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1.  Primary ectopic atypical meningioma in the renal hilum: a case report 
BMC Cancer  2014;14(1):763.
Background
Primary ectopic atypical meningioma involving the renal hilum is rare. This is, to our knowledge, only the second case report of a primary retroperitoneal meningioma and the first case of an atypical subtype in this location.
Case presentation
A 53-year-old Han Chinese man presented with a 2-year history of left-side flank pain. An oval-shaped retroperitoneal mass was found in the left renal hilum on computed tomography, which was resected en bloc along with the kidney via laparotomy. According to the World Health Organization criteria, the tumor was histopathologically classified as a meningioma (Grade II, atypical). Five years later, the tumor recurred at the primary site with a similar histopathology. The patient received palliative resection, followed by radiotherapy (4500 cGy in 25 fractions). No relapse was found at 6-month follow-up.
Conclusion
We describe the clinical, radiographic and histopathological features of an unusual case of aggressive ectopic meningioma in the renal hilum. The patient presented with a massive retroperitoneal tumor without primary cerebral or secondary metastatic lesions; the preoperative diagnosis was naturally confined to the common retroperitoneal malignancies. This case is of interest to oncologists, because of both its rare location and aggressiveness; it not only enriched the spectrum of primary ectopic meningioma, but also reminded us of potential recurrence of an atypical meningioma. This case raises the issue of the etiology of such a rare tumor that needs further investigation, and more importantly demands long-term follow-up result.
doi:10.1186/1471-2407-14-763
PMCID: PMC4200141  PMID: 25312235
Ectopic meningioma; Atypical meningioma; Retroperitoneal mass; Renal hilum
2.  Macrophage inhibitory cytokine 1 (MIC-1/GDF15) as a novel diagnostic serum biomarker in pancreatic ductal adenocarcinoma 
BMC Cancer  2014;14(1):578.
Background
Macrophage inhibitory cytokine 1 (MIC-1/GDF15) has been identified as a potential novel biomarker for detection of pancreatic cancer (PCa). However, the diagnostic value of serum MIC-1 for pancreatic ductal adenocarcinoma (PDAC), particularly for those at the early stage, and the value for treatment response monitoring have not yet been investigated.
Methods
MIC-1 expression in tumor tissue was analyzed by RT-PCR from 64 patients with PDAC. Serum MIC-1 levels were detected by ELISA in 1472 participants including PDAC, benign pancreas tumor, chronic pancreatitis and normal controls. The diagnostic performance of MIC-1 was assessed and compared with CA19.9, CEA and CA242, and the value of it as a predictive indicator for therapeutic response and tumor recurrence was also evaluated.
Results
MIC-1 levels were significantly elevated in PDAC tissues as well as serum samples. The sensitivity of serum MIC-1 for PDAC diagnosis was much higher than that of CA19.9 (65.8% vs. 53.3%) with similar specificities. Furthermore, serum MIC-1 detected 238 out of 377 (63.1%) CA19.9-negative PDAC. Moreover, receiver operating characteristic (ROC) curve analysis also showed that serum MIC-1 had a better performance compared with CA19.9 in distinguishing early-stage PDAC from normal serum with a higher sensitivity (62.5% vs. 25.0% respectively). Notably, serum MIC-1 level was significantly decreased in patients with PDAC after curative resection and returned to elevated levels when tumor relapse occurred.
Conclusions
Serum MIC-1 is significantly elevated in most PDAC, including those with negative CA19.9 and early stage disease, and thus may serve as a novel diagnostic marker in early diagnosis and postoperative monitoring of PDAC.
doi:10.1186/1471-2407-14-578
PMCID: PMC4133074  PMID: 25106741
3.  Cytotoxicity of VEGF121/rGel on vascular endothelial cells resulting in inhibition of angiogenesis is mediated via VEGFR-2 
BMC Cancer  2011;11:358.
Background
The fusion protein VEGF121/rGel composed of the growth factor VEGF121 and the plant toxin gelonin targets the tumor neovasculature and exerts impressive anti-vascular effects. We have previously shown that VEGF121/rGel is cytotoxic to endothelial cells overexpressing VEGFR-2 but not to endothelial cells overexpressing VEGFR-1. In this study, we examined the basis for the specific toxicity of this construct and assessed its intracellular effects in vitro and in vivo.
