bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficient Inhibition of Intra-Peritoneal Tumor Growth and Dissemination of Human Ovarian Carcinoma Cells in Nude Mice by Anti-L1-Cell Adhesion Molecule Monoclonal Antibody Treatment
Authors: Arlt Matthias J.E. , Novak-Hofer Ilse , Gast Daniela , Gschwend Verena , Moldenhauer Gerhard , Grünberg Jürgen , Honer Michael , Schubiger P. August , Altevogt Peter , Krüger Achim
Published: January 2006

The L1 cell adhesion molecule is implicated in the control of proliferation, migration, and invasion of several tumor cell types in vitro. Recently, L1 overexpression was found to correlate with tumor progression of ovarian carcinoma, one of the most common causes of cancer-related deaths in gynecologic malignant diseases. To evaluate L1 as a potential target for ovarian cancer therapy, we investigated the effects of anti-L1 monoclonal antibodies (chCE7 and L1-11A) on proliferation and migration of L1-positive human SKOV3ip ovarian carcinoma cells in vitro and the therapeutic efficacy of L1-11A against i.p. SKOV3ip tumor growth in nude mice. In vitro, both anti-L1 antibodies efficiently inhibited the proliferation of SKOV3ip cells as well as other L1-expressing tumor cell lines (renal carcinoma, neuroblastoma, and colon carcinoma). On two cell lines, hyper-cross-linking of L1-11A with a secondary antibody was necessary for significant inhibition of proliferation, indicating that cross-linking of L1 is required for the antiproliferative effect. L1-negative prostate carcinoma cells were not influenced by antibody treatment. Biweekly treatment of ovarian carcinoma-bearing mice with L1-11A led to a dose-dependent and significant reduction of tumor burden (up to −63.5%) and ascites formation (up to −75%). This effect was associated with reduced proliferation within the tumors. L1-directed antibody-based inhibition of peritoneal growth and dissemination of human ovarian carcinoma cells represents important proof-of-principle for the development of a new therapy against one of the leading gynecologic malignant diseases. (Cancer Res 2006; 66(2): 936-43)
Restoring E-Cadherin Expression Increases Sensitivity to Epidermal Growth Factor Receptor Inhibitors in Lung Cancer Cell Lines
Authors: Witta Samir E. , Gemmill Robert M. , Hirsch Fred R. , Coldren Christopher D. , Hedman Karla , Ravdel Larisa , Helfrich Barbara , Dziadziuszko Rafal , Chan Daniel C. , Sugita Michio , Chan Zeng , Baron Anna , Franklin Wilbur , Drabkin Harry A. , Girard Luc , Gazdar Adi F. , Minna John D. , Bunn Paul A.
Published: January 2006

The epidermal growth factor receptor (EGFR) is overexpressed in the majority of non–small cell lung cancers (NSCLC). EGFR tyrosine kinase inhibitors, such as gefitinib and erlotinib, produce 9% to 27% response rates in NSCLC patients. E-Cadherin, a calcium-dependent adhesion molecule, plays an important role in NSCLC prognosis and progression, and interacts with EGFR. The zinc finger transcriptional repressor, ZEB1, inhibits E-cadherin expression by recruiting histone deacetylases (HDAC). We identified a significant correlation between sensitivity to gefitinib and expression of E-cadherin, and ZEB1, suggesting their predictive value for responsiveness to EGFR-tyrosine kinase inhibitors. E-Cadherin transfection into a gefitinib-resistant line increased its sensitivity to gefitinib. Pretreating resistant cell lines with the HDAC inhibitor, MS-275, induced E-cadherin along with EGFR and led to a growth-inhibitory and apoptotic effect of gefitinib similar to that in gefitinib-sensitive NSCLC cell lines including those harboring EGFR mutations. Thus, combined HDAC inhibitor and gefitinib treatment represents a novel pharmacologic strategy for overcoming resistance to EGFR inhibitors in patients with lung cancer. (Cancer Res 2006; 66(2); 944-50)
The Synthetic Compound CC-5079 Is a Potent Inhibitor of Tubulin Polymerization and Tumor Necrosis Factor-α Production with Antitumor Activity
Authors: Zhang Ling-Hua , Wu Lei , Raymon Heather K. , Chen Roger S. , Corral Laura , Shirley Michael A. , Krishna Narla Rama , Gamez Jim , Muller George W. , Stirling David I. , Bartlett J. Blake , Schafer Peter H. , Payvandi Faribourz
Published: January 2006

We have found that the synthetic compound CC-5079 potently inhibits cancer cell growth in vitro and in vivo by a novel combination of molecular mechanisms. CC-5079 inhibits proliferation of cancer cell lines from various organs and tissues at nanomolar concentrations. Its IC50 value ranges from 4.1 to 50 nmol/L. The effect of CC-5079 on cell growth is associated with cell cycle arrest in G2-M phase, increased phosphorylation of G2-M checkpoint proteins, and apoptosis. CC-5079 prevents polymerization of purified tubulin in a concentration-dependent manner in vitro and depolymerizes microtubules in cultured cancer cells. In competitive binding assays, CC-5079 competes with [3H]colchicine for binding to tubulin; however, it does not compete with [3H]paclitaxel (Taxol) or [3H]vinblastine. Our data indicate that CC-5079 inhibits cancer cell growth with a mechanism of action similar to that of other tubulin inhibitors. However, CC-5079 remains active against multidrug-resistant cancer cells unlike other tubulin-interacting drugs, such as Taxol and colchicine. Interestingly, CC-5079 also inhibits tumor necrosis factor-α (TNF-α) secretion from lipopolysaccharide-stimulated human peripheral blood mononuclear cells (IC50, 270 nmol/L). This inhibitory effect on TNF-α production is related to its inhibition of phosphodiesterase type 4 enzymatic activity. Moreover, in a mouse xenograft model using HCT-116 human colorectal tumor cells, CC-5079 significantly inhibits tumor growth in vivo. In conclusion, our data indicate that CC-5079 represents a new chemotype with novel mechanisms of action and that it has the potential to be developed for neoplastic and inflammatory disease therapy. (Cancer Res 2006; 66(2): 951-9)
Overexpression of c-Maf Contributes to T-Cell Lymphoma in Both Mice and Human
Authors: Morito Naoki , Yoh Keigyou , Fujioka Yuki , Nakano Takako , Shimohata Homare , Hashimoto Yuko , Yamada Akiko , Maeda Atsuko , Matsuno Fumihiko , Hata Hiroyuki , Suzuki Atsushi , Imagawa Shigehiko , Mitsuya Hiroaki , Esumi Hiroyasu , Koyama Akio , Yamamoto Masayuki , Mori Naoyoshi , Takahashi Satoru
Published: January 2006

