Cancer Science via MedWorm.com

ZAK inhibits human lung cancer cell growth via ERK and JNK activation in an AP-1-dependent manner

Cancer Science — Sat, 13 Mar 2010 00:00:00 +0100

Novel mixed-lineage kinase protein zipper sterile-[alpha]-motif kinase (ZAK) was first cloned by our laboratory. Lung cancer is the leading cause of cancer-related death in the world, including in Taiwan. Here, we wanted to investigate whether ZAK plays a potential role in lung cancer development. First, Western blot analysis results demonstrated that four cell lines expressed high levels of ZAK from among a panel of 10 lung cancer cell lines, and two of three normal lung cells expressed ZAK. ZAK gene expressions were down-regulated in lung cancers by real-time PCR analysis. Overexpression of ZAK suppressed cell proliferation in parallel with increased phosphorylated levels of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK). In contrast, ZAK silencing cells in...

BRCA1 and XRCC1 polymorphisms associated with survival in advanced gastric cancer treated with taxane and cisplatin

Cancer Science — Fri, 12 Mar 2010 00:00:00 +0100

This study evaluated the influence of genetic polymorphism influencing drug metabolism on survival in taxane- and cisplatin-treated advanced gastric cancer (AGC). Peripheral blood samples from 207 AGC patients treated with first-line chemotherapy of taxane and cisplatin were used. We investigated polymorphisms that influenced the metabolism of taxane (ATP-binding cassette transporter B1 (ABCB1)), cisplatin (glutathione S-transferase M1 (GSTM1), glutathione S-transferase P1 (GSTP1), glutathione S-transferase T1 (GSTT1), excision repair cross complementing 1 (ERCC1), X-ray Cross Complementing group 3 (XRCC3), X-ray Cross Complementing group 4 (XRCC4), X-ray Cross Complementing group 1 (XRCC1), breast cancer (BRCA1)), and 5-fluorouracil (methylene tetrahydrofolate reductase (MTHFR), thymidyla...

Clinical study of asbestos-related lung cancer in Japan with special reference to occupational history

Cancer Science — Wed, 10 Mar 2010 00:00:00 +0100

A total of 152 patients with asbestos-related lung cancer recognized by the criteria of Japanese compensation law for asbestos-related diseases were examined and compared with 431 patients with non-asbestos-related lung cancer. Male comprised 96% of patients. Ages ranged from 50 to 91 years with a median of 72 years. Eighty-nine percent were smokers or ex-smokers. Almost all patients had occupational histories of asbestos exposure. The median duration of asbestos exposure was 31 years and the median latency period was 47 years. Thirty-four percent of patients exhibited asbestosis and 81% exhibited pleural plaques by radiography. Regarding asbestos particles in the lung for 73 operated or autopsied patients, 62% had more than 5,000 particles per gram. On the other hand, 100% of non-asbestos...

Overexpression of yes-associated protein contributes to progression and poor prognosis of non-small-cell lung cancer

Cancer Science — Mon, 08 Mar 2010 00:00:00 +0100

This study aimed to assess the clinical significance and biological functions of YAP in non-small-cell lung cancer (NSCLC). We investigated the expression of YAP in 92 cases of NSCLC tissue by immunohistochemistry and found that YAP was expressed in 66.3% (61/92) cases and predominantly presented in the nucleus. The expression of YAP in NSCLC was significantly correlated with p-TNM stage (P = 0.0037) and lymph node metastasis (P = 0.0093). Importantly, YAP expression was associated with short overall survival. Further study in NSCLC cell lines in which YAP was either overexpressed or depleted confirmed that YAP markedly promoted cell proliferation and invasion. These results indicate that YAP plays an important role in NSCLC and might be a useful therapeutic target of NSCLC. (Cancer Sci 20...

TGF-β1 signal pathway may contribute to rhabdomyosarcoma development by inhibiting differentiation

Cancer Science — Sun, 07 Mar 2010 00:00:00 +0100

Overexpression of transforming growth factor-[beta]1 (TGF-[beta]1) and its downstream molecules in the rhabdomyosarcoma (RMS) RD cell line has been reported previously, but the regulatory role of TGF-[beta]1 on RMS has not been studied extensively. In the present study, we showed that expression of TGF-[beta]1 and its downstream molecules type II TGF-[beta] receptor (T[beta]RII) and Smad4 was significantly higher in RMS than in normal skeletal muscle, and there was a significant relationship between TGF-[beta]1 expression and histological grade. Gene silencing with TGF-[beta]1 short-hairpin RNA (shRNA)-expressing vectors significantly decreased the growth of RD cells, which was confirmed by caspase-3 (in vitro) and TUNEL (in vivo) assays. Moreover, a proportion of treated rhabdomyosarcoma ...

Imaging and biodistribution of Her2/neu expression in non-small cell lung cancer xenografts with 64Cu-labeled trastuzumab PET

Cancer Science — Thu, 04 Mar 2010 00:00:00 +0100

Non-small cell lung carcinomas (NSCLC) overexpress the Her2/neu gene in approximately 59% of cases. Trastuzumab, a humanized monoclonal antibody, interferes with Her2 signaling and is approved for the treatment of Her2/neu overexpressing breast cancer. However, its therapeutic use in Her2/neu overexpressing NSCLC remains obscure. The present study aimed to determine the role of 64Cu-labeled trastuzumab positron emission tomography (PET) for non-invasive imaging of Her2/neu expression in NSCLC. Trastuzumab was conjugated with the bifunctional chelator 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid (DOTA) and radiolabeled with 64Cu. The molecular specificity of DOTA-trastuzumab was determined in NSCLC cell lines with Her2/neu overexpression (NCI-H2170) and negative expression...

Secular trends in breast cancer mortality in five East Asian populations: Hong Kong, Japan, Korea, Singapore and Taiwan

Cancer Science — Wed, 03 Mar 2010 00:00:00 +0100

Breast cancer risk is increasing in most Asian female populations, but little is known about the long-term mortality trend of the disease among these populations. We extracted data for Hong Kong (1979[ndash]2005), Japan (1963[ndash]2006), Korea (1985[ndash]2006), and Singapore (1963[ndash]2006) from the World Health Organization (WHO) mortality database and for Taiwan (1964[ndash]2007) from the Taiwan cancer registry. The annual age-standardized, truncated (to [ge]20 years) breast cancer death rates for 11 age groups were estimated and joinpoint regression was applied to detect significant changes in breast cancer mortality. We also compared age-specific mortality rates for three calendar periods (1975[ndash]1984, 1985[ndash]1994, and 1995[ndash]2006). After 1990, breast cancer mortality t...

Circulating tumor cells as a surrogate marker for determining response to chemotherapy in patients with advanced gastric cancer

Cancer Science — Tue, 02 Mar 2010 00:00:00 +0100

This study investigates the hypothesis that CTCs can predict clinical outcomes in patients with AGC. From November 2007 to June 2009, 52 patients with AGC were enrolled into a prospective study. The chemotherapy regimen was an S-1-based regimen (S-1 with or without cisplatin) or paclitaxel. CTCs of whole blood at baseline, 2 weeks, and 4 weeks after initiation of chemotherapy, were isolated and enumerated using immunomagnetics. Patients with [ge]4 CTCs at 2-week points and 4-week points had a shorter median progression-free survival (PFS) (1.4, 1.4 months, respectively) than those with the median PFS of (Source: Cancer Science)

Foxo3a expression and acetylation regulate cancer cell growth and sensitivity to cisplatin

Cancer Science — Mon, 01 Mar 2010 00:00:00 +0100

In this study, we found that cisplatin-resistant cells were more sensitive to the anticancer agent mithramycin than their parental cells, and had a decreased level of Foxo3a expression. Foxo3a knockdown increased cell proliferation and resistance to cisplatin. On the other hand, mithramycin stimulated Foxo3a expression through reactive oxygen species production and sensitized cells to cisplatin, which was abolished by Foxo3a knockdown, while the acetylation status of Foxo3a was decreased in response to cisplatin treatment and was lower in cisplatin-resistant cells. Knockdown of Foxo3a-associated acetyltransferase p300 promoted cancer-cell growth and cisplatin resistance. In addition, non-acetylation-mimicking Foxo3a overexpression decreased cancer cell growth and sensitized cells to cispla...