Methods
We investigated the binding, cytotoxicity and internalization profile of VEGF121/rGel on endothelial cells expressing VEGFR-1 or VEGFR-2, identified its effects on angiogenesis models in vitro and ex vivo, and explored its intracellular effects on a number of molecular pathways using microarray analysis.
Results
Incubation of PAE/VEGFR-2 and PAE/VEGFR-1 cells with 125I-VEGF121/rGel demonstrated binding specificity that was competed with unlabeled VEGF121/rGel but not with unlabeled gelonin. Assessment of the effect of VEGF121/rGel on blocking tube formation in vitro revealed a 100-fold difference in IC50 levels between PAE/VEGFR-2 (1 nM) and PAE/VEGFR-1 (100 nM) cells. VEGF121/rGel entered PAE/VEGFR-2 cells within one hour of treatment but was not detected in PAE/VEGFR-1 cells up to 24 hours after treatment. In vascularization studies using chicken chorioallantoic membranes, 1 nM VEGF121/rGel completely inhibited bFGF-stimulated neovascular growth. The cytotoxic effects of VEGF121/rGel were not apoptotic since treated cells were TUNEL-negative with no evidence of PARP cleavage or alteration in the protein levels of select apoptotic markers. Microarray analysis of VEGF121/rGel-treated HUVECs revealed the upregulation of a unique "fingerprint" profile of 22 genes that control cell adhesion, apoptosis, transcription regulation, chemotaxis, and inflammatory response.
Conclusions
Taken together, these data confirm the selectivity of VEGF121/rGel for VEGFR-2-overexpressing endothelial cells and represent the first analysis of genes governing intoxication of mammalian endothelial cells by a gelonin-based targeted therapeutic agent.
doi:10.1186/1471-2407-11-358
PMCID: PMC3176242  PMID: 21849059
4.  Attenuated expression of HRH4 in colorectal carcinomas: a potential influence on tumor growth and progression 
BMC Cancer  2011;11:195.
Background
Earlier studies have reported the production of histamine in colorectal cancers (CRCs). The effect of histamine is largely determined locally by the histamine receptor expression pattern. Recent evidence suggests that the expression level of histamine receptor H4 (HRH4) is abnormal in colorectal cancer tissues. However, the role of HRH4 in CRC progression and its clinical relevance is not well understood. The aim of this study is to evaluate the clinical and molecular phenotypes of colorectal tumors with abnormal HRH4 expression.
Methods
Immunoblotting, real-time PCR, immunofluorescence and immunohistochemistry assays were adopted to examine HRH4 expression in case-matched CRC samples (n = 107) and adjacent normal tissues (ANTs). To assess the functions of HRH4 in CRC cells, we established stable HRH4-transfected colorectal cells and examined cell proliferation, colony formation, cell cycle and apoptosis in these cells.
Results
The protein levels of HRH4 were reduced in most of the human CRC samples regardless of grade or Dukes classification. mRNA levels of HRH4 were also reduced in both early-stage and advanced CRC samples. In vitro studies showed that HRH4 over-expression caused growth arrest and induced expression of cell cycle proteins in CRC cells upon exposure to histamine through a cAMP -dependent pathway. Furthermore, HRH4 stimulation promoted the 5-Fu-induced cell apoptosis in HRH4-positive colorectal cells.
Conclusion
The results from the current study supported previous findings of HRH4 abnormalities in CRCs. Expression levels of HRH4 could influence the histamine-mediated growth regulation in CRC cells. These findings suggested a potential role of abnormal HRH4 expression in the progression of CRCs and provided some new clues for the application of HRH4-specific agonist or antagonist in the molecular therapy of CRCs.
doi:10.1186/1471-2407-11-195
PMCID: PMC3128004  PMID: 21609450
5.  Seminal vesicle metastasis after partial hepatectomy for hepatocellular carcinoma 
BMC Cancer  2011;11:111.
Background
Metastasis to the seminal vesicle is extremely rare for hepatocellular carcinoma (HCC). To our knowledge, it has been not reported in literature. The purpose of the present paper was to report a case of metastasis to the seminal vesicle after HCC resection, along with its histological features and immunohistochemical characteristics.