c-Maf translocation or overexpression has been observed in human multiple myeloma. Although c-maf might function as an oncogene in multiple myeloma, a role for this gene in other cancers has not been shown. In this study, we have found that mice transgenic for c-Maf whose expression was direct to the T-cell compartment developed T-cell lymphoma. Moreover, we showed that cyclin D2, integrin β7, and ARK5 were up-regulated in c-Maf transgenic lymphoma cells. Furthermore, 60% of human T-cell lymphomas (11 of 18 cases), classified as angioimmunoblastic T-cell lymphoma, were found to express c-Maf. These results suggest that c-Maf might cause a type of T-cell lymphoma in both mice and humans and that ARK5, in addition to cyclin D2 and integrin β7, might be downstream target genes of c-Maf leading to malignant transformation. (Cancer Res 2006; 66(2): 812-9)
A Functional Variant in the Transcriptional Regulatory Region of Gene LOC344967 Cosegregates with Disease Phenotype in Familial Nasopharyngeal Carcinoma
Authors: Jiang Ri-Cheng , Qin Hai-De , Zeng Mu-Sheng , Huang Wei , Feng Bing-Jian , Zhang Feng , Chen Han-Kui , Jia Wei-Hua , Chen Li-Zhen , Feng Qi-Sheng , Zhang Ru-Hua , Yu Xing-Juan , Zheng Mei-Zhen , Zeng Yi-Xin
Published: January 2006

Nasopharyngeal carcinoma is a common malignancy in Southeast Asian countries, and genetic background is a well-known component of the complexity underlying its tumorigenic process. We have mapped a nasopharyngeal carcinoma susceptibility locus to chromosome 4p15.1-q12 in a previous linkage study on nasopharyngeal carcinoma pedigrees. In this study provided in this communication, we screened all the genes in this region, with a focus on exons, promoters, and the exon-intron boundary to identify nasopharyngeal carcinoma–associated mutations or functional variants. Importantly, we found a novel gene (LOC344967) with a single nucleotide polymorphism −32G/A in the promoter region. This gene is a member of the acyl CoA thioesterase family that plays an important role in fatty acid metabolism and is involved in the progression of various types of tumors. The −32A variant was found cosegregated with the disease phenotype in the nasopharyngeal carcinoma pedigrees that we previously used for the linkage study. Moreover, this −32A variant creates an activator protein (AP-1)–binding site in the transcriptional regulatory region of LOC344967, which significantly enhanced the binding of AP-1 to the promoter region and the transcription activity of the promoter in vivo. Furthermore, the expression of LOC344967 was significantly up-regulated at both mRNA and protein levels in nasopharyngeal carcinoma cells sharing the −32G/A genotype compared with nasopharyngeal carcinoma cells with the −32G/G genotype. Collectively, these results provide evidence that the −32A variant is a functional sequence change and may be related to nasopharyngeal carcinoma susceptibility in the families studied. (Cancer Res 2006; 66(2): 693-700)
Selective Targeting of Antitumor Immune Responses with Engineered Live-Attenuated Listeria monocytogenes
Authors: Yoshimura Kiyoshi , Jain Ajay , Allen Heather E. , Laird Lindsay S. , Chia Christina Y. , Ravi Sowmya , Brockstedt Dirk G. , Giedlin Martin A. , Bahjat Keith S. , Leong Meredith L. , Slansky Jill E. , Cook David N. , Dubensky Thomas W. , Pardoll Drew M. , Schulick Richard D.
Published: January 2006

Improved immunization and ex vivo T-cell culture strategies can generate larger numbers and more potent tumor-specific effector cells than previously possible. Nonetheless, the capacity of these cells to eliminate established tumors is limited by their ability to efficiently enter tumor-bearing organs and mediate their effector function. In the current study, we show that the administration of an engineered organ-homing microbe selectively targets tumor-specific immune responses to metastases within that organ. Specifically, an attenuated Listeria monocytogenes strain, which preferentially infects the liver following systemic administration, dramatically enhances the activity of a cancer vaccine against liver metastases but not metastases in the lung. This enhanced activity results from both local recruitment of innate immune effectors as well as concentration and increased activation of vaccine-induced antitumor T cells within the liver. These findings show a general approach to focus systemic cancer immunotherapies to specific organs bearing tumor metastases by taking advantage of differential tropisms and the proinflammatory nature of microbes. (Cancer Res 2006; 66(2): 1096-104)
Down-Regulation of Stem Cell Genes, Including Those in a 200-kb Gene Cluster at 12p13.31, Is Associated withIn vivoDifferentiation of Human Male Germ Cell Tumors
Authors: Korkola James E. , Houldsworth Jane , Chadalavada Rajendrakumar S.V. , Olshen Adam B. , Dobrzynski Debbie , Reuter Victor E. , Bosl George J. , Chaganti R.S.K.
Published: January 2006

