DEK oncoprotein regulates transcriptional modifiers and sustains tumor initiation activity in high-grade neuroendocrine carcinoma of the lung.

Lung cancer shows diverse histological subtypes. Large-cell neuroendocrine cell carcinoma and small-cell lung carcinoma show similar histological features and clinical behaviors, and can be classified as high-grade neuroendocrine carcinoma (HGNEC) of the lung. Here we elucidated the molecular classification of pulmonary endocrine tumors by copy-number profiling. We compared alterations of copy number with the clinical outcome of HGNEC and identified a chromosomal gain of the DEK oncogene locus (6p22.3) that was significantly associated with poor prognosis. We further confirmed that DEK overexpression was associated with poor prognosis in a larger set of HGNEC. Downregulation of DEK by small hairpin RNA led to a marked reduction of in vitro colony formation, in vivo tumorigenicity and chemo-resistance, and was associated with loss of lung cancer stem cell markers. Gene expression profiling revealed that DEK downregulation was associated with altered expression of transcriptional regulators, which specifically include known targets of interchromosomal translocations in hematopoietic tumors, and knockdown of these epigenetic modifiers affected colony formation activity. Our study showed that DEK overexpression, partly through an increase in its gene dose, mediates the activity of global transcriptional regulators and is associated with tumor initiation activity and poor prognosis in HGNEC.

Vandetanib (ZD6474), an inhibitor of VEGFR and EGFR signalling, as a novel molecular-targeted therapy against cholangiocarcinoma.

Cholangiocarcinoma is an intractable cancer, with no effective therapy other than surgical resection. Elevated vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) expressions are associated with the progression of cholangiocarcinoma. We therefore examined whether inhibition of VEGFR and EGFR could be a potential therapeutic target for cholangiocarcinoma. Vandetanib (ZD6474, ZACTIMA), a VEGFR-2/EGFR inhibitor, was evaluated. Four human cholangiocarcinoma cell lines were molecularly characterised and investigated for their response to vandetanib. In vitro, two cell lines (OZ and HuCCT1), both of which harboured KRAS mutation, were refractory to vandetanib, one cell line (TGBC24TKB) was somewhat resistant, and another cell line (TKKK) was sensitive. The most sensitive cell line (TKKK) had EGFR amplification. Vandetanib significantly inhibited the growth of TKKK xenografts at doses > or = 12.5 mg kg(-1) day(-1) (P<0.05), but higher doses (50 mg kg(-1) day(-1), P<0.05) of vandetanib were required to inhibit the growth of OZ xenografts. Vandetanib (25 mg kg(-1) day(-1)) also significantly (P=0.006) prolonged the time to metastasis in an intravenous model of TKKK metastasis. Inhibiting both VEGFR and EGFR signalling appears a promising therapeutic approach for cholangiocarcinoma. The absence of KRAS mutation and the presence of EGFR amplification may be potential predictive molecular marker of sensitivity to EGFR-targeted therapy in cholangiocarcinoma.

Expression profile of early lung adenocarcinoma: identification of MRP3 as a molecular marker for early progression.

Early lung adenocarcinoma is well-recognized as a small-sized non-invasive adenocarcinoma or localized non-mucinous bronchioloalveolar carcinoma (LNMBAC); however, the molecular events associated with these early lesions are not clear. To determine the genes involved in tumorigenesis at the early stage of lung adenocarcinoma, we compared the mRNA expression profiles of LNMBAC and normal lungs with an oligonucleotide array. Immunohistochemical analyses were performed to confirm the expression of detected genes. We identified 183 differentially expressed genes, of which 15 were up-regulated and 168 down-regulated. Among them, most up-regulated genes, such as AQP3 and Claudin-4, were expressed in both adenocarcinoma cells and type II alveolar pneumocytes, corresponding to the histological similarity between these cell types. However, multidrug resistant protein 3 (MRP3) was only expressed on tumour cell membranes and not in type II alveolar pneumocytes, as confirmed by immunohistochemistry. Moreover, the number of MRP3-positive cells significantly increased from AAH (the precursor lesion of lung adenocarcinoma) to LNMBAC. We conclude that MRP3 could be a novel molecular marker for LNMBAC, whose expression increases during the early progression of tumourigenesis.

Clinicopathological and prognostic significance of EGFR, VEGF, and HER2 expression in cholangiocarcinoma.

Epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and human epidermal growth factor receptor 2 (HER2) have been considered as potential therapeutic targets in cholangiocarcinoma, but no studies have yet clarified the clinicopathological or prognostic significance of these molecules. Immunohistochemical expression of these molecules was assessed retrospectively in 236 cases of cholangiocarcinoma, as well as associations between the expression of these molecules and clinicopathological factors or clinical outcome. The proportions of positive cases for EGFR, VEGF, and HER2 overexpression were 27.4, 53.8, and 0.9% in intrahepatic cholangiocarcinoma (IHCC), and 19.2, 59.2, and 8.5% in extrahepatic cholangiocarcinoma (EHCC), respectively. Clinicopathologically, EGFR overexpression was associated with macroscopic type (P=0.0120), lymph node metastasis (P=0.0006), tumour stage (P=0.0424), lymphatic vessel invasion (P=0.0371), and perineural invasion (P=0.0459) in EHCC, and VEGF overexpression with intrahepatic metastasis (P=0.0224) in IHCC. Multivariate analysis showed that EGFR expression was a significant prognostic factor (hazard ratio (HR), 2.67; 95% confidence interval (CI), 1.52-4.69; P=0.0006) and also a risk factor for tumour recurrence (HR, 1.89; 95% CI, 1.05-3.39, P=0.0335) in IHCC. These results suggest that EGFR expression is associated with tumour progression and VEGF expression may be involved in haematogenic metastasis in cholangiocarcinoma.

In breast carcinoma dysadherin expression is correlated with invasiveness but not with E-cadherin.

Reduction/loss of E-cadherin is associated with the development and progression of many epithelial tumours. Dysadherin, recently characterised by members of our research team, has an anti-cell-cell adhesion function and downregulates E-cadherin in a post-transcriptional manner. The aim of the present study was to study the role of dysadherin in breast cancer progression, in association with the E-cadherin expression and the histological type. We have selected ductal carcinoma, which is by far the most common type and lobular carcinoma, which has a distinctive microscopic appearance. Dysadherin and E-cadherin expression was examined immunohistochemically in 70 invasive ductal carcinomas, no special type (NST), and 30 invasive lobular carcinomas, with their adjacent in situ components. In ductal as well as in lobular carcinoma dysadherin was expressed only in the invasive and not in the in situ component, and this expression was independent of the E-cadherin expression. Specifically, all 10 (100%) Grade 1, 37 out of 45(82.2%) Grade 2 and six out of 15 (40%) Grade 3 invasive ductal carcinomas showed preserved E-cadherin expression, while 'positive dysadherin expression' was found in six out of 10 (60%) Grade 1, 34 out of 45(75.5%) Grade 2 and all 15 (100%) Grade 3 neoplasms. None of the 30 infiltrating lobular carcinomas showed preserved E-cadherin expression, while all the 30 infiltrating lobular carcinomas exhibited 'positive dysadherin expression'. Dysadherin may play an important role in breast cancer progression by promoting invasion and, particularly in lobular carcinomas, it might also be used as a marker of invasion.

Genomic loss and epigenetic silencing of very-low-density lipoprotein receptor involved in gastric carcinogenesis.

Homozygous loss in the genomic sequence, a mechanism for inactivating tumor-suppressor genes (TSGs) in cancer, has been used as a tag for the identification of novel TSGs, and array-based comparative genomic hybridization (array-CGH) has a great potential for high-throughput identification of this change. We identified a homozygous loss of the very-low-density lipoprotein receptor (VLDLR) gene (9p24.2) from genome-wide screening for copy-number alterations in 32 gastric cancer (GC) cell lines using array-CGH. Although previous reports demonstrated mRNA or protein expression of VLDLR in various cancers including GC, the association between genomic losses or epigenetic silencing of this gene and carcinogenesis has never been reported before. Homozygous deletion of VLDLR was also seen in primary GCs, albeit infrequently, and about half of GC cell lines showed lost or reduced VLDLR expression. The VLDLR expression was restored in gene-silenced GC cells after treatment with 5-aza 2'-deoxycytidine. According to methylation analyses, hypermethylation of the VLDLR promoter region, which all of GC lines without its expression showed, occurred in some primary GCs. Restoration of VLDLR type I expression in GC cells reduced colony formation. These results suggest that not only the expression of VLDLR but also genetic or epigenetic silencing of this gene may contribute to tumor formation and be involved in gastric carcinogenesis.

Diffusion anisotropy and diffusivity of white matter tracts within the temporal stem in Alzheimer disease: evaluation of the "tract of interest" by diffusion tensor tractography.