Case Presentation
A 46-year-old Chinese man was admitted to our hospital due to abdominal distension. He had a history of HCC related to hepatitis B virus infection. Moreover, left partial hepatectomy was performed in another hospital 28 months ago, and right partial hepatectomy for HCC recurrence in our hospital 4 months ago. After resection, radiofrequency ablation therapy had been performed. About 27 months after the initial operation, contrast-enhanced computed tomography (CT) of the pelvic cavity revealed a mass with homogeneous enhancement in the seminal vesicle. Transrectal needle biopsy revealed a poorly differentiated adenocarcinoma. Therefore, seminal vesiculectomy was resected. The histological diagnosis of the removed tumor was compatible with the original HCC. Immunohistochemical examination demonstrated that the tumor cells were positive for glypican-3 (GPC3), alpha-fetoprotein (AFP), hepatocyte paraffin-1 (Hep Par 1), cytokeratin 18 (CK 18), and hepatocyte antigen, which confirmed that the seminal vesicle tumor was a metastatic tumor of HCC. However, CT subsequently revealed multiple metastatic foci in the abdominal and pelvic cavities in May 2009 and August 2009, respectively.
Conclusion
The seminal vesicle is an extremely rare metastatic site for HCC, and the prognosis is very poor. A combination of clinical and pathological features is necessary for a correct diagnosis, and primary tumor should be excluded before diagnosing metastatic foci.
doi:10.1186/1471-2407-11-111
PMCID: PMC3079689  PMID: 21443783
seminal vesicle; hepatocellular carcinoma; metastasis; clinical pathology
6.  Antiangiogenic effects of pazopanib in xenograft hepatocellular carcinoma models: evaluation by quantitative contrast-enhanced ultrasonography 
BMC Cancer  2011;11:28.
Background
Antiangiogenesis is a promising therapy for advanced hepatocellular carcinoma (HCC), but the effects are difficult to be evaluated. Pazopanib (GW786034B) is a pan-vascular endothelial growth factor receptor inhibitor, the antitumor effects or antiangiogenic effects haven't been investigated in HCC.
Methods
In vitro direct effects of pazopanib on human HCC cell lines and endothelial cells were evaluated. In vivo antitumor effects were evaluated in three xenograft nude mice models. In the subcutaneous HCCLM3 model, intratumoral blood perfusion was detected by contrast-enhanced ultrasonography (CEUS), and serial quantitative parameters were profiled from the time-intensity curves of ultrasonograms.
Results
In vitro proliferation of various HCC cell lines were not inhibited by pazopanib. Pazopanib inhibited migration and invasion and induced apoptosis significantly in two HCC cell lines, HCCLM3 and PLC/PRF/5. Proliferation, migration, and tubule formation of human umbilical vein endothelial cells were inhibited by pazopanib in a dose-dependent manner. In vivo tumor growth was significantly inhibited by pazopanib in HCCLM3, HepG2, and PLC/PRF/5 xenograft models. Various intratumoral perfusion parameters changed over time, and the signal intensity was significantly impaired in the treated tumors before the treatment efficacy on tumor size could be observed. Mean transit time of the contrast media in hotspot areas of the tumors was reversely correlated with intratumoral microvessel density.
Conclusions
Antitumor effects of pazopanib in HCC xenografts may owe to its antiangiogenic effects, and the in vivo antiangiogenic effects could be evaluated by quantitative CEUS.
doi:10.1186/1471-2407-11-28
PMCID: PMC3033852  PMID: 21251271
7.  Boron neutron capture therapy induces apoptosis of glioma cells through Bcl-2/Bax 
BMC Cancer  2010;10:661.
Background
Boron neutron capture therapy (BNCT) is an alternative treatment modality for patients with glioma. The aim of this study was to determine whether induction of apoptosis contributes to the main therapeutic efficacy of BNCT and to compare the relative biological effect (RBE) of BNCT, γ-ray and reactor neutron irradiation.