Adult male germ cell tumors (GCTs) comprise distinct groups: seminomas and nonseminomas, which include pluripotent embryonal carcinomas as well as other histologic subtypes exhibiting various stages of differentiation. Almost all GCTs show 12p gain, but the target genes have not been clearly defined. To identify 12p target genes, we examined Affymetrix (Santa Clara, CA) U133A+B microarray (∼83% coverage of 12p genes) expression profiles of 17 seminomas, 84 nonseminoma GCTs, and 5 normal testis samples. Seventy-three genes on 12p were significantly overexpressed, including GLUT3 and REA (overexpressed in all GCTs) and CCND2 and FLJ22028 (overexpressed in all GCTs, except choriocarcinomas). We characterized a 200-kb gene cluster at 12p13.31 that exhibited coordinated overexpression in embryonal carcinomas and seminomas, which included the known stem cell genes NANOG, STELLA, and GDF3 and two previously uncharacterized genes. A search for other coordinately regulated genomic clusters of stem cell genes did not reveal any genomic regions similar to that at 12p13.31. Comparison of embryonal carcinoma with seminomas revealed relative overexpression of several stem cell–associated genes in embryonal carcinoma, including several core “stemness” genes (EBAF, TDGF1, and SOX2) and several downstream targets of WNT, NODAL, and FGF signaling (FGF4, NODAL, and ZFP42). Our results indicate that 12p gain is a functionally relevant change leading to activation of proliferation and reestablishment/maintenance of stem cell function through activation of key stem cell genes. Furthermore, the differential expression of core stem cell genes may explain the differences in pluripotency between embryonal carcinomas and seminomas. (Cancer Res 2006; 66(2): 820-7)
Efficient Induction of Tumor Antigen–Specific CD8+ Memory T Cells by Recombinant Lentivectors
Authors: Chapatte Laurence , Colombetti Sara , Cerottini Jean-Charles , Lévy Frédéric
Published: January 2006

The success of active cancer immunotherapy entails a robust induction of tumor-reactive effector and memory CD8+ T cells. We compared the in vivo immunogenicity of the melanoma-associated antigen Melan-A26-35 encoded by third-generation recombinant lentivector (rec. lv) or as peptide admixed with a strong adjuvant. Ex vivo analyses of immunized HLA-A2/H-2Kb mice showed that rec. lv triggered a stronger anti-Melan-A CD8+ T-cell response than peptide vaccine. Importantly, the majority of anti-Melan-A T cells elicited by rec. lv expressed the memory marker CD127 at the peak of the primary response. In those mice, memory T cells were detectable several months after priming and could be activated by recall peptide vaccination. These results show that immunization with rec. lv induces not only a strong antigen-specific CD8+ T-cell response but also a long-lasting T-cell memory against a bona fide tumor-associated antigen. (Cancer Res 2006; 66(2): 1155-60)
Roles of Myofibroblasts in Prostaglandin E2–Stimulated Intestinal Epithelial Proliferation and Angiogenesis
Authors: Shao Jinyi , Sheng George G. , Mifflin Randy C. , Powell Don W. , Sheng Hongmiao
Published: January 2006

Prostaglandins (PG) are produced throughout the gastrointestinal tract and are critical mediators for a complex array of physiologic and pathophysiologic processes in the intestine. Intestinal myofibroblasts, which express cyclooxygenase (COX) and generate PGE2, play important roles in intestinal epithelial proliferation, differentiation, inflammation, and neoplasia through secreting growth factors and cytokines. Here, we show that PGE2 activated human intestinal subepithelial myofibroblasts (18Co) through Gs protein–coupled E-prostanoid receptors and the cyclic AMP/protein kinase A pathway. 18Co cells and primary colonic myofibroblast isolates expressed a number of growth factors; several of them were dramatically regulated by PGE2. An epidermal growth factor–like growth factor, amphiregulin (AR), which was not expressed by untreated cells, was strongly induced by PGE2. Expression of vascular endothelial growth factor A (VEGFA) was rapidly increased by PGE2 exposure. Hepatocyte growth factor (HGF) was elevated in PGE2-treated myofibroblasts at both mRNA and protein levels. Thus, PGE2-activated myofibroblasts promoted the proliferation and migration of intestinal epithelial cells, which were attenuated by neutralizing antibodies to AR and HGF, respectively. Moreover, in the presence of PGE2, myofibroblasts strongly stimulated the migration and tubular formation of vascular endothelial cells. Neutralizing antibody to VEGFA inhibited the observed stimulation of migration. These results suggest that myofibroblast-generated growth factors are important mediators for PGE2-induced intestinal epithelial proliferation and angiogenesis, which play critical roles in intestinal homeostasis, inflammation, and neoplasia. (Cancer Res 2006; 66(2): 846-55)
Synergistic Effects of Gemcitabine and Gefitinib in the Treatment of Head and Neck Carcinoma
Authors: Chun Patrick Y. , Feng Felix Y. , Scheurer Ashley M. , Davis Mary A. , Lawrence Theodore S. , Nyati Mukesh K.
Published: January 2006

Although the combination of gemcitabine and radiation produces a high frequency of complete responses in the treatment of locally advanced head and neck cancer, substantial toxicity suggests that an improvement in the therapeutic index is required. The purpose of this study was to determine if gefitinib could improve the efficacy of gemcitabine and if drug schedule is important. We hypothesized that gemcitabine followed by gefitinib would be superior to the opposite order because of both cell cycle and growth factor signaling interactions. Using UMSCC-1 cells in vitro, we confirmed that gefitinib arrested cells in G1 and suppressed phospho-epidermal growth factor receptor (pY845EGFR) and that gemcitabine arrested cells in S phase and stimulated pY845EGFR. The schedule of gemcitabine followed by gefitinib caused arrest of cells in S phase. Gefitinib suppressed gemcitabine-mediated pY845EGFR stimulation. This schedule caused decreased pS473AKT, increased poly(ADP-ribose) polymerase cleavage, and increased apoptosis compared with gemcitabine alone. The schedule of gefitinib followed by gemcitabine also caused suppression of pY845EGFR but arrested cells in G1. This schedule in which gefitinib was used first was associated with stable levels of pS473AKT and minimal poly(ADP-ribose) polymerase cleavage and apoptosis. These results were reflected in experiments in nude mice bearing UMSCC-1 xenografts, in which there was greater tumor regression and apoptosis when animals received gemcitabine followed by gefitinib during the first week of therapy. These findings suggest that the schedule of gemcitabine followed by gefitinib may increase the therapeutic index over gemcitabine alone and, combined with clinical data, encourage exploration of combination of gemcitabine, EGFR inhibitors, and radiation. (Cancer Res 2006; 66(2): 981-8)
Activity of the Adenoviral E1A Deletion Mutant dl922-947 in Ovarian Cancer: Comparison with E1A Wild-type Viruses, Bioluminescence Monitoring, and Intraperitoneal Delivery in Icodextrin
Authors: Lockley Michelle , Fernandez Mario , Wang Yaohe , Li N. Fiona , Conroy Susan , Lemoine Nicholas , McNeish Iain
Published: January 2006

