bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tumor-Specific Inhibition of Membrane-Bound Complement Regulatory Protein Crry with Bispecific Monoclonal Antibodies Prevents Tumor Outgrowth in a Rat Colorectal Cancer Lung Metastases Model
Authors: Gelderman Kyra A. , Kuppen Peter J. K. , Okada Noriko , Fleuren Gert Jan , Gorter Arko 
Published: September 2005

AbstractMembrane-bound complement regulatory proteins (mCRP) inhibit complement-mediated tumor cell eradication in vitro and in vivo. Immunotherapy of cancer with monoclonal antibodies (mAbs) that activate complement might be hampered by expression of mCRP on tumor cells. An important strategy to improve mAb immunotherapy can be blocking or overwhelming mCRP at the tumor cells surface in a tumor-specific manner. In our study, we investigated the feasibility of this approach in vivo using bispecific mAbs (bi-mAbs). This study, performed in a syngeneic lung metastases model of rat (WAG/Rij) colorectal cancer, showed that modulation of mCRP on tumor cells resulted in significantly decreased tumor outgrowth. Opsonization of tumor cells with a bi-mAb directed against a tumor-associated antigen and rat mCRP Crry (MG42a*5I2) almost completely prevented the outgrowth of lung tumors (0–7 tumors/rat; n = 17). Opsonization with mAb-cobra venom factor conjugates significantly reduced the number of lung tumors (23–59 tumors; n = 12) compared with the unconjugated MG42a (175–246 tumors; n = 17; P = 0.008 and 0.014, respectively). The effect of MG42a*5I2 was shown to be caused by increased complement activation due to inhibition of Crry. Moreover, prophylactic treatment with MG42a*5I2 or MG42a showed comparable results (3–24 and 215–472 tumors, P = 0.02; n = 6) as observed with pre-opsonized tumor cells without noticeable side effects, despite binding of MG42a*5I2 to endothelium and leukocytes. These results demonstrate that Crry inhibits complement-mediated tumor cell eradication by immunotherapeutic mAbs and show that tumor-specific inhibition of complement regulatory proteins using bi-mAbs can significantly improve mAb-mediated immunotherapy.
Cyclooxygenase-2 Is Essential for HER2/
neu
to Suppress
N
- (4-Hydroxyphenyl)retinamide Apoptotic Effects in Breast Cancer Cells
Authors: Simeone Ann-Marie , Li Yu-Jiang , Broemeling Lyle D. , Johnson Marcella M. , Tuna Musaffe , Tari Ana M. 
Published: September 2005

Abstract
We reported that HER2/neu reduces the sensitivity of breast cancer cells to N-(4-hydroxyphenyl)retinamide (4-HPR) by suppressing nitric oxide production. We show that HER2/neu uses Akt to induce cyclooxygenase-2 (COX-2) expression and that inhibition of Akt or COX-2 increases 4-HPR-induced apoptosis and nitric oxide production. Apoptosis induced by the 4-HPR and COX-2 inhibitor combination, although unaffected by an anti-HER2/neu antibody, was reversed by the COX-2 product prostaglandin E2, indicating that COX-2 is a major mechanism by which HER2/neu suppresses 4-HPR apoptosis in breast cancer cells. Combining 4-HPR with COX-2 inhibitors may be a novel chemopreventive strategy against HER2/neu-overexpressing breast tumors.
Identification of Soluble NH2-Terminal Fragment of Glypican-3 as a Serological Marker for Early-Stage Hepatocellular Carcinoma
Authors: Hippo Yoshitaka , Watanabe Kiyotaka , Watanabe Akira , Midorikawa Yutaka , Yamamoto Shogo , Ihara Sigeo , Tokita Susumu , Iwanari Hiroko , Ito Yukio , Nakano Kiyotaka , Nezu Jun-ichi , Tsunoda Hiroyuki , Yoshino Takeshi , Ohizumi Iwao , Tsuchiya Masayuki , Ohnishi Shin , Makuuchi Masatoshi , Hamakubo Takao , Kodama Tatsuhiko , Aburatani Hiroyuki 
Published: September 2005