PURPOSE: Our aim was to determine whether diffusion anisotropy and diffusivity of white matter tracts of the temporal stem in patients with Alzheimer (AD) can be evaluated independently by using diffusion tensor tractography. MATERIALS AND METHODS: Subjects included 15 patients with AD (11 women and 4 men; mean age, 74 years) and 15 age-matched control subjects (11 women and 4 men; mean age, 72 years). Diffusion tensor images were acquired by using echo-planar imaging. We drew tractographies of the uncinate fasciculus, inferior occipitofrontal fasciculus, and Meyer's loop, with diffusion tensor analysis software. We measured diffusion anisotropy, diffusivity, and the number of voxels along the "tracts of interest" and used the Student t test to compare results between patients with AD and controls. RESULTS: Values of diffusion anisotropy of the bilateral uncinate fasciculus and left inferior occipitofrontal fasciculus were significantly lower for patients with AD than for controls. Also, values of diffusivity in the bilateral uncinate fasciculus were significantly greater for patients with AD than for controls. There was no significant difference in diffusion anisotropy or diffusivity along Meyer's loop between the 2 groups. There was no significant difference in the number of voxels included in all constructed tracts between patients with AD and controls. CONCLUSION: White matter tracts of the temporal stem can be evaluated independently by using diffusion tensor tractography, which appears to be a promising technique for determining changes in white matter in degenerative diseases.

Involvement of dysadherin and E-cadherin in the development of testicular tumours.

Testicular neoplasms are comprised of a variety of histologically different forms, and their pathogenesis has not been elucidated. Dysadherin is a recently described cell membrane glycoprotein, which has an anticell-cell adhesion function and downregulates E-cadherin. In this study, we examined immunohistochemically the expression of E-cadherin and dysadherin in 120 testicular neoplasms (37 seminomas-26 classic, five spermatocytic and six anaplastic-, 45 embryonal carcinomas, 10 mixed germ cell tumours, two yolk sac tumours, 10 mature and eight immature teratomas and eight non-Hodgkin B-cell lymphomas), clinical stage I. The intensity, the expression pattern and the percentage of neoplastic cell staining was recorded and correlated with the histologic type and vascular/lymphatic invasion. Dysadherin was not expressed in non-neoplastic germ cells, neither in CIS/ITGCNU, but it was highly expressed in all types of germ cell tumours, that demonstrated either embryonic phenotype or somatic differentiation, in most terminally differentiated neoplasms, and in all lymphomas. Dysadherin expression did not correlate with vascular invasion. Increased dysadherin expression was correlated with aberrant E-cadherin expression in most tumours. In 17% of embryonal carcinomas colocalisation of dysadherin and membranous E-cadherin staining was noted. This is the first report on dysadherin expression and its association with E-cadherin in testicular tumours. Since dysadherin is not normally expressed in non-neoplastic testis, it is conceivable that it plays a role in the neoplastic transformation of germ cells. In testicular tumours, as in other neoplasms, dysadherin downregulates E-cadherin expression, at least in part.

Expression of enamel proteins and LEF1 in adamantinomatous craniopharyngioma: evidence for its odontogenic epithelial differentiation.

AIMS: Adamantinomatous craniopharyngioma (ACP) resembles histologically some odontogenic tumours, such as ameloblastoma and calcifying odontogenic cyst. However, there has been no evidence that ACP differentiates also functionally as odontogenic epithelium. The aim of this study was to gain evidence of odontogenic epithelial differentiation in ACP by means of immunohistochemistry. Among normal human tissues, enamel proteins are expressed exclusively in teeth, and lymphoid enhancer factor 1 (LEF1), in co-operation with beta-catenin, play an important role in tooth development. The expression of these proteins is therefore indicative of odontogenic epithelial differentiation. METHODS AND RESULTS: The expression of enamel proteins and LEF1 was examined in 10 adamantinomatous and six papillary craniopharyngiomas. All the ACPs showed a variable degree of enamel protein expression, including amelogenin, enamelin and enamelysin, mainly in ghost cells. LEF1 was also heterogeneously expressed in ACPs; remarkably, its expression pattern was identical to that of nuclear beta-catenin accumulation. In contrast, none of the papillary craniopharyngiomas expressed enamel proteins or LEF1. CONCLUSIONS: These results suggest that ACP consistently shows odontogenic epithelial differentiation. Since ACPs harbour beta-catenin mutation, the inappropriate activation of beta-catenin/LEF1 complex-dependent transcription may play a critical role in ACP tumorigenesis.