The adenoviral mutant dl922-947 has potent activity in a variety of tumors. We investigated the efficacy of dl922-947 in ovarian carcinoma; compared its activity to wild-type adenovirus, dl309, and dl1520; and investigated the use of icodextrin to enhance activity in vivo. We also assessed the utility of luciferase bioluminescence imaging to quantify the response of human ovarian carcinoma xenografts to dl922-947. Ovarian carcinoma cell lines were transfected in vitro with dl922-947, adenovirus 5 wild-type (Ad5 WT), dl309, and dl1520 and monitored for S-phase induction, viral protein expression, replication, and overall survival. In vivo, the efficacy of dl922-947 when delivered in PBS or icodextrin to female nude mice bearing IGROV1 xenografts was determined. In vitro, dl922-947 induced lysis with greater efficacy than Ad5 WT, dl309, or dl1520 in all ovarian carcinoma cell lines tested, which was associated with earlier expression of viral proteins and S-phase induction. The lytic effect in immortalized ovarian surface epithelial cells confirmed that cellular retinoblastoma pathway status is a strong determinant of dl922-947 activity. In vivo, i.p. delivery of dl922-947 (5 × 109 particles daily × 5) increased median survival from 20 to 96 days (P < 0.0001) and delivery in icodextrin-enhanced survival further. However, delayed hepatic toxicity was evident in some dl922-947-treated mice, which was not dependent upon viral replication within tumor cells or the liver. dl922-947 has potency in ovarian carcinoma and i.p. delivery in icodextrin may enhance this activity. Immunocompetent models of ovarian carcinoma are required for further evaluation of hepatotoxicity. (Cancer Res 2006; 66(2): 989-98)
17-Allylamino-17-Demethoxygeldanamycin Synergistically Potentiates Tumor Necrosis Factor–Induced Lung Cancer Cell Death by Blocking the Nuclear Factor-κB Pathway
Authors: Wang Xia , Ju Wei , Renouard Jordan , Aden James , Belinsky Steven A. , Lin Yong
Published: January 2006

Nuclear factor-κB (NF-κB), a survival signal induced by tumor necrosis factor (TNF), contributes substantially to the resistance to TNF-induced cell death. Previous studies suggest that heat shock protein 90 (Hsp90) regulates the stability and function of receptor-interaction proteins (RIP) and IκB kinase β (IKKβ), the key components of the TNF-induced NF-κB activation pathway. In this study, we showed that the Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17AAG) was synergistic with TNF to induce apoptotic cell death in a panel of lung tumor-derived cell lines. Treatment with 17AAG caused degradation of RIP and IKKβ that, in turn, blocked TNF-induced NF-κB activation and antiapoptotic gene expression. The synergistic cytotoxicity was detected only when TNF treatment followed 17AAG preexposure. Importantly, the potentiation of cell death was abolished in NF-κB-disabled cells that express a nondegradable IκBα mutant (IκBαAA). These results suggest that the cytotoxicity seen with 17AAG and TNF treatment results from blocking TNF-induced NF-κB activation. The other components of the TNF receptor I signaling cascade were not altered, whereas TNF-induced c-Jun NH2-terminal kinase activation and apoptosis were potentiated. A similar synergism for inducing apoptosis was also observed in 17AAG-treated and TNF-related apoptosis-inducing ligand (TRAIL)–treated cancer cells. Our results suggest that NF-κB plays a key role in the resistance of lung cancer cells to TNF and TRAIL and that disabling this survival signal with 17AAG followed by TNF or TRAIL treatment could be an effective new therapeutic strategy for lung cancer. (Cancer Res 2006; 66(2): 1089-95)
MSF-A Interacts with Hypoxia-Inducible Factor-1α and Augments Hypoxia-Inducible Factor Transcriptional Activation to Affect Tumorigenicity and Angiogenesis
Authors: Amir Sharon , Wang Ruoxiang , Matzkin Haim , Simons Jonathan W. , Mabjeesh Nicola J.
Published: January 2006

Hypoxia-inducible factor-1 (HIF-1) is a key transcription factor in the signaling pathway that controls the hypoxic responses of cancer cells. Activation of the HIF system has been observed in carcinogenesis and numerous cancers. We found an interaction between a member of the mammalian septin gene family (MSF-A) and the HIF system. MSF-A is a nuclear protein that interacts with HIF-1α protein to prevent its ubiquitination and degradation, thus activating the HIF transcriptome. Cells overexpressing MSF-A protein exhibit increased HIF transcriptional activity and higher proliferation rates in vitro and in vivo. Xenograft-derived human tumors from these cells were larger and more vascular. These findings link a function of a septin protein with angiogenesis through activation of the HIF pathway. (Cancer Res 2006; 66(2): 856-66)
Structure of the Kinase Domain of an Imatinib-Resistant Abl Mutant in Complex with the Aurora Kinase Inhibitor VX-680
Authors: Young Matthew A. , Shah Neil P. , Chao Luke H. , Seeliger Markus , Milanov Zdravko V. , Biggs William H. , Treiber Daniel K. , Patel Hitesh K. , Zarrinkar Patrick P. , Lockhart David J. , Sawyers Charles L. , Kuriyan John
Published: January 2006