Mitochondria regulate the unfolded protein response leading to cancer cell survival under glucose deprivation conditions

Cancer Science — Sat, 27 Feb 2010 00:00:00 +0100

This study suggests a link between mitochondria and the ER during the UPR under glucose deprivation conditions and that mitochondria govern cell fate, not only through ATP production and apoptosis regulation, but also through modulating the UPR for cell survival. (Cancer Sci 2010) (Source: Cancer Science)

Pleomorphic phenotypes of gastrointestinal stromal tumors at metastatic sites with or without imatinib treatment

Cancer Science — Wed, 24 Feb 2010 00:00:00 +0100

In this study, we analyzed the genotypes and the histologic and immunohistochemical phenotypes of metastatic GISTs with and without imatinib treatment, and clarified the pleomorphic nature of metastatic GISTs. We examined 31 autopsy cases in which the patients died of multiple metastases of GISTs, and two surgically resected specimens with and without imatinib treatment. A total of 152 primary and metastatic lesions in 33 cases of GISTs were examined for histologic and immunohistochemical expression of KIT and CD34. We analyzed the expression of other receptor tyrosine kinases (RTKs) in KIT-negative lesions, including human EGFR-related 2 (HER2), epidermal growth factor receptor (EGFR), hepatocyte growth factor receptor (MET), platelet-derived growth factor receptor-[alpha] (PDGFRA), and p...

Immunohistochemical analysis of CYP2A13 in various types of human lung cancers

Cancer Science — Mon, 22 Feb 2010 00:00:00 +0100

In conclusion, we first found that the expression of CYP2A13 was markedly increased in non-small cell lung carcinomas. The high expression might be associated with the tumor development and progression in non-small cell lung carcinomas. (Cancer Sci 2010) (Source: Cancer Science)

Frequent transcriptional inactivation of Kallikrein 10 gene by CpG island hypermethylation in non-small cell lung cancer

Cancer Science — Mon, 22 Feb 2010 00:00:00 +0100

In conclusion, KLK10 acts as a functional tumor suppressor gene in NSCLC, epigenetic inactivation of KLK10 is a common event contributing to NSCLC pathogenesis and may be used as a potential biomarker. (Cancer Sci 2010) (Source: Cancer Science)

Sensitive immunohistochemical detection of WT1 protein in tumors with anti-WT1 antibody against WT1 235 peptide

Cancer Science — Mon, 22 Feb 2010 00:00:00 +0100

The Wilms' tumor 1 (WT1) gene is overexpressed in leukemia and various types of solid tumor, such as lung and colorectal cancer, and plays an oncogenic role in their tumorigenesis. Recent studies have demonstrated the potential of WT1-targeting cancer immunotherapy in clinical settings. As expression of WT1 protein in tumor cells is a prerequisite for WT1-targeting immunotherapy, immunohistochemical methods to detect WT1 protein with high sensitivity and specificity are required. In the present study, we developed a rabbit polyclonal antibody (WT1-R) against the 9-mer WT1 235 peptide, which is used for vaccination. The specificity of WT1-R was confirmed by immunoprecipitation, western blotting analysis, and competitive enzyme-linked immunosorbent assay. Immunocytochemistry showed the same ...

Major vault protein forms complexes with hypoxia-inducible factor (HIF)-1α and reduces HIF-1α level in ACHN human renal adenocarcinoma cells

Cancer Science — Thu, 18 Feb 2010 00:00:00 +0100

In this study, we focused on hypoxia-inducible factor-1[alpha] (HIF-1[alpha]), which is a master regulator of hypoxic responses, and found that: (i) MVP knockdown by RNA interference increases HIF-1[alpha] protein levels induced by hypoxia and hypoxia mimetics; (ii) MVP knockdown does not affect HIF-1[alpha] mRNA levels, but decreases the ubiquitination and degradation of HIF-1[alpha] protein; and (iii) vaults form complexes with HIF-1[alpha], PHD2, and pVHL. Taken together, these results suggest that vaults function as scaffolds in HIF-1[alpha] degradation pathway and promote the ubiquitination and degradation of HIF-1[alpha]. (Cancer Sci 2010) (Source: Cancer Science)

Identification of increased NBS1 expression as a prognostic marker of squamous cell carcinoma of the oral cavity

Cancer Science — Thu, 18 Feb 2010 00:00:00 +0100

In this study, we enrolled 148 OSCC for immunohistochemical (IHC) and clinical analysis. Data from 58 advanced non-oral-cavity HNSCC (NO-HNSCC) cases were also included for comparison due to the biological and clinical discrepancy between OSCC and HNSCC originated from the other sites (e.g. pharynx or larynx). First, we validated the NBS1 IHC results by real-time RT-PCR analysis, and an excellent correlation between the results of these two assays confirmed the reliability and robustness of IHC procedures and interpretation. NBS1 overexpression was an independent prognostic marker in both OSCC and NO-HNSCC cases. In OSCC, the prognostic significance of NBS1 was shown regardless of T stage and lymph node status. Increased NBS1 expression correlated with advanced T stage and recurrence/metas...

Toll-like receptor 9 expression in breast and ovarian cancer is associated with poorly differentiated tumors

Cancer Science — Sat, 13 Feb 2010 00:00:00 +0100

Toll-like receptor 9 (TLR9) activates the innate immune response when exposed to non-methylated CpG-DNA. TLR9 was recently shown to be expressed by cancer cells which have been previously characterized by global hypomethylation. We set out to examine the expression and molecular activity of TLR9 in breast and ovarian cancer cells. Firstly, we confirmed higher levels of hypomethylated DNA in the serum of patients with metastatic breast cancer (n = 18) versus age-matched tumor-free women (n = 18). In breast cancer cell lines and tissues, TLR9 mRNA expression was associated with estrogen-receptor (ER) status (n = 124, P = 0.005). Expression also correlated with increasing tumor grade in both breast (P = 0.03) and ovarian cancer specimens (n = 138, P = 0.04). Immunohistochemical analysis of fo...

Association between vitamin D and calcium intake and breast cancer risk according to menopausal status and receptor status in Japan

Cancer Science — Fri, 12 Feb 2010 00:00:00 +0100

We examined 1803 breast cancer patients and 3606 age- and menopausal status-matched noncancer controls. Among cases, 713 were assessed for ER, PR, and HER2 status. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated using conditional or unconditional logistic models adjusted for potential confounders. A significant inverse association was observed between vitamin D and calcium intake and breast cancer risk among all subjects, with top quartile ORs of 0.76 (95% CI, 0.63[ndash]0.90; trend P = 0.001) and 0.83 (95% CI, 0.69[ndash]0.99; trend P = 0.038), respectively. In analyses stratified by menopausal status, a significant association between risk and vitamin D was observed only among premenopausal women (trend P < 0.001), whereas that between risk and calcium intake was see...

Diagnostic performance of computer tomography, magnetic resonance imaging, and positron emission tomography or positron emission tomography/computer tomography for detection of metastatic lymph nodes in patients with cervical cancer: Meta-analys

Cancer Science — Thu, 11 Feb 2010 00:00:00 +0100

We performed a meta-analysis to compare diagnostic performances of computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET or PET/CT), for detection of metastatic lymph nodes in patients with cervical cancer. We searched MEDLINE (PubMed), EMBASE and the Cochrane Review database in December 2007. All articles were independently reviewed and selected by three evaluators. We estimated a summary receiver operating characteristic (sROC) curve. The area under the curve (AUC), Q*, and pooled weighted estimates of sensitivity and specificity for each modality by patient-based and region- or node-based data analyses and conducted pair-wise comparisons between modalities using the two-sample Z-test. Forty-one of 768 initially identified studies were included...

Inhibition of ErbB2 by Herceptin reduces survivin expression via the ErbB2–β-catenin/TCF4-survivin pathway in ErbB2-overexpressed breast cancer cells

Cancer Science — Thu, 11 Feb 2010 00:00:00 +0100

In this study, we found that Herceptin could inhibit the expression of survivin in ErbB2-overexpressed cell lines. Overexpression of survivin could abrogate the inhibition of cell growth induced by Herceptin. Herceptin could reduce survivin expression at the transcriptional level. The [beta]-catenin/T-cell factor (TCF) pathway played a very crucial role in this cascade. We found that Herceptin could reduce tyrosine phosphorylation levels of ErbB2 and [beta]-catenin. Herceptin treatment induced degradation of [beta]-catenin protein, resulting in reduced binding affinity of [beta]-catenin/TCF4 to the promoter region of survivin. When we cross-mutated the TCF4 binding sites in the promoter region of survivin, the reduction of survivin promoter activity almost diminished. Taken together, we sh...