Methods
The neutron beam was obtained from the Xi'an Pulsed Reactor (XAPR) and γ-rays were obtained from [60Co] γ source of the Fourth Military Medical University (FMMU) in China. Human glioma cells (the U87, U251, and SHG44 cell lines) were irradiated by neutron beams at the XAPR or [60Co] γ-rays at the FMMU with different protocols: Group A included control nonirradiated cells; Group B included cells treated with 4 Gy of [60Co] γ-rays; Group C included cells treated with 8 Gy of [60Co] γ-rays; Group D included cells treated with 4 Gy BPA (p-borono-phenylalanine)-BNCT; Group E included cells treated with 8 Gy BPA-BNCT; Group F included cells irradiated in the reactor for the same treatment period as used for Group D; Group G included cells irradiated in the reactor for the same treatment period as used for Group E; Group H included cells irradiated with 4 Gy in the reactor; and Group I included cells irradiated with 8 Gy in the reactor. Cell survival was determined using the 3-(4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium (MTT) cytotoxicity assay. The morphology of cells was detected by Hoechst33342 staining and transmission electron microscope (TEM). The apoptosis rate was detected by flow cytometer (FCM). The level of Bcl-2 and Bax protein was measured by western blot analysis.
Results
Proliferation of U87, U251, and SHG44 cells was much more strongly inhibited by BPA-BNCT than by irradiation with [60Co] γ-rays (P < 0.01). Nuclear condensation was determined using both a fluorescence technique and electron microscopy in all cell lines treated with BPA-BNCT. Furthermore, the cellular apoptotic rates in Group D and Group E treated with BPA-BNCT were significantly higher than those in Group B and Group C irradiated by [60Co] γ-rays (P < 0.01). The clonogenicity of glioma cells was reduced by BPA-BNCT compared with cells treated in the reactor (Group F, G, H, I), and with the control cells (P < 0.01). Upon BPA-BNCT treatment, the Bax level increased in glioma cells, whereas Bcl-2 expression decreased.
Conclusions
Compared with γ-ray and reactor neutron irradiation, a higher RBE can be achieved upon treatment of glioma cells with BNCT. Glioma cell apoptosis induced by BNCT may be related to activation of Bax and downregulation of Bcl-2.
doi:10.1186/1471-2407-10-661
PMCID: PMC3003659  PMID: 21122152
8.  Resveratrol represses YKL-40 expression in human glioma U87 cells 
BMC Cancer  2010;10:593.
Background
Glioblastoma multiforme (GBM) is the most malignant intracranial tumour that develops in both adults and children. Microarray gene analyses have confirmed that the human YKL-40 gene is one of the most over-expressed genes in these tumours but not in normal brain tissue. Clinical studies have shown that serum YKL-40 levels are positively correlated with tumour burden in addition to being an independent prognostic factor of a short relapse-free interval as well as short overall survival in patients with various cancers. Our previous study revealed that YKL-40 was closely correlated with the pathological grades of human primary astrocytomas and played a crucial role in glioma cell proliferation. Hence, YKL-40 could be an attractive target in the design of anti-cancer therapies.
Methods
Cell viability and invasion assays were performed to detect the cell proliferation and invasive ability of U87 cells induced by resveratrol (3, 5, 4'-trihydroxystilbene; Res) or YKL-40 small-interfering RNAs (siRNAs). In addition, the luciferase assay, real-time RT-PCR, western blotting, and ELISA were used to measure YKL-40 promoter activity, mRNA, and protein expression, respectively. The expressions of phosphor-ERK1/2 and ERK1/2 were determined by western blotting.
Results
Res inhibited U87 cell proliferation and invasion in vitro and repressed YKL-40 in U87 cells by decreasing the activity of its promoter and reducing mRNA transcription and protein expression in vitro. YKL-40 siRNA treatment also impaired the invasiveness of U87 cells. When U87 cells were cultured with 20 μM PD98059 (an ERK1/2 inhibitor) alone, with 20 μM PD98059 and 100 μM Res, or with 100 μM Res alone for 48 h, YKL-40 protein expression decreased most significantly in the Res-treated group. PD98059 partially reversed the decrease of YKL-40 protein expression induced by Res. Furthermore, phosphor-ERK1/2 expression was reduced by Res treatment in a time-dependent manner.