Abstract
For detection of hepatocellular carcinoma (HCC) in patients with liver cirrhosis, serum α-fetoprotein has been widely used, but its sensitivity has not been satisfactory, especially in small, well-differentiated HCC, and complementary serum marker has been clinically required. Glypican-3 (GPC3), a heparan sulfate proteoglycan anchored to the plasma membrane, is a good candidate marker of HCC because it is an oncofetal protein overexpressed in HCC at both the mRNA and protein levels. In this study, we demonstrated that its NH2-terminal portion [soluble GPC3 (sGPC3)] is cleaved between Arg358 and Ser359 of GPC3 and that sGPC3 can be specifically detected in the sera of patients with HCC. Serum levels of sGPC3 were 4.84 ± 8.91 ng/ml in HCC, significantly higher than the levels seen in liver cirrhosis (1.09 ± 0.74 ng/ml; P &lt; 0.01) and healthy controls (0.65 ± 0.32 ng/ml; P &lt; 0.001). In well- or moderately-differentiated HCC, sGPC3 was superior to α-fetoprotein in sensitivity, and a combination measurement of both markers improved overall sensitivity from 50% to 72%. These results indicate that sGPC3 is a novel serological marker essential for the early detection of HCC.
Role of Carbonic Anhydrase IX in Human Tumor Cell Growth, Survival, and Invasion
Authors: Robertson Naomi , Potter Christian , Harris Adrian L. 
Published: September 2005

Abstract
Carbonic anhydrase IX (CAIX) is a membrane-associated carbonic anhydrase (CA), strongly induced by hypoxia. CAIX is overexpressed in a variety of tumor types and associated with increased metastasis and poor prognosis. An inhibitor of CAs, acetazolamide has been reported to inhibit invasion. We used RNA interference (RNAi) to examine the function of CAIX in MDA468 and MDA231 breast carcinoma cells, which express high levels of CAIX under hypoxia. Hypoxia-induced CA activity was completely blocked by specific RNAi (P &lt; 0.01). RNAi-treated cells showed growth delay in dense monolayer culture and a 50% reduction in clonogenic survival under hypoxia. In the MDA468 cells, there was no effect of RNAi treatment on invasion. In a cell line that did not induce CAIX under hypoxia, RT112, we found no effect on the ability of cells transfected with CAIX to invade or migrate. Thus, CAIX plays an important role in the growth and survival of tumor cells under normoxia and hypoxia, making it a potential target for cancer therapy, but is not involved in invasion.
Systemic Retinoic Acid Treatment Induces Sodium/Iodide Symporter Expression and Radioiodide Uptake in Mouse Breast Cancer Models
Authors: Kogai Takahiko , Kanamoto Yoko , Che Lisa H. , Taki Katsumi , Moatamed Farhad , Schultz James J. , Brent Gregory A. 
Published: September 2005

Abstract
Lactating breast tissue and some breast cancers express the sodium/iodide symporter (NIS) and concentrate iodide. We recently demonstrated that all-trans retinoic acid (tRA) induces both NIS gene expression and iodide accumulation in vitro in well-differentiated human breast cancer cells (MCF-7). In the present study, we investigated the in vivo efficacy and specificity of tRA-stimulated iodide accumulation in mouse breast cancer models. Immunodeficient mice with MCF-7 xenograft tumors were treated with systemic tRA for 5 days. Iodide accumulation in the xenograft tumors was markedly increased, ∼15-fold greater than levels without treatment, and the effects were tRA dose dependent. Iodide accumulation in other organs was not significantly influenced by tRA treatment. Significant induction of NIS mRNA and protein in the xenograft tumors was observed after tRA treatment. Iodide accumulation and NIS mRNA expression were also selectively induced in breast cancer tissues in transgenic mice expressing the oncogene, polyoma virus middle T antigen. These data demonstrate selective induction of functional NIS in breast cancer by tRA. Treatment with short-term systemic retinoic acid, followed by radioiodide administration, is a potential tool in the diagnosis and treatment of some differentiated breast cancer.
Clustering of Minimal Deleted Regions Reveals Distinct Genetic Pathways of Human Hepatocellular Carcinoma
Authors: Jou Yuh-Shan , Lee Chih-Shia , Chang Ya-Hui , Hsiao Chin-Fu , Chen Chian-Feng , Chao Chuan-Chuan , Wu Lawrence S.H. , Yeh Shiou-Hwei , Chen Ding-Shinn , Chen Pei-Jer 
Published: September 2005