Borderline Brenner tumor of the ovary: MRI findings.

Ovarian Brenner tumor is an uncommon epithelial tumor that accounts for 1.5% to 2.5% of all ovarian neoplasms. These tumors are usually benign. Whereas the magnetic resonance imaging features of benign Brenner tumors have been described, reports of malignant findings are limited. We report a case of borderline malignant Brenner tumor that imaged as a cystic lesion with papillary projections and solid elements.

Regulation of DNaseY activity by actinin-alpha4 during apoptosis.

DNaseY, a Ca(2+)- and Mg(2+)-dependent endonuclease, has been implicated in apoptotic DNA degradation; however, the molecular mechanisms controlling its involvement in this process have not been fully elucidated. We have obtained evidence from yeast two-hybrid screening and coimmunoprecipitation experiments that DNaseY interacted physically with actinin-alpha4 and this interaction significantly enhanced its endonuclease activity. Accordingly, simultaneous overexpression of both proteins in PC12 cells dramatically increased the rate of apoptosis in response to teniposide' VM26. However, overexpression of DNaseY alone neither triggered apoptosis nor facilitated cell death in response to VM26 or serum deprivation. Instead, the overexpression of DNaseY increased the production of single-strand DNA breaks and evoked a profound upregulation of DNA repair pathways. Taken together, our results point to a novel regulatory mechanism of DNaseY activity and offer an explanation for why cells must first cleave key DNA repair and replication proteins before the successful execution of apoptosis.

Prognostic significance of dysadherin expression in advanced colorectal carcinoma.

A novel glycoprotein, dysadherin, has an anti-cell - cell adhesion function through downregulating E-cadherin. In this study, we investigated the expressions of dysadherin and E-cadherin in 82 patients with stage II and III colorectal carcinomas to determine the correlation between the two molecules and the clinicopathologic features of each tumour. Dysadherin was not expressed in normal colorectal epithelium. Fifty-one per cent of tumours showed dysadherin immunopositivity in over 50% of cancer cells. Thirty-eight per cent of tumours showed reduced E-cadherin immunopositivity. The increased expression of dysadherin was significantly associated with lung metastasis (P=0.003). The increased expression of dysadherin had a significant impact on patient survival (P=0.0099 and 0.0036, log-rank test for overall and recurrence-free survival rate, respectively). Furthermore, tumour with increased expression of dysadherin and reduced expression of E-cadherin showed the worst prognosis (P=0.0043 and 0.0028, log-rank test for overall and recurrence-free survival rate, respectively). These results suggest that increased dysadherin expression is a significant indicator of poor prognosis for patients with advanced colorectal carcinoma.

Population-based genetic alterations in Ewing's tumors from Japanese and European Caucasian patients.

BACKGROUND: The incidence of Ewing's tumors (ETs) is lower in Asians or African-Americans than in Caucasians. PATIENTS AND METHODS: Japanese ETs were available for analysis of chromosomal aberrations by comparative genomic hybridization (n = 16) and for expression of chimeric EWS transcripts by reverse-transcriptase polymerase chain reaction (n = 11). These results in Japanese patients were compared with those of 62 ETs in European Caucasian patients registered in the European Intergroup Cooperative Ewing's Sarcoma Study. RESULTS: Japanese patients with ET had lower overall survival (P = 0.0446) and relapse-free survival (P = 0.0371) compared with European Caucasian patients. Ten of 11 Japanese ETs and 31 of 62 European Caucasian ETs had type I (EWS exon 7 to FLI1 exon 6) fusion transcripts. In Japanese ETs, the median numbers of chromosomal aberrations were 2.0 and 6.0 in 11 primary tumors and five relapsed tumors, respectively. In European Caucasian ETs, the median number of changes were 2.5 and 5.0 in 52 primary and 10 relapsed tumors, respectively. Frequent gains were 8q (38%), 8p (31%) and 12q (25%) in Japanese ETs and 8q (52%), 8p (48%) and 12q (19%) in European Caucasian ETs. Frequent losses were 19q (44%), 19p (38%) and 17p (25%) in Japanese ETs and 16q (21%), 19q (18%) and 17p (15%) in European Caucasian ETs. The incidence of losses of 19p (P = 0.0215) and 19q (P = 0.0277) were significantly higher in Japanese ETs than in European Caucasian ETs. An amplification (1p33-p34) was observed in only one Japanese ET. CONCLUSIONS: Japanese patients with ET in this study had a worse prognosis than European Caucasian patients. In molecular genetic analyses, Japanese ETs had a higher frequency of loss of chromosome 19 than European Caucasian ETs. Different genetic aberrations may explain the different incidences and prognoses of ET between Caucasian and Japanese patients.

