable mass in the sigmoid colon with luminal narrowing that did not allow passage of the scope. The lesion was biopsied and tattooed. Pathological evaluation of the lesion revealed invasive moderately differentiated, mucinous adenocarcinoma. At this point the origin of the tumor was unclear and the differential diagnosis included primary colorectal versus metastatic gallbladder. The patient was

Impact of Radiofrequency Ablation on Malignant Biliary Strictures: Results of a Collaborative Registry.

Radiofrequency ablation of malignant biliary strictures has been offered for the last 3 years, but only limited data have been published. To assess the safety, efficacy, and survival outcomes of patients receiving endoscopic radiofrequency ablation. Between April 2010 and December 2013, 69 patients with unresectable neoplastic lesions and malignant biliary obstruction underwent 98 radiofrequency ablation sessions with stenting. A total of 69 patients (22 male, aged 66.1 ± 13.3) were included in the registry. The etiology of malignant biliary stricture included unresectable cholangiocarcinoma (n = 45), pancreatic cancer (n = 19), gallbladder cancer (n = 2), gastric cancer (n = 1), and liver metastasis from colon cancer (n = 3). Seventy-eight percentage of patients had prior chemotherapy. All strictures were stented post-radiofrequency ablation with either plastic stents or metal stents. The mean stricture length treated was 14.3 mm. There was a statistically significant improvement in stricture diameter post-ablation (p < 0.0001). The likelihood of stricture improvement was significantly greater in pancreatic cancer-associated strictures [RR 1.8 (95 % 1.03-5.38)]. Seven patients (10 %) had adverse events, not linked directly to radiofrequency ablation. Median survival was 11.46 months (6.2-25 months). Radiofrequency ablation is effective and safe in malignant biliary obstruction and seems to be associated with improved survival.

Baicalein inhibits progression of gallbladder cancer cells by downregulating ZFX.

Baicalein, a widely used Chinese herbal medicine, has multiple pharmacological activities. However, the precise mechanisms of the anti-proliferation and anti-metastatic effects of baicalein on gallbladder cancer (GBC) remain poorly understood. Therefore, the aim of this study was to assess the anti-proliferation and anti-metastatic effects of baicalein and the related mechanism(s) on GBC. In the present study, we found that treatment with baicalein induced a significant inhibitory effect on proliferation and promoted apoptosis in GBC-SD and SGC996 cells, two widely used gallbladder cancer cell lines. Additionally, treatment with baicalein inhibited the metastasis of GBC cells. Moreover, we demonstrated for the first time that baicalein inhibited GBC cell growth and metastasis via down-regulation of the expression level of Zinc finger protein X-linked (ZFX). In conclusion, our studies suggest that baicalein may be a potential phytochemical flavonoid for therapeutics of GBC and ZFX may serve as a molecular marker or predictive target for GBC.

Skeletal Metastasis in Gallbladder Cancer from a High-Volume Tertiary Care Center of North India: a Series of Rare Occurrence

Gallbladder carcinoma is usually characterized by late diagnosis and poor prognosis. Skeletal metastases in gallbladder cancer have been rarely reported in literature. In this study, we evaluated the incidence of skeletal metastasis in gallbladder cancer at our high-volume center and their clinical presentation, radiological imaging, treatment received, outcome, and survival. Records of all gallbladder carcinoma patients registered in our department from October 2007-October 2012 were retrospectively reviewed to identify gallbladder cancer patients with skeletal metastasis and their data was collected and analyzed. Out of 340 cases of gallbladder carcinoma, 189 (55.58 %) were having stage IV disease. Of these, seven (2.1 %) patients had cytologically proven skeletal metastasis. All seven patients had advanced loco-regional abdominal disease with coexistent liver metastasis. Presenting symptoms were predominantly weight loss and back pain with markedly elevated serum alkaline phosphatase (median = 1231 IU/ml). Dorsolumbar vertebral metastasis was the most common site of skeletal metastasis in our series (5/7), followed by pelvic bone (2/7) while skull and sternal metastasis were present in one patient each. All these patients had short median survival (median = 30 days, range = 15-60 days). Incidence of skeletal metastasis in gallbladder cancer is very low (2.1 %). Axial skeleton was the most common site of bone metastasis. Gallbladder cancer with skeletal metastasis portends poor prognosis with rapidly fatal course.

ATP5b and β2-microglobulin are predictive markers for the prognosis of patients with gallbladder cancer.