We present a high-resolution (2.0 Å) crystal structure of the catalytic domain of a mutant form of the Abl tyrosine kinase (H396P; Abl-1a numbering) that is resistant to the Abl inhibitor imatinib. The structure is determined in complex with the small-molecule inhibitor VX-680 (Vertex Pharmaceuticals, Cambridge, MA), which blocks the activity of various imatinib-resistant mutant forms of Abl, including one (T315I) that is resistant to both imatinib and BMS-354825 (dasatinib), a dual Src/Abl inhibitor that seems to be clinically effective against all other imatinib-resistant forms of BCR-Abl. VX-680 is shown to have significant inhibitory activity against BCR-Abl bearing the T315I mutation in patient-derived samples. The Abl kinase domain bound to VX-680 is not phosphorylated on the activation loop in the crystal structure but is nevertheless in an active conformation, previously unobserved for Abl and inconsistent with the binding of imatinib. The adoption of an active conformation is most likely the result of synergy between the His396Pro mutation, which destabilizes the inactive conformation required for imatinib binding, and the binding of VX-680, which favors the active conformation through hydrogen bonding and steric effects. VX-680 is bound to Abl in a mode that accommodates the substitution of isoleucine for threonine at residue 315 (the “gatekeeper” position). The avoidance of the innermost cavity of the Abl kinase domain by VX-680 and the specific recognition of the active conformation explain the effectiveness of this compound against mutant forms of BCR-Abl, including those with mutations at the gatekeeper position. (Cancer Res 2006; 66(2): 1007-14)
Significance of Murine Retroviral Mutagenesis for Identification of Disease Genes in Human Acute Myeloid Leukemia
Authors: Erkeland Stefan J. , Verhaak Roel G.W. , Valk Peter J.M. , Delwel Ruud , Löwenberg Bob , Touw Ivo P.
Published: January 2006

Retroviral insertion mutagenesis is considered a powerful tool to identify cancer genes in mice, but its significance for human cancer has remained elusive. Moreover, it has recently been debated whether common virus integrations are always a hallmark of tumor cells and contribute to the oncogenic process. Acute myeloid leukemia (AML) is a heterogeneous disease with a variable response to treatment. Recurrent cytogenetic defects and acquired mutations in regulatory genes are associated with AML subtypes and prognosis. Recently, gene expression profiling (GEP) has been applied to further risk stratify AML. Here, we show that mouse leukemia genes identified by retroviral insertion mutagenesis are more frequently differentially expressed in distinct subclasses of adult and pediatric AML than randomly selected genes or genes located more distantly from a virus integration site. The candidate proto-oncogenes showing discriminative expression in primary AML could be placed in regulatory networks mainly involved in signal transduction and transcriptional control. Our data support the validity of retroviral insertion mutagenesis in mice for human disease and indicate that combining these murine screens for potential proto-oncogenes with GEP in human AML may help to identify critical disease genes and novel pathogenetic networks in leukemia. (Cancer Res 2006; 66(2): 622-6)
Antitumor Activity of Epidermal Growth Factor Receptor–Related Protein Is Mediated by Inactivation of ErbB Receptors and Nuclear Factor-κB in Pancreatic Cancer
Authors: Zhang Yuxiang , Banerjee Sanjeev , Wang Zhiwei , Xu Hu , Zhang Liyue , Mohammad Ramzi , Aboukameel Amro , Adsay Nazmi V. , Che Mingxin , Abbruzzese James L. , Majumdar Adhip P.N. , Sarkar Fazlul H.
Published: January 2006

The erbB family of receptor tyrosine kinases plays critical roles in human cancers, including pancreatic cancer. Discovering a specific agent, which targets multiple members of the erbB family, would be important in pancreatic cancer therapy. Recently, we isolated a novel negative regulator of epidermal growth factor receptor (EGFR), termed EGFR-related protein (ERRP), whose expression attenuates EGFR activation. In the current study, we examined the effects of recombinant ERRP on the growth and ligand-induced activation of multiple members of erbB family in three pancreatic cancer cell lines that express varying levels of EGFR and other member(s) of its family, specifically HER-2. Additionally, we compared the growth inhibitory effect of ERRP with that of Erbitux or Herceptin. Our results showed that ERRP is most effective in inhibiting proliferation of BxPC-3, HPAC, and PANC-1 pancreatic cancer cells. ERRP also inhibited ligand-induced activation of EGFR, HER-2, and HER-3 (ErbB3). In contrast, Erbitux and Herceptin only partially or modestly inhibited activation of EGFR, HER-2, and HER-3. Most importantly, ERRP was found to inhibit pancreatic tumor growth in a severe combined immunodeficient mouse xenograft model. The antitumor activity of ERRP correlates well with tumor differentiation and down-regulation of nuclear factor-κB activity. In summary, our results suggest that ERRP is an effective pan-erbB inhibitor, which could be a potential therapeutic agent for pancreatic cancers expressing different levels and subclasses of erbB family of proteins. (Cancer Res 2006; 66(2): 1025-32)
Polymorphisms in RET and Its Coreceptors and Ligands as Genetic Modifiers of Multiple Endocrine Neoplasia Type 2A
Authors: Lesueur Fabienne , Cebrian Arancha , Robledo Mercedes , Niccoli-Sire Patricia , Svensson Karl-Axel , Pinson Stephane , Leyland Jean , Whittaker Joanne , Pharoah Paul D. , Ponder Bruce A.J.
Published: January 2006