Abstract
Systematic scan and statistical analysis of loss of heterozygosity (LOH) has been widely used to define chromosomal aberrations in various cancers for cloning of tumor suppressor genes and for development of prognostic markers. However, the establishment of novel strategies is needed, so that the nonrandom but heterogeneous chromosomal aberration data could provide significant insights into our understanding of molecular pathogenesis of cancers. After comprehensive allelotyping of recurrent allelic losses with 441 highly informative microsatellite markers and overlapping LOH regions on human hepatocellular carcinoma (HCC) chromosomes, 33 minimal deleted regions (MDRs) were revealed. Five and 15 of the 33 MDRs have physical intervals in less than 5 and 10 Mb, respectively, with the smallest MDR9p1 of 2.2 Mb located at 9p21.3-p21.2. Statistical and Kaplan-Meier survival analysis revealed a significant association between the loss of MDR15q1 (15q21.1-q22.2) and the HCC patient survival (adjusted P = 0.033). After cluster analysis of 33 MDRs that represented LOH profiles of each HCC tissue based on clinicopathological features and p53 mutations, two major genetic pathways, low-stage and advanced-stage HCC, were uncovered based on high concordance of MDR clusters. We propose that the definition of genome-wide MDRs on the cancer genome not only narrows down the location of existing tumor suppressor genes to facilitate positional candidate cloning and develop potential prognostic markers after statistical association of MDRs with clinicopathological features but also dissects genetic interactions and pathways of chromosomal aberrations in tumorigenesis.
Differential Response of Human Ovarian Cancer Cells to Induction of Apoptosis by Vitamin E Succinate and Vitamin E Analogue, α-TEA
Authors: Anderson Kristen , Simmons-Menchaca Marla , Lawson Karla A. , Atkinson Jeffrey , Sanders Bob G. , Kline Kimberly 
Published: September 2005

Abstract
A vitamin E derivative, vitamin E succinate (VES; RRR-α-tocopheryl succinate), and a vitamin E analogue, 2,5,7,8-tetramethyl-2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy acetic acid (α-TEA), induce human breast, prostate, colon, lung, cervical, and endometrial tumor cells in culture to undergo apoptosis but not normal human mammary epithelial cells, immortalized, nontumorigenic breast cells, or normal human prostate epithelial cells. Human ovarian and cervical cancer cell lines are exceptions, with α-TEA exhibiting greater proapoptotic effects. Although both VES and α-TEA can induce A2780 and subline A2780/cp70 ovarian cancer cells to undergo DNA synthesis arrest within 24 h of treatment, only α-TEA is an effective inducer of apoptosis. VES or α-TEA treatment of cp70 cells with 5, 10, or 20 μg/ml for 3 days induced 5, 6, and 19% versus 9, 36, and 71% apoptosis, respectively. Colony formation data provide additional evidence that cp70 cells are more sensitive to growth inhibition by α-TEA than VES. Differences in stability of the ester-linked succinate moiety of VES versus the ether-linked acetic acid moiety of α-TEA were demonstrated by high-performance liquid chromatography analyses that showed α-TEA to remain intact, whereas VES was hydrolyzed to the free phenol, RRR-α-tocopherol. Pretreatment of cp70 cells with bis-(p-nitrophenyl) phosphate, an esterase inhibitor, before VES treatment, resulted in increased levels of intact VES and apoptosis. Taken together, these data show α-TEA to be a potent and stable proapoptotic agent for human ovarian tumor cells and suggest that endogenous ovarian esterases can hydrolyze the succinate moiety of VES, yielding RRR-α-tocopherol, an ineffective apoptotic-inducing agent.
Sigma Receptors and Cancer
Authors: Aydar Ebru , Palmer Christopher P. , Djamgoz Mustafa B. A. 
Published: September 2005