The differences in clinical, pathological, and biological characteristics between adenocarcinoma (AC) and squamous cell/adenosquamous carcinoma (SC/ASC) of the gallbladder have not been well documented. This study investigates the clinical and pathological associations of ATP5B and β2M with benign and malignant lesions of the gallbladder. In this study, ATP5B and β2M expression in 46 SC/ASCs and 80 ACs were examined using immunohistochemistry. The rate of ATP5B positive expression was significantly lower, while the rate of β2M expression was significantly higher, in AC and SC/ASC than in gallbladder adenomas, gallbladder polyps, or gallbladder epithelium with stone (P < 0.01). More SC/ASCs had larger tumor mass and good differentiation compared to ACs. Positive β2M and negative ATP5B expression were significantly associated with large tumor size, high TNM stage, lymph node metastasis, and invasion of SC/ASCs and ACs. Univariate Kaplan-Meier analysis showed that positive β2M (P < 0.05 or P < 0.001) expression and negative ATP5B (P < 0.001) expression were significantly associated with decreased overall survival in both SC/ASC and AC patients. Multivariate Cox regression analysis showed that negative ATP5B expression is an independent-prognostic factor for poor prognosis in both SC/ASC (P < 0.01) and AC (P < 0.001) patients. Positive β2M expression is an independent-prognostic factor for poor prognosis in AC (P < 0.05) patients. Our study suggested that positive β2M expression or loss of ATP5B expression in tumor tissues is closely related to the metastasis, invasion, and poor-prognosis of gallbladder cancer.

O2-9-3 - Prothymosin and Parathymosin α are Prognostic Markers in Sc/Asc of Gallbladder

Background: Squamous cell/adenosquamous carcinomas (SC/ASC) are rare and little is known about the differences in clinical, pathological and biological characteristics between them.Methods: Prothymosin and parathymosin α expression were examined in 46 SC/ASC and 80 AC samples using EnVision immunohistochemistry and analyzed their correlations with clinicopathological characteristics.Results: Prothymosin and parathymosin α positive expression in SC/ASCs and ACs with mass maximal diameter ≤ 3cm, TNM staging I/II, no lymphnode metastasis, no adjacent invasion and radical excision were significantly lower than in those with maximal diameter of mass > 3cm, TNM IV, lymphnode metastasis, adjacent invasion and non-radical excision. Univariate Kaplan-Meier analysis showed differentiation, maximal diameter of mass, TNM, lymphnode metastasis, adjacent invasion, operation protocol, Prothymosin and parathymosin α expression were closely associated with overall survival in both SC/ASC and ACs. Survival of patients with Prothymosin and parathymosin α positive expression was significantly lower than those with negative expression. Multivariate Cox regression analysis showed poor differentiation, tumor size > 3cm, TNM III/IV, lymphnode metastasis, adjacent invasion, non-radical excision, Prothymosin and parathymosin α positive expression were negatively correlated with postoperative survival rate, positively correlated with mortality in both SC/ASCs and ACs. They were independent predictors of poor prognosis in SC/ASC.Conclusions: Our study suggested overexpression of Prothymosin and parathymosin α is closely related to the development, metastasis, invasion and poor prognosis of gallbladder cancer. They maybe important biomarkers and independent prognostic factors in SC/ASCs.

Risk factors of lymphatic metastasis complement poor radiological detection in gallbladder cancer

To explore risk factors of lymphatic metastasis (LM) in gallbladder cancer, and their potential to complement unsatisfactory radiological detection. Radiological detection of LM by computed tomography (CT) was reported to fail in more than 60% of patients with pathological LM. In order to find risk factors highly suggestive of LM other than radiological manifestations, the documents of 63 patients were analyzed statistically. Except for 4 patients having T1a disease, in whom cholecystectomy is enough for radical resection, 59 patients underwent lymphadenectomy with at least 3 lymph nodes dissected. Fifty point eight percent (32/63) of patients were found to have LM during pathological examination. The median number of dissected lymph nodes was 6 (range 3-20). Only 31.3% (10/32) of patients with LM were detected by CT. Through multivariate analysis, two risk factors of LM were discovered as age < 60 years (OR = 6.24; P < 0.01) and carbohydrate antigen (CA) 19-9 elevation (OR = 5.70; P < 0.05). By analysis of patients with pathological LM but failed to be detected by CT, 81.8% (18/22) of patients had at least one risk factor, including 31.3% (10/32) who had the risk factor of age < 60 years, and 37.5% (12/32) who had the risk factor of CA 19-9 elevation. Besides, among patients with LM (n = 32), those whose age were younger than 60 years (OR = 3.41; P < 0.05) were more likely to have 3 or more positive lymph nodes. Age < 60 years and CA 19-9 elevation could complement radiological detection of LM. Patients aged < 60 years are at higher risk of multiple positive nodes.