Germ line missense mutations in the RET proto-oncogene are responsible for the inherited cancer syndrome multiple endocrine neoplasia type 2A (MEN2A). The clinical presentation of the disease and the age at onset varies even within families, where patients carry the same mutation. These variations in phenotypes suggest a role for genetic modifiers, and recently, it has been reported that polymorphisms within RET (G691S/S904S) may have such a modifier effect on the age at onset. Here, we investigate whether this observed association could be confirmed in a larger set of 384 individuals from MEN2 families from four different European populations. In addition, we tested as modifiers four other single nucleotide polymorphisms (SNPs), which we have found in a previous association study of RET, its coreceptors, and ligands to be associated with the risk of developing sporadic medullary thyroid carcinoma. We could not replicate the association between G691S/S904S and modifier effects in MEN2A families in any of the four European families analyzed. Of the other SNPs tested, only RET A432A showed a positive weak effect on tumor spectrum within MEN2A, which requires replication in a larger series. (Cancer Res 2006; 66(2): 1177-80)
De novoInduction of a Cancer/Testis Antigen by 5-Aza-2′-Deoxycytidine Augments Adoptive Immunotherapy in a Murine Tumor Model
Authors: Guo Z. Sheng , Hong Julie A. , Irvine Kari R. , Chen G. Aaron , Spiess Paul J. , Liu Yang , Zeng Gang , Wunderlich John R. , Nguyen Dao M. , Restifo Nicholas P. , Schrump David S.
Published: January 2006

Recent studies suggest that immunotherapy targeting specific tumor-associated antigens (TAAs) may be beneficial in cancer patients. However, most of these TAAs are tumor type specific and heterogeneous among patients, thus limiting their applications. Here, we describe the de novo induction of a cancer/testis antigen (CTA) for immunotherapy of tumors of various histologies. The murine CTA P1A, normally expressed only in a few tumor lines, could be induced de novo in all P1A-negative cancer lines of eight histologic origins in vitro and in various murine xenografts by systemic administration of 5-aza-2′-deoxycytidine. The induction of P1A expression correlated strongly with demethylation of the CpG island in the promoter region of this gene. The induced antigen was processed and presented properly for recognition by H-2Ld-restricted P1A-specific CTLs. The combination of a demethylating agent and adoptive transfer of P1A-specific CTL effectively treated lung metastases in syngeneic mice challenged with P1A-negative 4T1 mammary carcinoma cells. These data show a novel strategy of combined chemoimmunotherapy of cancer targeting a CTA induced de novo in a broad range of tumor histologies, and support further evaluation of chromatin-remodeling agents for human cancer therapy. (Cancer Res 2006; 66(2): 1105-13)
Identification of a Putative Tumor Suppressor Gene Rap1GAP in Pancreatic Cancer
Authors: Zhang Lizhi , Chenwei Li , Mahmood Redah , Golen Kenneth van , Greenson Joel , Li Gangyong , D'Silva Nisha J. , Li Xiangquan , Burant Charles F. , Logsdon Craig D. , Simeone Diane M.
Published: January 2006

Human chromosome 1p35-p36 has long been suspected to harbor a tumor suppressor gene in pancreatic cancer and other tumors. We found that expression of rap1GAP, a gene located in this chromosomal region, is significantly down-regulated in pancreatic cancer. Only a small percentage of preneoplastic pancreatic intraductal neoplasia lesions lost rap1GAP expression, whereas loss of rap1GAP expression occurred in 60% of invasive pancreatic cancers, suggesting that rap1GAP contributes to pancreatic cancer progression. In vitro and in vivo studies showed that loss of rap1GAP promotes pancreatic cancer growth, survival, and invasion, and may function through modulation of integrin activity. Furthermore, we showed a high frequency of loss of heterozygosity of rap1GAP in pancreatic cancer. Collectively, our data identify rap1GAP as a putative tumor suppressor gene in pancreatic cancer. (Cancer Res 2006; 66(2): 898-906)
Age-Related Changes of the Cervix Influence Human Papillomavirus Type Distribution
Authors: Castle Philip E. , Jeronimo Jose , Schiffman Mark , Herrero Rolando , Rodríguez Ana C. , Bratti M. Concepción , Hildesheim Allan , Wacholder Sholom , Long L. Rodney , Neve Leif , Pfeiffer Ruth , Burk Robert D.
Published: January 2006

Approximately 15 human papillomavirus (HPV) types cause virtually all cervical cancer whereas other HPV types are unrelated to cancer. We were interested in whether some noncarcinogenic types differ from carcinogenic in their affinity for the cervical transformation zone, where nearly all HPV-induced cancers occur. To examine this possibility, we tested cervical specimens from 8,374 women without cervical precancer and cancer participating in a population-based study in Guanacaste for >40 HPV types using PCR. We compared age-group specific prevalences of HPV types of the α9 species, which are mainly carcinogenic and include HPV16, to the genetically distinct types of the α3/α15 species (e.g., HPV71), which are noncarcinogenic and common in vaginal specimens from hysterectomized women. We related HPV detection of each group to the location of the junction between the squamous epithelium of the ectocervix and vagina and the columnar epithelium of the endocervical canal. Models evaluated the independent effects of amount of exposed columnar epithelium (ectopy) and age on the presence of α9 or α3/α15 types. Prevalence of α9 types (7.6%) peaked in the youngest women, declined in middle-aged women, and then increased slightly in older women. By contrast, prevalence of α3/α15 types (7.6%) tended to remain invariant or to increase with increasing age. Detection of α9 infections increased (Ptrend < 0.0005) but α3/α15 infections decreased (Ptrend < 0.0005) with increasing exposure of the columnar epithelia. Older age and decreasing cervical ectopy were independently positively associated with having an α3/α15 infection compared with having an α9 infection. These patterns need to be confirmed in other studies and populations. We suggest that these genetically distinct groups of HPV types may differ in tissue preferences, which may contribute to their differences in carcinogenic potential. (Cancer Res 2006; 66(2): 1218-24)
The Penetration of Anticancer Drugs through Tumor Tissue as a Function of Cellular Adhesion and Packing Density of Tumor Cells
Authors: Grantab Rama , Sivananthan Shankar , Tannock Ian F.
Published: January 2006