Anti-miR-21 oligonucleotide sensitizes leukemic K562 cells to arsenic trioxide by inducing apoptosis

Cancer Science — Thu, 11 Feb 2010 00:00:00 +0100

Arsenic trioxide (ATO), an ancient traditional Chinese medicine, has been successfully used as a therapeutic agent for leukemia. Drug resistance and toxicity are major concerns with the treatment. MicroRNAs (miRNAs) are endogenous small non-coding RNA molecules that might modulate cellular sensitivity to anticancer drugs. miRNA-21 (miR-21) is one of the most prominent miRNAs involved in various aspects of human cancers. However, miR-21 has been rarely characterized in chronic myelogenous leukemia (CML). Here, we used a specific anti-miR-21 oligonucleotide (AMO-miR-21) to sensitize K562 cells to ATO by degradation of miR-21. The results showed that both AMO-miR-21 and ATO caused growth inhibition, apoptosis, and G1-phase arrest in K562 cells. Meanwhile, AMO-miR-21 significantly promoted ATO...

Epidermal growth factor-dependent enhancement of invasiveness of squamous cell carcinoma of the breast

Cancer Science — Mon, 08 Feb 2010 00:00:00 +0100

Factors that promote the aggressiveness of squamous cell carcinoma of the breast are not well understood. To examine the involvement of cell motility and the mechanism of this behavior, a squamous cell carcinoma cell line of the breast (HBC9) was established from a metastatic lymph node of a Japanese woman. HBC9 expressed epidermal growth factor receptor (EGFR), but was negative for Her2 or Her3.The invasive ability of HBC9 was compared with that of four breast ductal carcinoma cell lines by Matrigel invasion assay. EGF stimulation induced the formation of surface protrusions and cell migration in HBC9 cells, and significantly increased the number of cells migrating through the Matrigel. The invasive ability of HBC9 was compared with other cell lines of breast carcinoma; it was much greate...

High frequencies of less differentiated and more proliferative WT1-specific CD8+ T cells in bone marrow in tumor-bearing patients: An important role of bone marrow as a secondary lymphoid organ

Cancer Science — Sat, 06 Feb 2010 00:00:00 +0100

In this study, to clarify the immune response to the WT1 antigen, WT1-specific CD8+ T cells that were spontaneously induced in patients with solid tumor were comparatively analyzed in both bone marrow (BM) and peripheral blood (PB). WT1-specific CD8+ T cells more frequently existed in BM than in PB, whereas frequencies of naïve (CCR7+ CD45RA+), central memory (CCR7+ CD45RA[minus]), effector-memory (CCR7[minus] CD45RA[minus]), and effector (CCR7[minus] CD45RA+) subsets were not significantly different between BM and PB. However, analysis of these subsets for the expression of CD57 and CD28, which were associated with differentiation, revealed that effector-memory and effector subsets of the WT1-specific CD8+ T cells in BM had less differentiated phenotypes and more proliferative potential ...

Cantharidin, a potent and selective PP2A inhibitor, induces an oxidative stress-independent growth inhibition of pancreatic cancer cells through G2/M cell-cycle arrest and apoptosis

Cancer Science — Fri, 05 Feb 2010 00:00:00 +0100

Cantharidin is an active constituent of mylabris, a traditional Chinese medicine. It is a potent and selective inhibitor of protein phosphatase 2A (PP2A) that plays an important role in control of cell cycle, apoptosis, and cell-fate determination. Owing to its antitumor activity, cantharidin has been frequently used in clinical practice. In the present study, we investigated the therapeutic potential of cantharidin in pancreatic cancer. Cantharidin efficiently inhibited the growth of pancreatic cancer cells, but presented a much lighter toxicity effect against normal pancreatic duct cells. It caused G2/M cell-cycle arrest that was accompanied by the down-regulation of cyclin-dependent kinase 1 (CDK1) and up-regulation of p21 expression. It induced apoptosis and elevated the expressions of...

Influence of the prodrugs 5-fluorocytosine and CPT-11 on ovarian cancer cells using genetically engineered stem cells: tumor-tropic potential and inhibition of ovarian cancer cell growth

Cancer Science — Fri, 05 Feb 2010 00:00:00 +0100

Recent studies have shown that genetically engineered stem cells (GESTECs) to produce suicide enzymes that convert non-toxic prodrugs to toxic metabolites selectively migrate toward tumor sites and reduce tumor growth. In the present study, we evaluated whether these GESTECs were capable of migrating to human ovarian cancer cells and examined the potential therapeutic efficacy of the gene-directed enzyme prodrug therapy against ovarian cancer cells in vitro. The expression of cytosine deaminase (CD) or carboxyl esterase (CE) mRNA of GESTECs was confirmed by RT-PCR. A modified transwell migration assay was performed to determine the migratory capacity of GESTECs to ovarian cancer cells. GESTECs (HB1.F3.CD or HB1.F3.CE cells) engineered to express a suicide gene (CD or CE) selectively migrat...

Analysis of DOK-6 function in downstream signaling of RET in human neuroblastoma cells

Cancer Science — Wed, 03 Feb 2010 00:00:00 +0100

Point mutations and structural alterations of the RET tyrosine kinase gene cause multiple endocrine neoplasia type 2 (MEN 2) and papillary thyroid carcinoma, respectively. RET activation by glial cell line-derived neurotrophic factor (GDNF) is essential for the development of the enteric nervous system and the kidney. The signal through RET tyrosine kinase requires several adaptor proteins including the DOK (downstream of kinase) family of proteins. Of the seven members of the DOK protein family, DOK-1, -4, -5, and -6 have been reported to play roles in the GDNF[ndash]RET signaling pathway. Although DOK-6 has been shown to bind to RET and promote GDNF-induced neurite outgrowth in mouse Neuro2A cells, DOK-6 function in human cells remains unclear. In the present study, we investigated the r...

Vasohibin-1 as a potential predictor of aggressive behavior of ductal carcinoma in situ of the breast

Cancer Science — Wed, 03 Feb 2010 00:00:00 +0100

In this study, we first evaluated mRNA expression of vasohibin-1 and CD31 in 39 Japanese female breast carcinoma specimens including 22 invasive ductal carcinoma (IDC) and 17 ductal carcinoma in situ (DCIS) using a real-time quantitative RT-PCR (QRT-PCR) with LightCycler system. In addition, we also immunolocalized vasohibin-1 and CD31 and compared their immunoreactivity to nuclear grades and histological grades of 100 carcinoma cases (50 IDC and 50 DCIS). There were no statistically significant differences of CD31 mRNA expression and the number of CD31 positive vessels between DCIS and IDC (P = 0.250 and P = 0.191, respectively), whereas there was a statistically significant difference in vasohibin-1 mRNA expression and the number of vasohibin-1 positive vessels in DCIS and IDC (P = 0.022...

Vasohibin-1 as a potential predictor of aggressive behavior of ductal carcinoma in situ of the breast

Cancer Science — Wed, 03 Feb 2010 00:00:00 +0100

The cell death machinery governed by the p53 tumor suppressor in response to DNA damage

Cancer Science — Wed, 03 Feb 2010 00:00:00 +0100

The cellular response to genotoxic stress that damages DNA includes cell cycle arrest, activation of DNA repair, and in the event of irreparable damage, induction of apoptosis. However, the signals that determine cell fate, that is, survival or apoptosis, are largely unclear. The tumor suppressor p53 has been implicated in many important cellular processes, including regulation of apoptotic cell death. When cells encounter genotoxic stress, certain sensors for DNA lesions eventually stabilize and activate p53. Subsequently, p53 exerts its tumor suppressor function by transactivating numerous target genes. Active p53 is subjected to a complex and diverse array of covalent post-translational modifications, which selectively influence the expression of p53 target genes. In this regard, the mo...

Combination of RET siRNA and irinotecan inhibited the growth of medullary thyroid carcinoma TT cells and xenografts via apoptosis

Cancer Science — Tue, 02 Feb 2010 00:00:00 +0100

The objective of this study was to examine whether small interfering RNA (siRNA) and its combined treatment with CPT-11 could inhibit MTC cell growth in vitro and in vivo. The transfection of RET siRNA suppressed RET expression, reduced proliferation, and increased caspase-3/7 activity via the down-regulation of Bcl-2 expression. Combined treatments with CPT-11 or SN-38 significantly increased caspase 3/7 activity compared with RET siRNA, CPT-11 or SN-38 treatment alone. Importantly, intratumoral injection of RET siRNA along with intravenous injection of CPT-11 significantly inhibited the tumor growth of MTC xenografts via an increased apoptotic effect. These findings that RET siRNA enhanced sensitivity for CPT-11 will provide a novel strategy for the treatment of MTC with RET mutation. (C...