Abstract
The sigma (σ) receptor and its agonists have been implicated in a myriad of cellular functions, biological processes and diseases. Whereas the precise molecular mechanism(s) of σ receptors and their involvement in cancer cell biology have not been elucidated, recent work has started to shed some light on these issues. A molecular model has been proposed for the cloned σ1 receptor; the precise molecular nature of the σ2 receptor remains unknown. σ receptors have been found to be frequently up-regulated in human cancer cells and tissues. σ2 receptor drugs particularly have been shown to have antiproliferative effects. An interesting possibility is that σ and/or σ1 drugs could produce anticancerous effects by modulating ion channels. As well as proliferation, a variety of other metastatic cellular behaviors such as adhesion, motility, and secretion may also be affected. Other mechanisms of σ receptor action may involve interaction with ankyrin and modulation of intracellular Ca2+ and sphingolipid levels. Although more research is needed to further define the molecular physiology of σ receptors, their involvement in the cellular pathophysiology of cancer raises the possibility that σ drugs could be useful as novel therapeutic agents.
A Polymorphism in the
CDKN1B
Gene Is Associated with Increased Risk of Hereditary Prostate Cancer
Authors: Chang Bao-li , Zheng Siqun L , Isaacs Sarah D. , Wiley Kathy E. , Turner Aubrey , Li Ge , Walsh Patrick C. , Meyers Deborah A. , Isaacs William B. , Xu Jianfeng 
Published: September 2005

Abstract
The loss of cell cycle control is believed to be an important mechanism in the promotion of carcinogenesis. CDKN1B (p27) belongs to the Cip/Kip family and functions as an important cell cycle gatekeeper. Several lines of evidence from clinical studies and laboratory experiments demonstrate that CDKN1B is an important tumor suppressor gene in prostate cancer etiology. In addition, a case-control study has shown that the 326T/G (V109G) polymorphism in CDKN1B is associated with advanced prostate cancer. In light of the evidence for linkage between the chromosomal location of the CDKN1B gene (12p13) and prostate cancer susceptibility in several hereditary prostate cancer (HPC) populations, we hypothesized that sequence variants of CDKN1B play a role in HPC. To test this hypothesis, we first resequenced this gene in 96 HPC probands to identify germ-line mutations and sequence variants. We then genotyped the identified sequence variants among all family members of 188 HPC families and tested for their cosegregation with prostate cancer. In total, 10 sequence variants were identified, including three nonsynonymous changes. A family-based test, which is free from the effects of population stratification, revealed a significant association between single nucleotide polymorphism (SNP) -79C/T and prostate cancer (with a nominal P of 0.0005). The C allele of -79C/T was overtransmitted from parents to their affected offspring. Evidence for this association was primarily contributed by affected offspring whose age at diagnosis was &lt;65 years. Together with the previous association study in a sporadic prostate cancer population, our new findings additionally suggest that germ-line variants of this gene play a role in prostate cancer susceptibility.
herg1
Gene and HERG1 Protein Are Overexpressed in Colorectal Cancers and Regulate Cell Invasion of Tumor Cells
Authors: Lastraioli Elena , Guasti Leonardo , Crociani Olivia , Polvani Simone , Hofmann Giovanna , Witchel Harry , Bencini Lapo , Calistri Massimo , Messerini Luca , Scatizzi Marco , Moretti Renato , Wanke Enzo , Olivotto Massimo , Mugnai Gabriele , Arcangeli Annarosa 
Published: September 2005