To reach cancer cells in optimal quantities, therapeutic agents must be delivered to tumors through their imperfect blood vascular system, cross vessel walls into the interstitium, and penetrate multiple layers of tissue. Strategies to enhance drug penetration have potential to improve therapeutic outcome. The development of multicellular layers (MCLs), in which tumor cells are grown on a semipermeable Teflon support membrane, has facilitated quantification of drug penetration through solid tissue. The goals of the present study were to quantify the penetration of anticancer drugs as a function of cellular adhesion and packing density and to determine the effects of variable penetration on therapeutic efficacy in this model system. We compared the properties of MCLs grown from two epithelioid and round subclones of a colon carcinoma cell line. One pair of epithelioid and round sublines differed in expression of α-E-catenin, and both pairs generated MCLs with different packing density. The penetration of commonly used anticancer agents (paclitaxel, doxorubicin, methotrexate, and 5-fluorouracil) through MCLs derived from these cell lines was significantly greater through the round (loosely packed) than through the epithelioid (tightly packed) sublines. In MCLs treated with doxorubicin, we observed greater survival in the tightly packed cell lines than in the loosely packed cell lines. Impaired penetration of anticancer agents through MCLs derived from the tightly packed cell lines and relative resistance to killing of cells within them by doxorubicin treatment strengthen the role of tumor cell adhesion and packing density as contributing to drug resistance. (Cancer Res 2006; 66(2): 1033-9)
The Single Nucleotide Polymorphism IVS1+309 in Mouse Double Minute 2 Does Not Affect Risk of Familial Breast Cancer
Authors: Wilkening Stefan , Bermejo Justo Lorenzo , Burwinkel Barbara , Klaes Rüdiger , Bartram Claus R. , Meindl Alfons , Bugert Peter , Schmutzler Rita K. , Wappenschmidt Barbara , Untch Michael , Hemminki Kari , Försti Asta
Published: January 2006

The mouse double minute 2 (MDM2) oncoprotein promotes cell survival and cell cycle progression by inhibiting the p53 tumor suppressor protein. Further, MDM2 overexpression can inhibit DNA double-strand break repair in a p53-independent manner. Recently, it was shown that a single nucleotide polymorphism (SNP) in the MDM2 promoter was associated with an accelerated tumor formation in individuals with a p53 mutation. The present case-control study investigated the association of this SNP (IVS1+309) with the risk and the age of onset of familial breast cancer in patients with unknown p53 mutation status. Data from 549 women affected by familial breast cancer and 1,065 healthy controls were analyzed. The cases did not carry BRCA1/2 mutations. Cases and controls showed a similar genotype distribution and the SNP did not seem to modify the age of onset of familial breast cancer. The data were also examined taking into account the presence of any additional cancer after breast cancer and the family history of cases; however, no association was found. These results suggest that the SNP IVS1+309 alone affects neither the risk nor the age of onset of heritable breast cancer. (Cancer Res 2006; 66(2): 646-8)
Farnesyl and Geranylgeranyl Transferase Inhibitors Induce G1 Arrest by Targeting the Proteasome
Authors: Efuet Ekem T. , Keyomarsi Khandan
Published: January 2006

Isoprenoid inhibitors are being evaluated as agents for the treatment of cancer. Their antitumor activity is attributed to inhibition of post-translational modification of Ras, which is crucial for its translocation and attachment to the plasma membrane, and ultimate involvement in signal transduction. However, whether blocking of Ras is solely responsible for the observed antitumor activity is unresolved. In this report, we propose an alternate mechanism. Using breast tumor models, we show that agents possessing a lactone moiety, including statins (such as lovastatin) and the isoprenoid inhibitors (such as FTI-277 and GGTI-298), mediate their cell cycle inhibitory activities by blocking the chymotrypsin activity of the proteasome in vitro. This results in the accumulation of cyclin-dependent kinase inhibitors p21 and p27 with subsequent G1 arrest. Cells devoid of p21 were refractory to the growth-inhibitory activity of lovastatin, FTI-277, and GGTI-298. However, in these p21 null cells, isoprenylation of key substrates of farnesyl transferase (such as Ras) and of geranylgeranyl transferase (such as RAP-1) were inhibited by FTI-277 and GGTI-298, respectively, suggesting that although both these isoprenoid inhibitors reached and inhibited their intended targets, inhibition of the isoprenylation of Ras and RAP-1A are not sufficient to mediate G1 arrest. We also show that the cell cycle effects can be attributed to the functional lactone moiety of the aforementioned agents. Collectively, our data suggest that FTI and GGTI and other agents containing an active lactone moiety mediate G1 arrest via inhibition of the proteasome and up-regulation of p21, independent of the inhibition of isoprenylation of Ras or RAP-1. (Cancer Res 2006; 66(2): 1040-51)
Distinct Role of Macrophages in Different Tumor Microenvironments
Authors: Lewis Claire E. , Pollard Jeffrey W.
Published: January 2006

Macrophages are prominent in the stromal compartment of virtually all types of malignancy. These highly versatile cells respond to the presence of stimuli in different parts of tumors with the release of a distinct repertoire of growth factors, cytokines, chemokines, and enzymes that regulate tumor growth, angiogenesis, invasion, and/or metastasis. The distinct microenvironments where tumor-associated macrophages (TAM) act include areas of invasion where TAMs promote cancer cell motility, stromal and perivascular areas where TAMs promote metastasis, and avascular and perinecrotic areas where hypoxic TAMs stimulate angiogenesis. This review will discuss the evidence for differential regulation of TAMs in these microenvironments and provide an overview of current attempts to target or use TAMs for therapeutic purposes. (Cancer Res 2006; 66(2): 605-12)
Gene Conversion Is a Frequent Mechanism of Inactivation of the Wild-Type Allele in Cancers from MLH1/MSH2 Deletion Carriers
Authors: Zhang Jian , Lindroos Annette , Ollila Saara , Russell Anna , Marra Giancarlo , Mueller Hansjakob , Peltomaki Paivi , Plasilova Martina , Heinimann Karl
Published: January 2006