Combination of RET siRNA and irinotecan inhibited the growth of medullary thyroid carcinoma TT cells and xenografts via apoptosis

Cancer Science — Tue, 02 Feb 2010 00:00:00 +0100

Influence of the prodrugs 5-fluorocytosine and CPT-11 on ovarian cancer cells using genetically engineered stem cells: tumor-tropic potential and inhibition of ovarian cancer cell growth

Cancer Science — Tue, 02 Feb 2010 00:00:00 +0100

Girding for migratory cues: roles of the Akt substrate Girdin in cancer progression and angiogenesis

Cancer Science — Tue, 02 Feb 2010 00:00:00 +0100

Cell migration is a fundamental aspect of a multitude of physiological and pathological processes, including embryonic development, inflammation, angiogenesis, and cancer progression. A variety of proteins are essential for cell migration, but context-specific signaling pathways and promigratory proteins must now be identified for our understanding of cancer biology to continue to advance. In this review, we focus on the emerging roles of Girdin (also designated KIAA1212, APE, GIV, and HkRP1), a novel component of the phosphatidylinositol 3-kinase (PI3-K)/Akt signaling pathway that is a core-signaling transduction pathway in cancer progression. Girdin is expressed in some types of cancer cells and immature endothelial cells, and is therefore at the crossroads of multiple intracellular proc...

Initiation of malignancy by duodenal contents reflux and the role of ezrin in developing esophageal squamous cell carcinoma

Cancer Science — Fri, 29 Jan 2010 00:00:00 +0100

Gastroesophageal reflux has recently been implicated as a causative factor in upper aerodigestive tract carcinogenesis. Esophageal squamous cell carcinomas (ESCCs) have developed in duodenal-content reflux animals without any known carcinogen present. We established a cell line, designated ESCC-DR, from a thoracic metastatic tumor in a reflux animal. To gain insight into the genomic alterations associated with duodenal content reflux-induced carcinogenesis, we first performed comparative genomic hybridization using an Agilent rat 244K array in ESCC-DR and identified many chromosomal gains and losses. Of the many genes identified, we detected an interesting ezrin amplicon that has been recently reported in human ESCC. Ezrin, which cross-links the cytoskeleton and plasma membrane, is involve...

Clinicopathologic correlations of diffuse large B-cell lymphoma in rheumatoid arthritis patients treated with methotrexate

Cancer Science — Thu, 28 Jan 2010 00:00:00 +0100

This study included 29 patients who developed DLBCL after receiving MTX for rheumatoid arthritis. MTX was discontinued in all patients. Their median age was 62 years. Elevated lactate dehydrogenase (LDH) level was observed in 97% of the patients, bone marrow involvement in 17%, and involvement of extranodal sites in 41%. As for the cellular immunophenotype, CD20 was positive in 93%, CD5 in 3%, CD10 in 31%, BCL2 in 21%, BCL6 in 69%, and Epstein[ndash]Barr virus (EBV)-encoded small non-polyadenylated RNA (EBER) in 24%. Chemotherapy was started within 2 months after MTX withdrawal in 23 patients, of whom 12 patients received combination with rituximab. Spontaneous remission occurred in the remaining six patients. The EEBV-positive rate was 67% (4/6), and the four EBV-positive patients achieve...

Hyperthermia-associated carboplatin resistance: Differential role of p53, HSF1 and Hsp70 in hepatoma cells

Cancer Science — Thu, 28 Jan 2010 00:00:00 +0100

Due to substantial technical improvements, clinical application of heat as a co-adjuvant in cancer treatment is acquiring new interest. The effect of hyperthermia on hepatoma cell lines Hep3B (p53 defective) and HepG2 (p53 wild type) when investigated led to an interesting observation that Hep3B cells are more susceptible to heat stress than HepG2 cells. In addition, heat-induced carboplatin resistance was observed in HepG2 cells only. To investigate the reasons, heat shock response was explored and it was observed that heat stress augmented heat shock protein 70 (Hsp70) expression levels in HepG2 and not in Hep3B cells. Furthermore, in HepG2 cells, induced Hsp70 is regulated by both p53 and heat shock transcription factor 1 (HSF1) wherein HSF1 levels are modulated by p53. The data implies...

Novel chemoembolization using calcium-phosphate ceramic microsphere incorporating TNP-470, an anti-angiogenic agent

Cancer Science — Wed, 27 Jan 2010 00:00:00 +0100

The purpose of the present study was to develop a new method of chemoembolization to improve the therapeutic effectiveness and safety profile of cancer treatment. A chemoembolization approach was designed for human solid tumors using resorbable calcium-phosphate ceramic microspheres loaded with an agent anti-angiogenic to tumor vasculature in vivo. The human uterine sarcoma cell line FU-MMT-3 was used in this study because this tumor is aggressive and also exhibits a poor response to radiotherapy or any chemotherapy currently used. The calcium-phosphate ceramic microspheres loaded with TNP-470, an anti-angiogenic agent, were injected into FU-MMT-3 xenografts in nude mice three times per week for 8 weeks. The treatment using TNP-470-loaded microspheres suppressed tumor growth, compared to t...

Combination of vesicular stomatitis virus matrix protein gene therapy with low-dose cisplatin improves therapeutic efficacy against murine melonoma

Cancer Science — Fri, 22 Jan 2010 00:00:00 +0100

Vesicular stomatitis virus (VSV) matrix protein (MP) can directly induce apoptosis via the mitochondrial pathway due to the inhibition of host gene expression. Our previous studies have demonstrated that MP gene therapy efficiently suppressed the growth of malignant tumor in vitro and in vivo. The present study was designed to determine the possibility that the combination of MP gene therapy with low-dose cisplatin would improve therapeutic efficacy against murine melanoma. Immunocompetent C57BL/6 mice bearing B16-F10 melanoma were established. Mice were treated once every 5 days with i.v. administration of 10 [mu]g pVAX-MP/30 [mu]g liposome complex per mouse for 16 days and i.p. delivery of cisplatin at 4 mg/kg/mouse on days 6 and 12 after the initiation of MP treatment. We found that MP ...

Glutathione S-transferase A4 is a positive marker for rat hepatic foci induced by clofibrate and genotoxic carcinogens

Cancer Science — Fri, 22 Jan 2010 00:00:00 +0100

Peroxisome proliferators (PP), including clofibrate (CF), are non-genotoxic rodent carcinogens, and oxidative DNA damages are suggested as a causative event for carcinogenesis. Gene expression profiles differ between hepatic lesions induced by PP and genotoxic carcinogens. Our previous study revealed that expression of L-bifunctional enzyme (enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase, BE) was repressed in preneoplastic lesions induced by PP, whereas it was enhanced in the surrounding tissues. In the present study, we immunohistochemically examined expression of the specific glutathione S-transferase (GST) form, GST-A4, which detoxifies 4-hydroxy-alkenal, the end-product of lipid peroxides, and nuclear factor-erythroid 2-related factor 2 (Nrf2), a transcription factor for many gene...

Matrix metalloproteinase-7 as a marker of metastasis and predictor of poor survival in bladder cancer

Cancer Science — Wed, 20 Jan 2010 00:00:00 +0100

Matrix metalloproteinases (MMPs) play an important role in tumor progression and metastasis. Here, we investigated the prognostic relevance of MMP-7 in urinary bladder cancer. MMP-7 gene expression was measured in tissue samples of 101 patients using quantitative real-time PCR. Circulating MMP-7 serum levels of 98 individuals (79 patients and 19 controls) were analyzed by enzyme-linked immunosorbent assay. The results were compared with the clinical follow-up data, performing Kaplan[ndash]Meier log-rank test as well as univariate and multivariate Cox analysis. In representative cases, immunohistochemical analysis for MMP-7 was performed. We detected significantly elevated MMP-7 levels both in tissue and serum samples of patients with metastatic disease (P = 0.001 and P = 0.002). Multivaria...