Immature glandular features in squamous cell carcinoma of the uterine cervix as an independent indicator of resistance to radiotherapy.

The aim of this study was to evaluate the significance of "immature glandular features" in cervical squamous cell carcinoma (SCC) as an indicator of tumor radioresistance. Pretreatment biopsied tissue specimens of cervical SCC from 100 patients who were uniformly treated with radiotherapy alone were classified into clinically radioresistant (cR) and radiosensitive (cS) groups. Seven histologic parameters comprising glassy cells, signet ring cells, squamous differentiation, recognizable gland, nuclear atypia, stromal response, and mitotic counts were examined. Glassy cells and signet ring cells were regarded as "immature glandular features". The correlation of these seven parameters with tumor response to radiotherapy and patient prognosis was analyzed by univariate and multivariate analyses. As objective indicators of glandular differentiation, alcian-blue staining and immunostaining of cytokeratins 7 and 20 were also performed. It was revealed that immature glandular features, absence of squamous differentiation, and low nuclear atypia were significant indicators of radioresistance of the tumor and of poorer patient prognosis. Combining those histological parameters, the present SCC cases were classified into 26 pathologically radioresistant (pR) and 74 radiosensitive (pS) groups. In the pR group, 54% (14 of 26) were clinically radioresistant, whereas 20% (15 of 74) of the pS group were clinically radioresistant (P = 0.002). The overall prognosis of the pR group was much poorer than that of the pS group (P < 0.0001). This correlation also held true in cases of identical stage and age. We could not show objectively glandular differentiation of "immature glandular features". Nonetheless, the identification of "immature glandular features" was effective in predicting the radiotherapy resistance of cervical SCC and poorer patient prognosis.

Implications of peritoneal washing cytology in patients with potentially resectable pancreatic cancer.

BACKGROUND: The aim of this study was to assess the implications of positive peritoneal washing cytology for management of patients with potentially resectable pancreatic cancer. METHODS: Cytological examination of peritoneal washings was performed in 134 patients who underwent surgical resection for pancreatic adenocarcinoma. The clinicopathological findings and the relationship between cytology results (including cytomorphology) and survival were investigated. RESULTS: One hundred and fourteen patients (85 per cent) had negative cytology results (group 1). Excluding one patient with atypical cells, positive cytology results were obtained in 19 patients (14 per cent): 16 patients without macroscopic peritoneal metastases (group 2) and three patients with minimal macroscopic peritoneal metastases (group 3). The patients in group 2 had significantly larger (P < 0.001) and more advanced (P = 0.022) tumours than those in group 1. However, there were no significant differences in postoperative cumulative survival rates between groups 1 and 2 (P = 0.347). Two patients in group 2 are long-term survivors (40 and 58 months). In cytomorphological analyses, the presence of clusters with ragged edges and isolated carcinoma cells can be considered to indicate a high risk of peritoneal recurrence. CONCLUSION: Positive cytology does not directly predict peritoneal carcinomatosis and, while associated with advanced disease, does not contraindicate radical surgery.

Detection of genes expressed in primary colon cancers by in situ hybridisation: overexpression of RACK 1.

AIMS: The isolation of various genes that are expressed in a region specific manner is considered useful for research in molecular pathology. In situ hybridisation (ISH) was used in a screening procedure to isolate these genes efficiently, using colon cancer as a model. METHODS: Suppression subtractive hybridisation (SSH) between colon cancer tissue samples and corresponding non-cancerous tissues was performed. Genes showing high expression in the cancers were selected using macro-DNA array analysis. As a final screening procedure, conventional ISH was performed to isolate genes expressed specifically in colon cancers. RESULTS: Sixty nine clones were selected by SSH and macro-DNA array analyses. These clones were then analysed by ISH to examine their expression patterns. ISH screening revealed that all the clones screened showed more intense signals in colon cancers than in non-cancerous tissues. Among them, RACK 1, which is a protein kinase C receptor and a homologue of the G protein beta subunit, was expressed intensely in colon cancer cells. RACK 1 expression was evaluated in multiple samples by ISH, and the results confirmed that RACK 1 was universally overexpressed in cells of all 11 colon cancers examined. CONCLUSIONS: Many genes, including RACK 1, expressed in colon cancer cells can be isolated efficiently by this method, and their precise expression pattern can be evaluated. These results indicate that ISH is an excellent technique for systemic screening of genes expressed in a region specific manner.