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominantly inherited cancer predisposition syndrome caused by germ line mutations in DNA mismatch repair genes, predominantly MLH1 and MSH2, with large genomic rearrangements accounting for 5% to 20% of all mutations. Although crucial to the understanding of cancer initiation, little is known about the second, somatic hit in HNPCC tumorigenesis, commonly referred to as loss of heterozygosity. Here, we applied a recently developed method, multiplex ligation–dependent probe amplification, to study MLH1/MSH2 copy number changes in 16 unrelated Swiss HNPCC patients, whose cancers displayed microsatellite instability and loss of MLH1 or MSH2 expression, but in whom no germ line mutation could be detected by conventional screening. The aims of the study were (a) to determine the proportion of large genomic rearrangements among Swiss MLH1/MSH2 mutation carriers and (b) to investigate the frequency and nature of loss of heterozygosity as a second, somatic event, in tumors from MLH1/MSH2 germ line deletion carriers. Large genomic deletions were found to account for 4.3% and 10.7% of MLH1 and MSH2 mutations, respectively. Multiplex ligation–dependent probe amplification analysis of 18 cancer specimens from two independent sets of Swiss and Finnish MLH1/MSH2 deletion carriers revealed that somatic mutations identical to the ones in the germ line occur frequently in colorectal cancers (6 of 11; 55%) and are also present in extracolonic HNPCC-associated tumors. Chromosome-specific marker analysis implies that loss of the wild-type allele predominantly occurs through locus-restricted recombinational events, i.e., gene conversion, rather than mitotic recombination or deletion of the respective gene locus. (Cancer Res 2006; (66)2: 659-64)
Ductal Access for Prevention and Therapy of Mammary Tumors
Authors: Murata Satoshi , Kominsky Scott L. , Vali Mustafa , Zhang Zhe , Garrett-Mayer Elizabeth , Korz Dorian , Huso David , Baker Sharyn D. , Barber James , Jaffee Elizabeth , Reilly R. Todd , Sukumar Saraswati
Published: January 2006

In cancer patients and in those at high risk, systemic exposure to agents for therapy or prevention is accompanied by undesirable side effects. We hypothesized that it is possible to prevent and treat breast cancer by introducing anticancer agents into the mammary ductal network. Here, we show the efficacy of intraductally administered anticancer agents 4-hydroxytamoxifen and pegylated liposomal doxorubicin (PLD) in the prevention and treatment of breast cancer using the rat N-methyl-N′-nitrosourea–induced and spontaneous HER-2/neu transgenic mouse (neu-N) models of breast cancer. Intraductal administration of PLD to neu-N mice caused regression of established tumors and prevented tumor development more effectively than i.v. injection (P < 0.0001). Intraductal administration resulted in lower circulating levels of PLD compared with i.v. administration, with no evidence of systemic toxicity or long-term histopathologic changes in the mammary gland. Compared with systemic administration, intraductal injection provides direct access to breast lesions with higher local and lower systemic drug exposure. These studies suggest that this approach has potential for application to prevention and neoadjuvant therapy of early breast cancer. (Cancer Res 2006; 66(2): 638-45)
Chronic Paraneoplastic Cutaneous Syndrome Preceding an Indolent Variant of Mantle Cell Lymphoma: Favorable Response to Rituximab
Authors: Nemets Anatoly , Ronen Meir , Lugassy Gilles
Published: January 2006

Mantle cell lymphoma (MCL) is an aggressive type of malignant lymphoma with short median survival despite conventional therapy. We describe the unusual case of a 66-year-old man with a chronic skin rash which preceded the occurrence of an indolent MCL by 2 years. Repeated skin biopsies did not show involvement by the lymphoma. Short therapy with rituximab resulted in the complete and lasting resolution of the cutaneous lesions.
Factors That Modulate the Pkn4 Kinase Cascade in Myxococcusxanthus
Authors: Nariya Hirofumi , Inouye Sumiko
Published: January 2006

Myxococcusxanthus, a gram-negative developmental bacterium, contains a large number of protein Ser/Thr kinases (PSTKs). Among these PSTKs, Pkn4 is shown to be 6-phosphofructokinase (PFK) kinase. PFK associates with the regulatory domain of Pkn4 (Pkn4RD) and is activated 2.7-fold upon phosphorylation at Thr-226 by Pkn4. The activation of PFK is required to consume glycogen accumulated during early development and is essential for efficient sporulation. Three new factors, MkapA, MkapB and MkapC have been identified that associate with Pkn4 by the yeast two-hybrid screen and each contains well-known protein-protein interaction domains. MkapB interacts with Pkn4 in a phosphorylation-dependent manner and remains associated with Pkn4 after its phosphorylation. Binding of MkapB to Pkn4 prevents the interaction of Pkn4 with PFK and consequently PFK phosphorylation and activation. A pfk-pkn4 deletion mutant accumulates glycogen at a rate two folds higher than the parent strain, DZF1, at the stationary phase and early development stage, it is unable to consume glycogen during development and produces only 3.4% of the DZF1 spore yield. In contrast, an mkapB deletion mutant exhibits a 24 h delay in fruiting body formation, accumulates less glycogen in the stationary phase and gives rise to 6.4% of the DZF1 spore yield. In addition to Pkn4, MkapA associates with other membrane-associated PSTKs, Pkn1, Pkn2, Pkn8 and Pkn9, while MkapB associates with Pkn8 and Pkn9, and MkapC with Pkn8. These results indicate that there are complex PSTK networks in M. xanthus sharing common modulating factors.