Establishment of six new human biliary tract carcinoma cell lines and identification of MAGEH1 as a candidate biomarker for predicting the efficacy of gemcitabine treatment

Cancer Science — Wed, 20 Jan 2010 00:00:00 +0100

The aim of this study was to establish new biliary tract carcinoma (BTC) cell lines and identify predictive biomarkers for the potential effectiveness of gemcitabine therapy. Surgical specimens of BTC were transplanted directly into immunodeficient mice to establish xenografts, then subjected to in vitro cell culture. The gemcitabine sensitivity of each cell line was determined and compared with the genome-wide gene expression profile. A new predictive biomarker candidate was validated using an additional cohort of gemcitabine-treated BTC cases. From 55 BTC cases, we established 19 xenografts and six new cell lines. Based on their gemcitabine sensitivity, 10 BTC cell lines (including six new and four publicly available ones) were clearly categorized into two groups, and MAGEH1 mRNA express...

Prognostic significance of genetic alterations detected by high-density single nucleotide polymorphism array in gastric cancer

Cancer Science — Tue, 19 Jan 2010 00:00:00 +0100

We sought to identify genomic changes that could be useful for clinical application, focusing on chromosomal instability and using a high-density single nucleotide polymorphism (SNP) array. We analyzed 34 gastric cancer cell lines for areas of DNA that exhibited copy number changes using the Affymetrix GeneChip Human Mapping 50 K Arrays. The results obtained with the cell lines were verified in 42 gastric cancer tissues using genomic PCR, quantitative real-time PCR, and loss of heterozygosity (LOH) analyses. Twenty-six local homozygous deletion regions, including 13 novel loci, and 31 recurrent high-grade gain regions, encompassing 14 novel loci, were found in the gastric cancer cell lines. Among the genes detected for high-grade gain in the cell lines, MYC, PAK1, and ITGB4BP showed copy n...

Mechanism of antitumor effect of a novel bFGF binding peptide on human colon cancer cells

Cancer Science — Tue, 19 Jan 2010 00:00:00 +0100

In this study, we first demonstrated that a novel bFGF-binding peptide (named P7) inhibited proliferation of several colon cancer cell lines including HT-29, LoVo, and Caco2 cells stimulated by bFGF. Further investigations with HT-29 cells indicated that P7 arrested the cell cycle at the G0/G1 phase of bFGF-stimulated cells, reduced the levels of phospho-Erk1/Erk2 induced by bFGF, and caused significant changes in the expression of proteins related to proliferation, cell cycle, and cancer. Our results suggested that the bFGF-binding peptide has a potential antitumor effect on colon cancer. (Cancer Sci 2010; 00: 000[ndash]000) (Source: Cancer Science)

Aurora A selective inhibitor MLN8237 suppresses the growth and survival of HTLV-1-infected T-cells in vitro

Cancer Science — Tue, 19 Jan 2010 00:00:00 +0100

In this study, we addressed this question by comparing the effects of MLN8237, a selective inhibitor of Aurora A, on cell viability, cell cycle progression, and induction of apoptosis in HTLV-1-infected and -uninfected T-cell lines. MLN8237 reduced the viability of HTLV-1-infected T-cell lines within 24 h, but its effects on that of HTLV-1-uninfected T-cell lines were moderate. MLN8237 induced early apoptosis of HTLV-1-infected T-cell lines without induction of polyploidy. It induced p53 and p21 expression in HTLV-1-infected but not in -uninfected T-cell lines, suggesting that MLN8237-treated HTLV-1-infected T-cell lines exit from mitosis and activate a p53-dependent postmitotic G1 checkpoint, leading to G1 arrest followed by the induction of apoptosis. Our results suggest that specific in...

Wnt signaling stabilizes the DIXDC1 protein through decreased ubiquitin-dependent degradation

Cancer Science — Tue, 19 Jan 2010 00:00:00 +0100

Wnt signaling plays key roles in development, cell growth, differentiation, polarity formation, neural development, and carcinogenesis. DIX Domain Containing 1 (DIXDC1), a novel component of the Wnt pathway, was recently cloned. DIXDC1 is the human homolog of Ccd1, a positive regulator of the Wnt signaling pathway during zebrafish neural patterning. Little has been known about DIXDC1 gene expression regulation. In the present study, we showed that the DIXDC1 protein was induced upon Wnt-3a stimulation, whereas the DIXDC1 mRNA level was not significantly increased after Wnt-3a treatment. Positive DIXDC1 staining was detected in colon cancer cells and was colocalized with [beta]-catenin staining. However, the DIXDC1 mRNA expression decreased in human colon cancer cells compared to the matche...

Frequent hypermethylation and loss of heterozygosity of the testis derived transcript gene in ovarian cancer

Cancer Science — Mon, 18 Jan 2010 00:00:00 +0100

Testis derived transcript (TES) is a candidate tumor suppressor gene located at the human chromosome 7q31, and its function in ovarian cancer is still unknown. Using ovarian cancer cell lines and tissue samples, we demonstrated that both loss of heterozygosity and hypermethylation of the TES gene occurred in ovarian cancer at high frequencies, and there were significant correlations between TES expression and hypermethylation or loss of heterozygosity. We also detected methylation in ovarian cancer cell line A2780 after treatment with 5-aza-2-deoxycytidine. The expression level of TES was enormously up-regulated, then caused changes to the biological behaviors of A2780 cells: cell growth properties were greatly impaired, colony formatting abilities were suppressed to very low levels, and t...

Coordinate action of membrane-type matrix metalloproteinase -1 (MT1-MMP) and MMP-2 enhances pericellular proteolysis and invasion

Cancer Science — Mon, 18 Jan 2010 00:00:00 +0100

Membrane-type matrix metalloproteinase-1 (MT1-MMP) mediates cleavage of not only MMP-2/gelatinase A for activation, but also a variety of substrates including type I collagen (reviewed in Cancer Sci 2005; 96: 212[ndash]7). MMP-2 activation involves tissue inhibitor of MMP (TIMP)-2 as a bridging molecule between MT1-MMP and pro-MMP-2. Thus, net activity of MT1-MMP and MMP-2 is regulated in a complex manner depending on TIMP-2 concentration. During invasive growth of tumor cells in type I collagen matrix, MT1-MMP initiates denaturation of collagen into gelatin, which is subsequently digested further by MMP-2 adjacent to MT1-MMP. Coordinate action of MT1-MMP and MMP-2 may facilitate pericellular proteolysis, and enhance not only tumor invasion/migration but also cell growth. Tetraspanins as b...

Expression and regulation mechanisms of Sonic Hedgehog in breast cancer

Cancer Science — Fri, 15 Jan 2010 00:00:00 +0100

Sonic Hedgehog (Shh) plays an essential role in vertebrate organogenesis as well as the development of some cancers, including breast cancer. The aim of the present study was to characterize more precisely its role in breast carcinogenesis and elucidate its regulation mechanisms. The expression of Shh was investigated in 97 breast carcinomas and 22 paired non-tumorous tissues (distant from the primary tumor) by immunohistochemistry and in four breast cell lines by Western blotting. We also analyzed the methylation status of the Shh gene with methylation-specific PCR and assessed whether nuclear factor-kappa B (NF-[kappa]B) and Gli1 were expressed in breast tissues by immunohistochemistry. Our results showed that Shh protein expression in breast carcinomas was significant higher than that i...

Diversity of genome profiles in malignant lymphoma

Cancer Science — Wed, 13 Jan 2010 00:00:00 +0100

Characteristic chromosome translocations are associated with specific disease entities, and are known to play a pivotal role in lymphoma development. Chromosome translocation alone, however, is not sufficient to produce tumors. Factors including the microenvironment and epigenetic and genetic alterations other than chromosome translocations have been shown to play a role in lymphoma development. Follicular lymphoma cells proliferate in close contact with follicular dendritic cells. Mucosa-associated lymphoid tissue (MALT) lymphoma cells proliferate at the marginal zone area of reactive follicles which are formed by preceding chronic inflammation. The importance of genetic alterations other than chromosome translocation has been recognized since the introduction of array comparative genomic...