TGF-β upregulates miR-182 expression to promote gallbladder cancer metastasis by targeting CADM1

Transforming growth factor β (TGF-β) plays important roles in tumor metastasis by regulating miRNAs expression. miR-182 is an important molecule in the regulation of cancer progression. The aim of the study is to assess the role of miR-182 in TGF-β-induced cancer metastasis. In the present study, we found that miR-182 levels are significantly upregulated in GBC tissues compared with normal controls, and miR-182 expression is remarkably increased in primary tumors that subsequently metastasized, when compared to those primary tumors that did not metastasize. TGF-β induces miR-182 expression in GBC cells, and overexpression of miR-182 promotes GBC cell migration and invasion, whereas miR-182 inhibition suppresses TGF-β-induced cancer cell migration and invasion. The blockage of miR-182 by a specific inhibitor effectively inhibits pulmonary metastases in vivo. We further identified that the cell adhesion molecule1 (CADM1) is a new target gene of miR-182. miR-182 negatively regulates CADM1 expression in vitro and in vivo. Importantly, re-expression of CADM1 in GBC cells partially abrogates miR-182-induced cell invasion. miR-182 is an important mediator of GBC metastasis, thus offering a new target for the development of therapeutic agents against GBC.

A comparative study of clinicopathological significance, FGFBP1, and WISP-2 expression between squamous cell/adenosquamous carcinomas and adenocarcinoma of the gallbladder

The differences in clinical, pathological, and biological characteristics between adenocarcinoma (AC) and squamous cell/adenosquamous carcinoma (SC/ASC) of gallbladder cancer have not been well documented. This study is to compare the clinicopathological characteristics and FGFBP1 and WISP-2 expression between AC and SC/ASC patients. We examined FGFBP1 and WISP-2 expression in 46 SC/ASC and 80 AC samples using immunohistochemistry and analyzed their correlations with clinicopathological characteristics. SC/ASCs occur more frequently in older patients and often correspond to larger tumor masses than ACs. Positive FGFBP1 and negative WISP-2 expression were significantly associated with lymph node metastasis and invasion of SC/ASCs and ACs. In addition, positive FGFBP1 and negative WISP-2 expression were significantly associated with differentiation and TMN stage in ACs. Univariate Kaplan-Meier analysis showed that either elevated FGFBP1 (p < 0.001) or lowered WISP-2 (p < 0.001) expression was closely associated with decreased overall survival in both SC/ASC and AC patients. Multivariate Cox regression analysis showed that positive FGFBP1 expression (p = 0.001) or negative WISP-2 expression (p = 0.035 for SC/ASC and p = 0.009 for AC) is an independent predictor of poor prognosis in both SC/ASC and AC patients. We also revealed that differentiation, tumor size, TNM stage, lymph node metastasis, invasion, and surgical procedure were associated with survival of both SC/ASC and AC patients. Our study suggested that the overexpression of FGFBP1 or loss of WISP-2 expression is closely related to the metastasis, invasion and poor prognosis of gallbladder cancer.

Rare case of gallbladder cancer presenting with meta- stasis to bone and brain in an African American male discovered by F18-FDG PET/CT

The most common site of metastasis in gallbladder cancer is the liver. To our knowledge, there are no reports in the literature of gallbladder cancer metastasizing to both the brain parenchyma and the bone. There are only 5 prior reports of gallbladder cancer metastasis to the bone in the English Language literature. Likewise, gallbladder neoplasm metastasizing into the brain parenchyma is extremely rare. We present a rare case of gallbladder cancer presenting with metastases to both the brain parenchyma and the bone in a 71 year old African American male. This patient had early bone metastasis evidenced by hypermetabolic lesions on FDG PET/CT imaging, without density abnormalities of the bone tissue. Gastrointestinal (GI) tumors are commonly detected by CT but for metastasis, F18-FDG PET/CT has higher sensitivity and higher positive predictive value than CT. Since at the initial presentation, most patients suffering from gallbladder cancer tend to have metastatic disease, we raise a question as to whether F18-FDG PET/CT scans should be included in the routine work-up protocol.