Conclusions
We demonstrated for the first time that Res represses YKL-40 expression in vitro; in addition, the ERK1/2 pathway is involved in this repression. This finding could extend the prospective use of Res in glioma research and enlarge the armamentarium for treating gliomas.
doi:10.1186/1471-2407-10-593
PMCID: PMC2988030  PMID: 21029458
9.  Residual hepatocellular carcinoma after oxaliplatin treatment has increased metastatic potential in a nude mouse model and is attenuated by Songyou Yin 
BMC Cancer  2010;10:219.
Background
The opposite effects of chemotherapy, which enhance the malignancy of treated cancers such as hepatocellular carcinoma (HCC), are not well understood. We investigated this phenomenon and corresponding mechanisms to develop a novel approach for improving chemotherapy efficacy in HCC.
Methods
Human hepatocellular carcinoma cell lines HepG2 (with low metastatic potential) and MHCC97L (with moderate metastatic potential) were used for the in vitro study. An orthotopic nude mouse model of human HCC was developed using MHCC97L cells. We then assessed the metastatic potential of surviving tumor cells after in vitro and in vivo oxaliplatin treatment. The molecular changes in surviving tumor cells were evaluated by western blot, immunofluorescence, and immunohistochemistry. The Chinese herbal extract Songyou Yin (composed of five herbs) was investigated in vivo to explore its effect on the metastatic potential of oxaliplatin-treated cancer cells.
Results
MHCC97L and HepG2 cells surviving oxaliplatin treatment showed enhanced migration and invasion in vitro. Residual HCC after in vivo oxaliplatin treatment demonstrated significantly increased metastasis to the lung (10/12 vs. 3/12) when re-inoculated into the livers of new recipient nude mice. Molecular changes consistent with epithelial-mesenchymal transition (EMT) were observed in oxaliplatin-treated tumor tissues and verified by in vitro experiments. The Chinese herbal extract Songyou Yin (4.2 and 8.4 g/kg) attenuated EMT and inhibited the enhanced metastatic potential of residual HCC in nude mice (6/15 vs. 13/15 and 3/15 vs. 13/15, respectively).
Conclusions
The surviving HCC after oxaliplatin treatment underwent EMT and demonstrated increased metastatic potential. Attenuation of EMT by Songyou Yin may improve the efficacy of chemotherapy in HCC.
doi:10.1186/1471-2407-10-219
PMCID: PMC2880993  PMID: 20487542
10.  The subcellular localization of IGFBP5 affects its cell growth and migration functions in breast cancer 
BMC Cancer  2009;9:103.
Background
Insulin-like growth factor binding protein 5 (IGFBP5) has been shown to be associated with breast cancer metastasis in clinical marker studies. However, a major difficulty in understanding how IGFBP5 functions in this capacity is the paradoxical observation that ectopic overexpression of IGFBP5 in breast cancer cell lines results in suppressed cellular proliferation. In cancer tissues, IGFBP5 resides mainly in the cytoplasm; however, in transfected cells, IGFBP5 is mainly located in the nucleus. We hypothesized that subcellular localization of IGFBP5 affects its functions in host cells.
Methods
To test this hypothesis, we generated wild-type and mutant IGFBP5 expression constructs. The mutation occurs within the nuclear localization sequence (NLS) of the protein and is generated by site-directed mutagenesis using the wild-type IGFBP5 expression construct as a template. Next, we transfected each expression construct into MDA-MB-435 breast cancer cells to establish stable clones overexpressing either wild-type or mutant IGFBP5.
Results
Functional analysis revealed that cells overexpressing wild-type IGFBP5 had significantly lower cell growth rate and motility than the vector-transfected cells, whereas cells overexpressing mutant IGFBP5 demonstrated a significantly higher ability to proliferate and migrate. To illustrate the subcellular localization of the proteins, we generated wild-type and mutant IGFBP5-pDsRed fluorescence fusion constructs. Fluorescence microscopy imaging revealed that mutation of the NLS in IGFBP5 switched the accumulation of IGFBP5 from the nucleus to the cytoplasm of the protein.
Conclusion
Together, these findings imply that the mutant form of IGFBP5 increases proliferation and motility of breast cancer cells and that mutation of the NLS in IGFBP5 results in localization of IGFBP5 in the cytoplasm, suggesting that subcellular localization of IGFBP5 affects its cell growth and migration functions in the breast cancer cells.
doi:10.1186/1471-2407-9-103
PMCID: PMC2670316  PMID: 19341485
11.  Identification of genes regulated by Wnt/β-catenin pathway and involved in apoptosis via microarray analysis 
BMC Cancer  2006;6:221.