Up-regulation of pro-inflammatory genes as adaptation to hypoxia in MCF-7 cells and in human mammary invasive carcinoma microenvironment

Cancer Science — Tue, 12 Jan 2010 00:00:00 +0100

The role of tumor cells in synthesizing pro-inflammatory molecules is still controversial. Here we report that hypoxic treatment of the MCF-7 human mammary adenocarcinoma cell line induced activation of hypoxia-inducible factor 1[alpha] (HIF-1[alpha]) and nuclear factor-kappa B (NF-[kappa]B). Importantly, hypoxia regulated expression of alarmin receptors such as the receptor for advanced glycation end products (RAGE) and the purinoreceptor (P2X7R), and up-regulated inflammatory response (IR) genes such as the inducible enzymes nitric oxide synthase (NOS2), cycloxygenase (COX2), and the acute-phase protein pentraxin-3 (PTX3). Hypoxia also stimulated chemokine (C-X-C motif) receptor 4 (CXCR4) mRNA synthesis. In fact, the CXCR4 ligand stromal-derived factor-1[alpha] (SDF-1[alpha]) increased i...

Pigpen, a nuclear coiled body component protein, is involved in angiogenesis

Cancer Science — Tue, 12 Jan 2010 00:00:00 +0100

In this study, we searched for molecules that function during angiogenesis with PILSAP. We performed proteome analysis of nuclear extracts from embryoid bodies (EBs) made from ES cells transfected with mutant PILSAP lacking aminopeptidase activity and mock EBs. We identified pigpen, a 67-kDa nuclear coiled body component protein. Immunoprecipitation and western blotting demonstrated the binding of PILSAP and pigpen in endothelial cells (ECs), and this interaction was enhanced by VEGF and bFGF. Pigpen was reported to be expressed in actively growing ECs such as those in embryos and tumors. However, whether Pigpen is involved in angiogenesis is not known. Therefore, we examined the effect of pigpen on angiogenesis by silencing pigpen with siRNA (siPigpen). Compared with scrambled RNA (scrPig...

Augmentation of 3-methylcholanthrene-induced bioactivation in the human hepatoma cell line HepG2 by the calcium channel blocker nicardipine

Cancer Science — Sat, 09 Jan 2010 00:00:00 +0100

The abilities of the dihydropyridine calcium channel blocker nicardipine (Nic) to induce cytochrome P450 1 family enzymes (CYP1s) and to enhance the 3-methylcholanthrene (MC)-mediated induction of CYP1s and formation of MC-DNA adduct were examined in the human hepatoma cell line HepG2. The results from real time RT-PCR analysis demonstrated that Nic could induce CYP1 mRNAs and enhance the MC-mediated induction of the CYP1 mRNAs. The luciferase-reporter gene assay using the HepG2-A10 cell line, which has been previously established for the screening of aryl hydrocarbon receptor (AhR) activators, also indicated the augmentation of MC-mediated activation of AhR (induction of luciferase) by Nic, although Nic showed limited capacity for the activation of AhR. Furthermore, the results from the W...

Cellular context-dependent "colors" of transforming growth factor-β signaling

Cancer Science — Fri, 08 Jan 2010 00:00:00 +0100

Transforming growth factor (TGF)-[beta] signaling has interesting characteristics in the context of cancer. Although perturbations of TGF-[beta] signaling are strongly implicated in cancer progression, TGF-[beta] signaling has both tumor-suppressive and tumor-promoting effects. For example, TGF-[beta] inhibits cancer cell proliferation in some cellular contexts, but promotes it in others. Although several approaches to treating cancer have been considered using TGF-[beta]-based therapeutic strategies, the contradictory behaviors of TGF-[beta] have made these approaches complex. To put them to practical use, either the tumor-suppressive or tumor-promoting arm needs to be specifically manipulated. However, there is virtually no method to specifically regulate a certain cell response induced ...

Cyclin-dependent kinase inhibitor SU9516 enhances sensitivity to methotrexate in human T-cell leukemia Jurkat cells

Cancer Science — Tue, 05 Jan 2010 00:00:00 +0100

Methotrexate (MTX) has been used to treat various hematological malignancies. Since MTX prevents tumor cells from proliferating by inhibiting dihydrofolate reductase (DHFR), DHFR expression is a key determinant of resistance to MTX in malignant hematological tumor cells. The antiproliferative effect of MTX was significantly enhanced by the knockdown of DHFR expression by siRNA in Jurkat cells. Therefore, a novel strategy down-regulating DHFR expression seems promising for enhancing sensitivity to MTX. We found that SU9516, a cyclin-dependent kinase inhibitor, reduced the expression of both DHFR mRNA and protein. Moreover, we found that DHFR promoter activity was attenuated by SU9516 dependent on the E2F site. Finally, pretreatment with SU9516 significantly enhanced sensitivity to MTX in a ...

hTERT-promoter-dependent oncolytic adenovirus enhances the transduction and therapeutic efficacy of replication-defective adenovirus vectors in pancreatic cancer cells

Cancer Science — Mon, 04 Jan 2010 00:00:00 +0100

In this study, we investigated the effect of the human telomerase reverse transcriptase (hTERT)-CRAd, Ad5/3hTERTE1, which possesses the tumor-specific hTERT promoter with the chimeric fiber 5/3, on the transgene expression and therapeutic efficacy of a replication-defective adenovirus vector expressing NK4 under the control of the CMV promoter, Ad-NK4. In addition, we established a new strategy to target both cancer cells and cancer[ndash]stromal interactions. Human pancreatic cancer cells were infected with Ad-NK4 and either Ad5/3hTERTE1 (CRAd-combination group) or Ad5/3hTERTLuc (control-combination group). In the CRAd-combination group, Ad-NK4-delivered transgene expression was increased, leading to an enhanced inhibitory effect on the invasion of cancer cells. In in vivo experiments, NK...

Epidermal growth factor receptor intron 1 CA dinucleotide repeat polymorphism and survival of advanced gastric cancer patients treated with cetuximab plus modified FOLFOX6

Cancer Science — Sat, 26 Dec 2009 00:00:00 +0100

Cetuximab is a monoclonal antibody targeting epidermal growth factor receptor (EGFR). The present study investigated the association between germline genetic polymorphisms and the treatment outcome of cetuximab plus modified leucovovin, fluorouracil, and oxaliplatin (FOLFOX)6 chemotherapy in advanced gastric cancer (AGC). DNA from peripheral blood mononuclear cells of 38 patients enrolled in a phase II study of cetuximab plus modified FOLFOX6 were analyzed for 16 polymorphisms in eight genes (EGFR, epidermal growth factor, transforming growth factor-[alpha] (TGFA), thymidylate synthase, excision repair cross-complementation group 1, Xeroderma pigmentosum group D, and fragment c gamma receptors (FCGR)2A and 3A). The EGFR intron 1 CA repeat polymorphism was associated with survival. Twenty-o...

Altered phenotype of lymphatic endothelial cells induced by highly metastatic OTSCC cells contributed to the lymphatic metastasis of OTSCC cells

Cancer Science — Mon, 21 Dec 2009 00:00:00 +0100

This article aims to explore cancer cell-induced changes of LEC, and study the tumor[ndash]lymphatic endothelium interaction. Here, LECs were co-cultured with highly and poorly metastatic tongue cancer cells. The differences in biologic behaviors and gene expression profiles between them were examined. The results showed that LECs induced by highly metastatic cancer cells displayed abnormal biologic behaviors, and could secrete chemokines to promote the migration of cancer cells. Therefore, biologic properties and functional status of LECs in oral tongue squamous cell carcinoma (OTSCC) might be a positive factor in lymphatic dissemination. (Source: Cancer Science)

CD133 expression in rectal cancer after preoperative chemoradiotherapy

Cancer Science — Sat, 19 Dec 2009 00:00:00 +0100

CD133-positive cells have been reported to possess a cancer-initiating-cell phenotype and the property of resistance to chemoradiation therapy in colorectal cancer. The aim of the present study was to evaluate quantitative and locational changes in CD133-positive cells in rectal cancer patients who received preoperative chemoradiation therapy. The prognostic significance of CD133 expression in patients with preoperative chemoradiation therapy was also analyzed. Immunohistochemical staining for CD133 and cancer-initiating-cell marker CD44 were performed in 92 surgically resected rectal cancers. Of the 92 cases, 43 patients received preoperative chemoradiation therapy and 49 patients underwent surgery alone. Forty pretherapic biopsy specimens from 43 patients in preoperative chemoradiation t...