CFL1 and Arp3 are Biomarkers for Metastasis and Poor Prognosis of Squamous Cell/Adenosquamous Carcinomas and Adenocarcinomas of Gallbladder

Cofilin-1 (CFL1) and Arp3 expression in 46 squamous cell and adenosquamous carcinomas (SC/ASCs) and 80 adenocarcinomas (ACs) were measured by using immunohistochemistry. Positive CFL1 and Arp3 expression were significantly associated with large tumor size, high TNM stage, lymph node metastasis, and decreased overall survival in both SC/ASC and AC patients (p < .001). Multivariate Cox regression analysis showed that positive CFL1 and Arp3 expression are independent poor-prognostic factors for both SC/ASC and AC patients. Our study suggested that positive CFL1 and Arp3 expression are closely related to tumor progression, metastasis, and poor prognosis of gallbladder cancer.

Establishment and characterization of a cell line, EH-GB2, derived from hepatic metastasis of gallbladder cancer

Gallbladder cancer is a fatal neoplasia with an extremely low survival rate. Liver invasion and metastasis are the most common causes of death; however, the metastatic mechanism is still unclear, and no effective treatment methods are available. To provide comprehensive and profound approaches in investigating the metastatic mechanism and treatment methods, new cell lines derived from liver metastasis are urgently needed. A hepatic metastasis lesion was obtained from a 65-year-old patient, and was treated using a primary culture method to establish a novel gallbladder cancer cell line. Different invitro/invivo methods were used to characterize the phenotypes of this cell line. The gallbladder cancer cell line was named EH-GB2, with a roughly 48-h doubling time. The cell line represents stronger colony formation and migration abilities than the control group. The cells showed complicated chromosomal abnormalities. EH-GB2 cells showed epithelial-to-mesenchymal transition (EMT) and the mRNA expression levels of E-cadherin and integrin were decreased, and those of vimentin, Snail, Twist, matrix metalloproteinase-1 (MMP-1) and MMP-2 were increased in comparison with control cells. The invivo study demonstrated that EH-GB2 cells show significant tumorigenicity in nude mice. The EH-GB2 established gallbladder cancer cell line is useful for future studies of gallbladder cancer development, progression, metastasis and therapy.

Vascular endothelial growth factor-D promotes growth, lymphangiogenesis and lymphatic metastasis in gallbladder cancer

Lymph node metastasis is a major prognostic factor for patients with gallbladder cancer (GBC), and greater understanding of the molecule mechanism of lymph node metastasis in GBC is needed to improve prognosis. VEGF-D has been implicated in the control of lymphangiogenesis in many carcinomas, but the biological function of VEGF-D in human GBC remains unclear. In this study, we analyzed the role of the VEGF-D in human GBC cells and addressed the functional role of VEGF-D using a xenograft mouse model. We examined the expression of VEGF-D in three human gallbladder cancer cell lines. A lentivirus-based effective VEGF-D siRNA vector was infected into GBC NOZ cells. The effect of VEGF-D siRNA on GBC NOZ cells was investigated by cell proliferation assay and invasion assay. Furthermore, we examined the role of VEGF-D-SiRNA on GBC NOZ cells in the mice of subcutaneous and orthotopic xenograft tumor. Our results are as follows: VEGF-D mRNA and protein were expressed in all three GBC cell lines (GBC-SD, NOZ, and SGC-996). We successfully selected D-3/siRNA as the most effective siRNA to silence VEGF-D expression after four VEGF-D siRNA plasmid transfection in NOZ cells. VEGF-D mRNA and protein expression were suppressed by lentivirus-mediated D-3/siRNA. D-3-RNAi-LV inhibited NOZ cells proliferation and invasion ability in vitro. D-3-RNAi-LV inhibited tumor growth and lymphangiogenesis in the NOZ cell subcutaneous xenograft model. D-3-RNAi-LV inhibited lymphangiogenesis and lymphatic metastasis in the NOZ cell orthotopic xenograft model. Furthermore, D-3-RNAi-LV inhibited tumor ascites and hepatic invasion in the NOZ cell orthotopic xenograft model. In conclusion, VEGF-D is involved and plays an important role in GBC progression, suggesting that VEGF-D may be a potential molecular target in the treatment of GBC.