Background
Wnt/β-catenin pathway has critical roles in development and oncogenesis. Although significant progress has been made in understanding the downstream signaling cascade of this pathway, little is known regarding Wnt/β-catenin pathway modification of the cellular apoptosis.
Methods
To identify potential genes regulated by Wnt/β-catenin pathway and involved in apoptosis, we used a stably integrated, inducible RNA interference (RNAi) vector to specific inhibit the expression and the transcriptional activity of β-catenin in HeLa cells. Meanwhile, we designed an oligonucleotide microarray covering 1384 apoptosis-related genes. Using oligonucleotide microarrays, a series of differential expression of genes was identified and further confirmed by RT-PCR.
Results
Stably integrated inducible RNAi vector could effectively suppress β-catenin expression and the transcriptional activity of β-catenin/TCF. Meanwhile, depletion of β-catenin in this manner made the cells more sensitive to apoptosis. 130 genes involved in some important cell-apoptotic pathways, such as PTEN-PI3K-AKT pathway, NF-κB pathway and p53 pathway, showed significant alteration in their expression level after the knockdown of β-catenin.
Conclusion
Coupling RNAi knockdown with microarray and RT-PCR analyses proves to be a versatile strategy for identifying genes regulated by Wnt/β-catenin pathway and for a better understanding the role of this pathway in apoptosis. Some of the identified β-catenin/TCF directed or indirected target genes may represent excellent targets to limit tumor growth.
doi:10.1186/1471-2407-6-221
PMCID: PMC1574340  PMID: 16959035
12.  Application of serum SELDI proteomic patterns in diagnosis of lung cancer 
BMC Cancer  2005;5:83.
Background
Currently, no satisfactory biomarkers are available to screen for lung cancer. Surface-Enhanced Laser Desorption/ionization Time-of- Flight Mass Spectrometry ProteinChip system (SELDI-TOF-MS) is one of the currently used techniques to identify biomarkers for cancers. The aim of this study is to explore the application of serum SELDI proteomic patterns to distinguish lung cancer patients from healthy individuals.
Methods
A total of 208 serum samples, including 158 lung cancer patients and 50 healthy individuals, were randomly divided into a training set (including 11 sera from patients with stages I/II lung cancer, 63 from patients with stages III/IV lung cancer and 20 from healthy controls) and a blinded test set (including 43 sera from patients with stages I/II lung cancer, 41 from patients with stages III/IV lung cancer and 30 from healthy controls). All samples were analyzed by SELDI technology. The spectra were generated on weak cation exchange (WCX2) chips, and protein peaks clustering and classification analyses were made using Ciphergen Biomarker Wizard and Biomarker Pattern software, respectively. We additionally determined Cyfra21-1 and NSE in the 208 serum samples included in this study using an electrochemiluminescent immunoassay.
Results
Five protein peaks at 11493, 6429, 8245, 5335 and 2538 Da were automatically chosen as a biomarker pattern in the training set. When the SELDI marker pattern was tested with the blinded test set, it yielded a sensitivity of 86.9%, a specificity of 80.0% and a positive predictive value of 92.4%. The sensitivities provided by Cyfra21-1 and NSE used individually or in combination were significantly lower than that of the SELDI marker pattern (P < 0.005 or 0.05, respectively). Based on the results of the test set, we found that the SELDI marker pattern showed a sensitivity of 91.4% in the detection of non-small cell lung cancers (NSCLC), which was significantly higher than that in the detection of small cell lung cancers (P < 0.05); The pattern also had a sensitivity of 79.1% in the detection of lung cancers in stages I/II.
Conclusion
These results suggest that serum SELDI protein profiling can distinguish lung cancer patients, especially NSCLC patients, from normal subjects with relatively high sensitivity and specificity, and the SELDI-TOF-MS is a potential tool for the screening of lung cancer.
doi:10.1186/1471-2407-5-83
PMCID: PMC1183195  PMID: 16029516

Results 1-12 (12)