Irrespective of CD34 expression, lineage-committed cell fraction reconstitutes and re-establishes transformed Philadelphia chromosome-positive leukemia in NOD / SCID / IL-2Rγc−/− mice

Cancer Science — Fri, 18 Dec 2009 00:00:00 +0100

Stem cells of acute myeloid leukemia (AML) have been identified as immunodeficient mouse-repopulating cells with a Lin[minus]CD34+38[minus] phenotype similar to normal hematopoietic stem cells. To identify the leukemia-propagating stem cell fraction of Philadelphia chromosome-positive (Ph+) leukemia, we serially transplanted human leukemia cells from patients with chronic myeloid leukemia blast crisis (n = 3) or Ph+ acute lymphoblastic leukemia (n = 3) into NOD/SCID/IL-2R[gamma]c[minus]/[minus] mice. Engrafted cells were almost identical to the original leukemia cells as to phenotypes, IGH rearrangements, and karyotypes. CD34+CD38[minus]CD19+, CD34+38+CD19+, and CD34[minus]CD38+CD19+ fractions could self-renew and transfer the leukemia, whereas the CD34[minus]CD38+CD19+ fraction did not st...

Dominant-negative derivative of EBNA1 represses EBNA1-mediated transforming gene expression during the acute phase of Epstein–Barr virus infection independent of rapid loss of viral genome

Cancer Science — Wed, 16 Dec 2009 00:00:00 +0100

The oncogenic human herpes virus, the Epstein[ndash]Barr virus (EBV), expresses EBNA1 in almost all forms of viral latency. EBNA1 plays a major role in the maintenance of the viral genome and in the transactivation of viral transforming genes, including EBNA2 and latent membrane protein (LMP-1). However, it is unknown whether inhibition of EBNA1 from the onset of EBV infection disrupts the establishment of EBV's latency and transactivation of the viral oncogenes. To address this, we measured EBV infection kinetics in the B cell lines BALL-1 and BJAB, which stably express a dominant-negative EBNA1 (dnE1) fused to green fluorescent protein (GFP). The EBV genome was surprisingly unstable 1 week post-infection: the average loss rate of EBV DNA from GFP- and GFP-dnE1-expressing cells was 53.4% ...

Recurrence and mortality dynamics for breast cancer patients undergoing mastectomy according to estrogen receptor status: Different mortality but similar recurrence

Cancer Science — Wed, 16 Dec 2009 00:00:00 +0100

The purpose was to ascertain whether the recurrence risk patterns for patients with estrogen receptor (ER)-positive (P) and ER-negative (N) breast cancer support the ER-related clinical divergence suggested by the observed different mortality patterns and gene expression profiles. Both recurrence and death were considered in a series of 771 patients undergoing mastectomy. ER status was available for 539 patients. The hazard rates for recurrence and mortality throughout 15 years of follow-up were assessed. The recurrence dynamics displays a bimodal pattern for both ERP and ERN tumors with comparable peak timings. The two curves cross during the 3rd year. By contrast, the mortality dynamics are definitely different for ERP and ERN tumors: during the early follow-up period ERN patients have t...

The role of oxysterol binding protein-related protein 5 in pancreatic cancer

Cancer Science — Wed, 16 Dec 2009 00:00:00 +0100

The expression of oxysterol binding protein-related protein (ORP) 5 is related to invasion and a poor prognosis in pancreatic cancer patients. ORP5 induced the expression of sterol response element binding protein (SREBP) 2 and activated the downstream gene of sterol response element. ChIP using SREBP2 antibody revealed that histone deacetylase 5 (HDAC5) was one of the downstream genes of SREBP2. The effect of HMG-CoA reductase inhibitors (statins) were analyzed according to the expression level of ORP5. The invasion rate and growth was suppressed in cells that strongly expressed ORP5 in a time- and dose-dependent manner, but had less effect in cells weakly expressing ORP5, suggesting that when the potential of invasion and growth relies on the cholesterol synthesis pathway, it becomes sen...

Serial analysis of gene expression of esophageal squamous cell carcinoma: ADAMTS16 is upregulated in esophageal squamous cell carcinoma

Cancer Science — Wed, 16 Dec 2009 00:00:00 +0100

Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies worldwide. To identify potential diagnostic markers for ESCC and therapeutic targets for ESCC, we used Serial Analysis of Gene Expression (SAGE) on one ESCC sample. We obtained a total of 14 430 tags, including 5765 that were unique. By comparing SAGE tags from the ESCC sample with those from normal human squamous esophagus, we found several genes that were differentially expressed between ESCC and normal squamous esophagus. Among these, we focused on the ADAM metallopeptidase with thrombospondin type 1 motif, 16 (ADAMTS16) gene because quantitative RT-PCR analysis showed a high level of ADAMTS16 expression in eight out of 20 ESCC samples (40%), but not in 15 kinds of normal tissues. Western blot analysis also...

Silencing of secreted protein acidic and rich in cysteine inhibits the growth of human melanoma cells with G1 arrest induction

Cancer Science — Wed, 16 Dec 2009 00:00:00 +0100

The overexpression of secreted protein acidic and rich in cysteine (SPARC) is associated with increased aggressiveness and poor prognosis in malignant melanoma. Its roles and underlying mechanisms on melanoma cell growth, however, are not fully clarified. To validate the potential of SPARC as a therapeutic target, we examined the effect of the knockdown of SPARC with SPARC-specific siRNA on the growth of human melanoma cell lines. SPARC siRNAs exerted a potent knockdown effect. Silencing of SPARC resulted in growth inhibition with G1 arrest accompanied by accumulation of p21, a G1 cyclin-dependent kinase inhibitor, in MeWo and CRL1579 cells. Moreover, the induction of p53 was observed in MeWo cells, but not in CRL1579 cells. Conditioned media containing SPARC from MeWo cells could not rest...

Lactobacillus rhamnosus GG induces tumor regression in mice bearing orthotopic bladder tumors

Cancer Science — Tue, 15 Dec 2009 00:00:00 +0100

The present gold standard for bladder cancer is Mycobacterium bovis, Bacillus Calmette Guerin (BCG) immunotherapy. But it has a non-responder rate of 30[ndash]50% and side effects are common. Lactobacillus casei strain Shirota has been reported to reduce the incidence of recurrence in bladder cancer patients and to cure tumor-bearing mice. Our aim was to determine if Lactobacillus rhamnosus GG (LGG) could be as efficacious as BCG in a murine model of bladder cancer. MB49 bladder cancer cells secreting human prostate-specific antigen were implanted orthotopically in female C57BL/6 mice and urinary prostate-specific antigen levels were used as a marker of tumor growth. Mice were treated with either live or lyophilized LGG given via intravesical instillation, or both oral and intravesical LGG...

(−)-Epigallocatechin-3-gallate induces Du145 prostate cancer cell death via downregulation of inhibitor of DNA binding 2, a dominant negative helix-loop-helix protein

Cancer Science — Mon, 14 Dec 2009 00:00:00 +0100

([minus])-Epigallocatechin-3-gallate (EGCG) is one of the major polyphenol components in green tea. It effectively induces apoptosis in prostate cancer cells. The anticancer effect of this reagent is appealing because it is a natural component of a popular daily beverage that has proven harmless for thousands of years, making it a good candidate chemopreventive agent. EGCG suppresses cell growth and causes cell death, but the mechanisms are not well characterized, especially in androgen-independent prostate cancer cells. In the present study, using Affymetrix genechip Hu133 2.0, we analyzed the gene expression patterns of the androgen-independent prostate cancer cell line Du145, treated with or without EGCG, and found 40 genes whose expression levels were altered (>twofold, either upregula...

3-Methylcholanthrene-induced transforming growth factor-β-producing carcinomas, but not sarcomas, are refractory to regulatory T cell-depletion therapy

Cancer Science — Fri, 11 Dec 2009 00:00:00 +0100

Regulatory T cells (Tregs) are major immunosuppressors in tumor-bearing hosts. Although Treg-depletion therapy has been shown to induce a complete cure in tumor-bearing mice, this treatment is not always successful. Using 3-methylcholanthrene-induced primary mouse tumors, we examined the distinct regulation of Treg-mediated immunosuppression between carcinomas and sarcomas. We showed that the number of Tregs was greatly increased in squamous cell carcinoma (SCC)-bearing mice compared with sarcoma-bearing mice. This appeared to be because SCC produced higher levels of active transforming growth factor (TGF)-[beta], which is essential for inducing Tregs, compared with sarcoma. Moreover, SCC, but not sarcomas, were refractory to Treg-depletion therapy by treatment with anti-CD25 mAb. The refr...