Overexpression of tetraspanin CO-029 in hepatocellular carcinoma.

BACKGROUND/AIMS: The molecules involved in the progression of hepatocellular carcinoma (HCC) are not fully understood. The aim of this study was to elucidate the crucial genes involved in cancer progression and metastasis. METHODS: Selectively expressed genes were screened using differential display analysis, and then further analyzed by real-time quantitative reverse-transcription polymerase chain reaction (RT-PCR) and immunohistochemistry. RESULTS: Tetraspanin CO-029 was found to be frequently and significantly overexpressed in HCC. Real-time quantitative RT-PCR showed that the CO-029 mRNA level was 1.7 times higher (P=0.030) in cancerous tissues than in non-cancerous tissues. mRNA expression of the other tetraspanins, CD9 and CD82, was downregulated in HCC, especially in tumors with intrahepatic spreading (portal vein invasion and/or intrahepatic metastasis). In contrast, mRNA expression of CO-029 tended to be increased in cancerous tissue showing intrahepatic spreading compared with tumors without such spreading. Immunohistochemical analysis revealed that CO-029 was overexpressed in poorly differentiated HCCs compared with well to moderately differentiated tumors (P<0.001), and in HCCs showing intrahepatic spreading compared with those without spreading (P=0.019). CONCLUSIONS: Our findings suggest that CO-029 has some roles in the promotion of metastasis of HCC.

Comparison of gadobenate dimeglumine with gadopentetate dimeglumine for magnetic resonance imaging of liver tumors.

RATIONALE AND OBJECTIVES: To compare gadobenate dimeglumine (Gd-BOPTA) with gadopentetate dimeglumine (Gd-DTPA) for magnetic resonance imaging of the liver. METHODS: The contrast agent Gd-BOPTA or Gd-DTPA was administered at a dose of 0.1 mmol/kg to 257 patients suspected of having malignant liver tumors. Dynamic phase images, spin-echo images obtained within 10 minutes of injection, and delayed images obtained 40 to 120 minutes after injection were acquired. All postcontrast images were compared with unenhanced T1-weighted and T2-weighted images obtained immediately before injection. A full safety assessment was performed. RESULTS: The contrast efficacy for dynamic phase imaging was moderately or markedly improved in 90.9% (110/121) and 87.9% (109/124) of patients for Gd-BOPTA and Gd-DTPA, respectively. At 40 to 120 minutes after injection, the cor- responding improvements were 21.7% (26/120) and 11.6% (14/121) for spin-echo sequences and 44.5% (53/119) and 19.0% (23/121) for breath-hold gradient-echo sequences, respectively. The differences at 40 to 120 minutes after injection were statistically significant (P < 0.02). Increased information at 40 to 120 minutes after injection compared with information acquired within 10 minutes of injection was available for 24.0% (29/121) of patients with Gd-BOPTA and for 14.5% (18/124) of patients with Gd-DTPA (P < 0.03). Adverse events were seen in 4.7% (6/128) and 1.6% (2/127) of patients receiving Gd-BOPTA and Gd-DTPA, respectively. The difference was not statistically significant. CONCLUSIONS: The efficacy of Gd-BOPTA is equivalent to that of Gd-DTPA for liver imaging during the dynamic phase and superior during the delayed (40-120 minutes) phase of contrast enhancement. Both agents are safe for use in magnetic resonance imaging of the liver.

Involvement of c-Src in carcinoma cell motility and metastasis.

Carcinoma cells exhibit dysfunction / dysregulation of cell adhesion systems that correlates with their abilities to migrate, invade, and metastasize. Here we show that the tyrosine kinase c-Src is required for motility and metastasis of two carcinoma cell lines. Adherent KYN-2 cells having a high level of c-Src kinase activity become scattered, extend lamellipodia, and exhibit high motility. Expression of a dominant-negative mutant form of c-Src caused formation of stress fibers and focal adhesions, and markedly reduced motility. HCT15 cells extended lamellipodia and became scattered in response to lysophosphatidic acid stimulation in parallel with transient activation of c-Src, which was inhibited by expression of a dominant-negative mutant form of c-Src or treatment with a specific Src kinase inhibitor. Furthermore, implantation of dominant-negative c-Src transfectants into the peritoneal cavity of SCID mice resulted in reduced peritoneal dissemination compared with control transfectants. These findings indicate that c-Src activation is critically involved in carcinoma cell migration and metastasis.