Abstract
The acquisition of the capacity to invade surrounding tissues confers a more malignant phenotype to tumor cells and is necessary for the establishment of metastases. The understanding of the molecular mechanisms underlying cell invasion in human solid tumors such as colorectal cancers could provide not only more sensitive prognostic analyses but also novel molecular targets for cancer therapy.
We report in this article that K+ ion channels belonging to the HERG family are important determinants for the acquisition of an invasive phenotype in colorectal cancers. The herg1 gene and HERG1 protein are expressed in many colon cancer cell lines, and the activity of HERG channels modulates colon cancer cell invasiveness. Moreover, the amount of HERG1 protein expressed on the plasma membrane is directly related to the invasive phenotype of colon cancer cells.
Finally, both the herg1 gene and HERG1 protein were expressed in a high percentage of primary human colorectal cancers, with the highest incidence occurring in metastatic cancers, whereas no expression could be detected either in normal colonic mucosa or in adenomas.
Hepatocyte Growth Factor Sensitizes Human Ovarian Carcinoma Cell Lines to Paclitaxel and Cisplatin
Authors: Rasola Andrea , Anguissola Sergio , Ferrero Norma , Gramaglia Daniela , Maffe Antonella , Maggiora Piera , Comoglio Paolo M. , Di Renzo M. Flavia 
Published: September 2005

Abstract
The hepatocyte growth factor (HGF) receptor, encoded by the MET oncogene, is expressed in ∼70% of human ovarian carcinomas and overexpressed in 30% of cases. Because HGF is known to protect cells from apoptosis, we investigated whether receptor expression modifies ovarian cancer cell response to chemotherapy. The apoptotic effect of the front-line chemotherapeutic drugs paclitaxel and cisplatin on cells treated with HGF was studied. In ovarian cancer cell lines, pretreatment with HGF surprisingly enhances the apoptotic response to low doses of paclitaxel and cisplatin. HGF empowers specifically the intrinsic apoptotic pathway, whereas it protects cells from extrinsic Fas-induced apoptosis. Chemotherapy sensitization is specific for HGF because another growth factor (e.g., epidermal growth factor) increases ovarian cancer cell survival. In nonovarian cancer cell models, as expected, HGF provides protection from drug-induced apoptosis. These data show that HGF sensitizes ovarian carcinoma cells to low-dose chemotherapeutic agents. This suggests that HGF may be used to improve response to chemotherapy in a set of human ovarian carcinomas molecularly classified based on the MET oncogene expression.
Tumor Suppressor Maspin Is Up-Regulated during Keratinocyte Senescence, Exerting a Paracrine Antiangiogenic Activity
Authors: Nickoloff Brian J. , Lingen Mark W. , Chang Bey-Dih , Shen Mei , Swift Mari , Curry Jonathan , Bacon Patricia , Bodner Barbara , Roninson Igor B. 
Published: September 2005