Inhibition of mTORC1 activity by REDD1 induction in myeloma cells resistant to bortezomib cytotoxicity

Cancer Science — Fri, 11 Dec 2009 00:00:00 +0100

The combination of bortezomib and dexamethasone is becoming the reference induction treatment for multiple myeloma patients younger than 65 years. Despite its advantage over vincristin adryamicin dexamethasone induction treatment, bortezomib does not benefit all patients. We hypothesize that heterogeneity of the response experienced by myeloma patients is, at least in part, due to genomic variations in the malignant plasma cells. To test this hypothesis we used gene expression profiling to identify early responsive genes induced by bortezomib in resistant myeloma cells. Our study revealed: (i) a dramatic induction of REDD1, a negative regulator of mammalian target of rapamycin kinase complex 1 (mTORC1) activity, in these cells; (ii) a transient cell size decrease associated with REDD1 over...

Mantle cell lymphoma shows three morphological evolutions of classical, intermediate, and aggressive forms, which occur in parallel with increased labeling index of cyclin D1 and Ki-67

Cancer Science — Thu, 10 Dec 2009 00:00:00 +0100

Although the 2008 World Health Organization classification defines two subtypes of mantle cell lymphoma (MCL), classical and aggressive, we often encounter MCL with both features in the same site. We named this feature "MCL with focal aggressive form (intermediate MCL)". In the present study, we reclassified 237 patients with cyclin D1 (CCND1)-positive MCL on the basis of the concept of intermediate MCL, and analyzed the correlation of this reclassification with immunohistochemical detection of CCND1, Ki-67, p53, p27Kip1, and p21WAF/Cip1. The median overall survival was 77, 31, and 18 months for classical, intermediate, and aggressive MCL, respectively, showing a statistically significant difference (P < 0.0001). The expression levels of CCND1, Ki-67, p53, and p21WAF/Cip1 in aggressive MCL...

Genistein synergizes with arsenic trioxide to suppress human hepatocellular carcinoma

Cancer Science — Wed, 09 Dec 2009 00:00:00 +0100

This study sought to determine whether genistein synergizes with ATO to combat hepatocellular carcinoma (HCC). Three human HCC cell lines, namely HepG2, Hep3B, and SK-Hep-1, were incubated with ATO, genistein, or ATO + genistein. The cells were also pretreated with antioxidant agents N-acetyl-L-cysteine (NAC) or butylated hydroxyanisole (BHA). Cell viability, apoptosis, intracellular reactive oxygen species (ROS), mitochondrial membrane potential ([Delta][Psi]m), expression of Bcl-2, Bax, caspase-9, and -3, and release of cytochrome c into the cytosol were examined. The synergistic effect of ATO and genistein was also assessed using HepG2 xenografts subcutaneously established in BALB/c nude mice. The results show that genistein synergized with ATO to reduce viability, induce apoptosis, and...

Effect of axitinib (AG-013736) on fatigue, thyroid-stimulating hormone, and biomarkers: A phase I study in Japanese patients

Cancer Science — Wed, 09 Dec 2009 00:00:00 +0100

Axitinib is an oral, potent, and selective inhibitor of vascular endothelial growth factor receptor (VEGFR) 1, 2, and 3. This phase I study evaluated the safety, pharmacokinetics, pharmacodynamics, antitumor activity, and recommended starting dose of axitinib in patients with advanced solid tumors. Twelve patients received single-dose axitinib 5 mg and were monitored for [ge]48 h. Continuous 5 mg twice-daily dosing was then initiated. One patient had dose-limiting toxicity (grade 3 proteinuria and fatigue). Common treatment-related adverse events were anorexia, fatigue, and diarrhea. Grade 3 treatment-related adverse events were fatigue and hypertension. Maximum axitinib plasma concentration occurred 1[ndash]4 h after steady-state dosing. Eleven patients experienced thyroid-stimulating hor...

Antitumor activity of anti-C-ERC/mesothelin monoclonal antibody in vivo

Cancer Science — Wed, 09 Dec 2009 00:00:00 +0100

In this study, we investigated the antitumor activity of C-ERC/mesothelin-specific mouse monoclonal antibody, 22A31, against tumors derived from a human mesothelioma cell line, ACC-MESO-4, in a xenograft experimental model using female BALB/c athymic nude mice. Treatment with 22A31 did not inhibit cell proliferation of ACC-MESO-4 in vitro; however, therapeutic treatment with 22A31 drastically inhibited tumor growth in vivo. 22A31 induced antibody-dependent cell-mediated cytotoxicity by natural killer (NK) cells, but not macrophages, in vitro. Consistently, the F(ab')2 fragment of 22A31 did not inhibit tumor growth in vivo, nor did it induce antibody-dependent cell mediated cytotoxicity (ADCC) in vitro. Moreover, NK cell depletion diminished the antitumor effect of 22A31. Thus, 22A31 induce...

Heavy smoking history interacts with chemoradiotherapy for esophageal cancer prognosis: A retrospective study

Cancer Science — Wed, 09 Dec 2009 00:00:00 +0100

In this study we retrospectively analyzed 364 patients with esophageal squamous cell cancer who were treated between 2001 and 2005 at our institution. Background characteristics, including smoking history, were analyzed as potential prognostic factors. Of the 363 patients, 76 patients (20.9%) were non-smokers or light smokers (non-heavy), whereas 287 patients (79.1%) were heavy smokers. The 5-year survival rate for non-heavy smokers and heavy smokers was 61.8% (95% confidence interval [CI]: 49.1[ndash]72.2) vs 44.6% (95% CI: 38.2[ndash]50.9), respectively. In a multivariate Cox model (adjusted for age, gender, performance status, alcohol consumption, histology, tumor length, International Union Against Cancer [UICC] stage, and treatment), the hazard ratio for heavy smokers in comparison wi...

Histone acetylation and steroid receptor coactivator expression during clofibrate-induced rat hepatocarcinogenesis

Cancer Science — Tue, 08 Dec 2009 00:00:00 +0100

Peroxisome proliferators (PPs), non-genotoxic rodent carcinogens, cause the induction of the peroxisomal fatty acid [beta]-oxidation system, including bifunctional enzyme (BE) and 3-ketoacyl-CoA thiolase (TH), in the liver. GST M1 gene is polymorphic in Sprague[ndash]Dawley rats, NC- and KS-type. The KS-type rats showed enhanced susceptibility to ethyl-[alpha]-chlorophenoxyisobutyrate (clofibrate, CF), one of the PPs. The degree of BE induction was higher in the KS-type and preneoplastic foci developed after 6[ndash]8 weeks of treatment, whereas no foci developed in the NC-type. In the preset study, factors involved in different BE inducibility were investigated. There were no differences in hepatic peroxisome proliferator-activated receptor (PPAR) [alpha] levels between them. Among variou...

Genome-wide identification of chemosensitive single nucleotide polymorphism markers in colorectal cancers

Cancer Science — Tue, 08 Dec 2009 00:00:00 +0100

Improved methods for predicting chemoresponsiveness involving the identification of polymorphic markers is highly desirable, considering narrow therapeutic index and frequent resistance to anti-cancer regimens. The genome-wide screening of chemosensitive single nucleotide polymorphisms (SNPs) was undertaken in association with in vitro chemosensitivity assays in 104 colorectal cancer patients for the initial screening step. Allele frequency, linkage disequilibrium, potential function, and Hardy[ndash]Weinberg equilibrium of the candidate SNPs were then determined for the identifying step. Finally, clinical association analysis in the other 260 evaluable patients or cell viability assays of transfected RKO cells was used to verify candidate SNPs for the validation step. In total, 12 SNPs to...

Immunological evaluation of personalized peptide vaccination monotherapy in patients with castration-resistant prostate cancer

Cancer Science — Mon, 07 Dec 2009 00:00:00 +0100

We previously reported that personalized peptide vaccine (PPV) therapy in combination with leutenizing hormone-releasing hormone (LH-RH) analog and estramustine phosphate in certain cases is safe and capable of inducing both immune responses and clinical responses for metastatic castration-resistant prostate cancer (CRPC) patients. In the present study, PPV monotherapy was given to CRPC patients. Twenty-three patients with metastatic CRPC were treated with PPV without any additional treatment modalities, including LH-RH analogs. Samples were analyzed for peptide-specific cytotoxic T-lymphocyte (CTL) precursor analysis and peptide-reactive IgG. Toxicity and immunological and clinical responses were assessed on a three-monthly basis. Seventeen patients were available for immunological and cl...

High expression of BUBR1 is one of the factors for inducing DNA aneuploidy and progression in gastric cancer