Isolation of a human gallbladder cancer cell clone with high invasive phenotype in vitro and metastatic potential in orthotopic model and inhibition of its invasiveness by heparanase antisense oligodeoxynucleotides

The mechanisms involved in gallbladder cancer metastasis still remain unclear to date. The poor understanding is due, in part, to the lack of ideal cell line and animal model for study. In the present study, 21 cell clones were isolated from the human gallbladder carcinoma cells GBC-SD and the cell clone GBC-SDH(i) with high invasive phenotype was fished out. The invasive phenotype and metastatic potential of GBC-SDH(i) were confirmed in a novel surgical orthotopic implantation model of gallbladder cancer in nude mice. Heparanase, an endoglycosidase that degrades heparan sulfate, is a critical mediator of tumor metastasis and angiogenesis. RT-PCR, real time RT-PCR and western blot showed that the expression levels of heparanase were significant difference between GBC-SDH(i) and its parent cells. After treated with antisense oligodeoxynucleotides, the heparanase mRNA and protein expression in GBC-SDH(i) cells were significantly decreased and its invasive potential in vitro was inhibited in a dose-dependent manner. The study provides a useful cell clone and a clinically relevant orthotopic tumor model for the metastatic study in human gallbladder cancer. The roles of heparanase in gallbladder cancer are also evaluated.

Expression of survivin and its relation to p53 in gallbladder cancer

目的 检测胆囊癌中凋亡抑制因子Survivin的表达,研究其与胆囊癌临床特征的关系,并探讨其与p53的相关性.方法 采用免疫组织化学技术检测45例胆囊癌组织、20例胆囊息肉、20例胆囊炎及10例正常胆囊组织中Survivin和p53表达.结果 45例胆囊癌组织中40例表达Survivin蛋白,34例表达p53蛋白,表达p53的病例中,31例表达Survivin阳性.而在胆囊息肉、胆囊炎及正常胆囊组织中不表达.且Survivin的表达与胆囊癌病人性别、年龄、肿瘤大小、病理分级、Nevin分期、淋巴结转移无关(P＞0.05),而p53与淋巴结转移密切相关(P＜0.01).结论 Survivin在胆囊癌中的高表达提示其可能与肿瘤的发生有关,Survivin和p53突变对凋亡抑制的协同作用在胆囊癌的发生发展过程中起重要作用。

Establishment of liver metastasis model of human gallbladder cancer and isolation of the subpopulation with high metastatic potential

To establish an experimental liver metastatic model of gallbladder cancer and isolate the subpopulation with high metastatic potential from the model, which may serve as a reliable tool in research on liver metastasis of gallbladder cancer in vivo and in vitro. Human gallbladder cancer cells of the line GBC-SD were cultured. Ten nude athymic BALB/c mice, aged 4 approximately 5 weeks, underwent inoculation of suspension of GBC-SD cells into the spleens and then their spleens were resected. Three weeks later laparotomy was performed to observe if liver metastasis occurred. Once liver metastasis was discovered, the mice were killed and the livers were taken out to undergo microscopy, tumor cells were isolated from the metastatic foci and cultured in vitro, and then inoculated into other 10 mice in the same way as their parents cells for the second round of selection. The similar steps were repeated, altogether for three rounds of selection and a total 30 mice were inoculated in 3 rounds so as to find subpopulation with high metastatic potential. Another 10 mice underwent subcutaneous inoculation, 90 days later the mice were killed to observe if pulmonary metastasis occurred. PCR was used to detect the 3 microsatellite sequences D14S68, D18S69, and D20S199 in the DNA samples of the gallbladder cancer cells of the parent cell line GBC-SD, the isolated cells of the subpopulation with high metastatic potential, and the liver of experimental animal. 90% of the mice inoculated subcutaneously with the GBC-SD cells developed subcutaneous tumors, however, no mouse in this group died and no pulmonary metastasis was found. The liver metastatic rate was 65% in the 10 mice undergoing intrasplenic inoculation. Thus a metastatic model of human gallbladder cancer in nude mice was established. The liver metastatic tumors were uniformly distributed throughout the liver parenchyma with predominance to the periphery. Despite multiple sites of involvement, the left lobes were most commonly affected in all experimental animals. Histological examination of the metastatic lesion demonstrated adenocarcinoma. Gross hepatic metastasis was detected 10, 7, and 5 weeks after the inoculation respectively in the first, second, and third round selection respectively with an incidence rate of metastases of 60%, 70%, and 90% respectively. From the third round metastatic model a subpopulation with high metastatic potential was isolated and designated as GBC-SD/M, which exhibited the similar histological characteristics as its parent cell line GBC-SD under inverted light microscopy. The three amplified bands at the sites 14S68, D18S69, and D20S199, amplified with the three pairs of specific primers for the three homo-specific microsatellites, were detected in the GBC-SD cells and GBC-SD/M cells, but not in the liver of tumor-bearing animal. A liver metastasis model of human gallbladder cancer has been established, a reliable and efficient tool for study on the metastasis of gallbladder cancer to liver in vivo. Isolated from hepatic metastasis, the line of GBC-SD/M is a subpopulation with high metastatic potential, retaining the histological properties and identification of genetic background of its parent cell line GBC-SD.