Abstract
Cell senescence is a physiological program of terminal growth arrest, which is believed to play an important role in cancer prevention. Senescent cells secrete multiple growth-regulatory proteins, some of which can affect tumor growth, survival, invasion, or angiogenesis. Changes in expression of different senescence-associated genes were analyzed in cultured human skin keratinocytes (KCs) that underwent replicative senescence or confluence-induced accelerated senescence. Senescent KC cultures showed a strong increase in mRNA and protein expression of maspin, a member of serine protease inhibitor family and an epithelial cell tumor suppressor with anti-invasive and antiangiogenic activities. Immunohistochemical analysis of 14 normal human skin samples (age range from 3 months to 84 years) showed that maspin is expressed by KCs in vivo and that the extent and intensity of maspin expression in the skin is significantly (P = 0.01) correlated with chronological age. Antiangiogenic activity of maspin secreted by senescent KCs was investigated in vitro by testing the effect of conditioned media from different KC cultures on endothelial cell migration in the presence or absence of several angiogenic factors. Media conditioned by senescent cultures (undergoing replicative or accelerated senescence), but not by proliferating KCs, strongly inhibited the stimulation of endothelial cell migration by all of the tested angiogenic factors. Neutralizing antibody against maspin abrogated this effect of conditioned media. These findings indicate that senescent KCs exert a paracrine antiangiogenic activity, and maspin is the principal contributor to this potentially tumor-suppressive effect of cellular senescence.
FGFR3
and
P53
Characterize Alternative Genetic Pathways in the Pathogenesis of Urothelial Cell Carcinoma
Authors: van Rhijn Bas W. G. , van der Kwast Theo H. , Vis André N. , Kirkels Wim J. , Boevé Egbert R. , Jöbsis Adriaan C. , Zwarthoff Ellen C. 
Published: September 2005

Abstract
Fibroblast growth factor receptor 3 (FGFR3) and P53 mutations are frequently observed in bladder cancer. We here describe the distribution of FGFR3 mutations and P53 overexpression in 260 primary urothelial cell carcinomas. FGFR3 mutations were observed in 59% and P53 overexpression in 25%. Interestingly, FGFR3 and P53 alterations were mutually exclusive, because they coincided in only 5.7% of tumors. Consequently, we propose that they characterize two alternative genetic pathways in urothelial cell carcinoma pathogenesis. The genetic alterations were reflected in the pathology and the clinical outcome, i.e., FGFR3 mutations were found in low-stage/-grade tumors and were associated with a favorable disease course, whereas P53 alterations were tied to adverse disease parameters.
Comparative Measurements of Hypoxia in Human Brain Tumors Using Needle Electrodes and EF5 Binding
Authors: Evans Sydney M. , Judy Kevin D. , Dunphy Isolde , Jenkins W. Timothy , Nelson Peter T. , Collins Ruth , Wileyto E. Paul , Jenkins Kevin , Hahn Stephen M. , Stevens Craig W. , Judkins Alexander R. , Phillips Peter , Geoerger Birgit , Koch Cameron J. 
Published: September 2005

Abstract
Hypoxia is known to be an important prognostic marker in many human cancers. We report the use of two oxygen measurement techniques in human brain tumors and compare these data with semiquantitative histological end points. Oxygenation was measured using the Eppendorf needle electrode and/or EF5 binding in 28 brain tumors. These data were compared with necrosis, mitosis, and endothelial proliferation. In some tumors, absolute EF5 binding was converted to tissue pO2 based on in vitro calibrations. Eppendorf electrode readings could not be used to identify WHO grade 1/2 versus WHO grade 3/4 tumors, they could not differentiate grade 3 versus grade 4 glial-derived neoplasms, nor did they correlate with necrosis or endothelial proliferation scores. EF5 binding increased as the tumor grade increased and was significantly associated with necrosis and endothelial proliferation. There was no statistically significant correlation between the two hypoxia detection techniques, although both methods indicated similar absolute ranges of tissue pO2. There was substantial inter- and intratumoral heterogeneity of EF5 binding in WHO grade 4 glial neoplasms. The majority of cells in glial-derived tumor had levels of hypoxia that were mild to moderate (defined herein as 10% to 0.5% pO2) rather than severe (defined as approximately 0.1% pO2). Immunohistochemical detection of EF5 binding tracks histological parameters in adult brain tumors, with increased binding associated with increasing necrosis and endothelial proliferation. The proportion of moderately to severely hypoxic cells is relatively low, even in the high-grade tumors. Human brain tumors are dominated by oxic to moderately hypoxic cells.