Demonstration of a biliobronchial fistula with a hepatoiminodiacetic acid scan

Biliobronchial fistula (BBF) is a rare complication after hepatic resection. A 68-year-old woman who had undergone a right hepatic trisegmentectomy followed by a hepaticojejunostomy with a Roux-en-Y anastomosis for gallbladder cancer and liver metastasis from colon cancer was admitted to our hospital for further investigation of persistent bilioptysis. We could not detect the cause of the bilioptysis on computed tomography or magnetic resonance cholangiopancreatography, but a hepatoiminodiacetic scan clearly showed the BBF. Endoscopic retrograde cholangiography is thought to be suitable for diagnosing BBF, but it is invasive and unavailable in patients who have undergone digestive reconstruction, such as a Roux-en-Y anastomosis. In such cases, hepatoiminodiacetic scanning should be used for diagnosing BBF.

PERORAL CHOLANGIOSCOPY USING A NEW THINNER VIDEOSCOPE (CHF‐B260)

The CHF‐B260 videoscope has a 3.4 mm outer diameter, 1.2 mm forceps channel, and two‐way angulations function (70° up and 70° down). Peroral cholangioscopy (POCS) was performed using the CHF‐B260 in 13 patients who were admitted to our hospital between October 2002 and June 2004. The CHF‐B260 was successfully inserted into the bile duct in all cases. Clear images were obtained in 11 patients. Endoscopic images for two cases of malignant stricture due to metastasis of colon cancer and gallbladder cancer were not clear because of bleeding from the tumors. POCS was performed safely in all patients without any complications. POCS with the CHF‐B260 was very useful for the diagnosis of biliary disorders. If the outer diameter and biopsy channel of CHF‐B260 are improved, POCS will become even more effective for the diagnosis of biliary disorder.

Gallbladder cancer treatment using adenovirus expressing the HGF/NK4 gene in a peritoneal implantation model.

Gallbladder cancer cells are stimulated by hepatocyte growth factor (HGF) in vitro and in vivo. We constructed an adenovirus vector, AdCMV.NK4, carrying the HGF antagonist HGF/NK4 (NK4) and evaluated whether or not this vector can suppress the peritoneal implantation of gallbladder cancer in a novel peritoneal injury mouse model. A human gallbladder cancer cell line (GB-d1) and human peritoneal mesothelial cells infected with the adenovirus vector produced a substantial level of NK4 protein. An invasion of GB-d1 cells was determined by a coculture with AdCMV.NK4-infected human mesothelial cells in vitro. Both the invasion and migration of GB-d1 cells were dramatically inhibited by this vector in a multiplicity of infection (MOI)-dependent manner. GB-d1 cells were intraperitoneally injected into the nude mice with peritoneal injury, followed by either AdCMV.NK4 or a control vector (AdCMV.LacZ). The incidence and the size of the metastatic tumor drastically decreased by AdCMV.NK4 (MOI 100: n=4, P<.0001). Real-time PCR analysis revealed a transient elevation of mouse HGF mRNA expression at the peritoneal injury sites. AdCMV.NK4 has been suggested to induce the inhibition of the implantation and growth of gallbladder cancer cells in vivo through its anti-HGF activity, and the use of NK4 gene transfer could be an effective modality for preventing peritoneal metastasis of gallbladder cancer.

Relationship between urokinase-type plasminogen activator receptor and vascular endothelial growth factor expression and metastasis of gallbladder cancer.

To investigate the relationship of urokinase type plasminogen activator receptor (uPAR) and vascular endothelial growth factor (VEGF) expression with clinical and pathological characteristics of human gallbladder cancer. uPAR and VEGF expressions in 68 gallbladder cancer tissues were detected with anti-receptor immunohistochemical stain. Expression rate of uPAR was 57.4% (39/68), and VEGF 51.5% (35/68) in gallbladder cancer tissues. Expression of both uPAR and VEGF was significantly related to metastasis, but not significantly correlated with differentiation stage and size of gallbladder cancer. Expression of uPAR and VEGF may be an invasive phenotype of gallbladder cancer and indicator for predicting prognoses, and uPAR expression is significantly correlated with the expression of VEGF.