bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 419: Periostin activates integrin alpha5/beta1 through AKT-dependent pathway in invasion of cholangiocarcinoma
Authors: Thuwajit Chanitra , Utispan Kusumawadee , Sonongbua Jumaporn , Thuwajit Peti 
Published: July 2012

Abstract
Cholangiocarcinoma (CCA), a cancer arising from bile duct epithelial cells, is a serious health problem in Thai people. It is a progressive tumor with high metastatic potency. Recently, our group has found that periostin, an extracellular matrix protein, mainly produced from stromal activated fibroblasts of CCA has strong impact to induce cancer cell invasion. This work aims to investigate specific integrins which are utilized by periostin to drive invasion of CCA cells. The activated intracellular signal transduction pathway is also explored. Seven Thai patients-derived CCA cell lines were investigated their integrin expression patterns by real time PCR. The results indicated high level of integrin alpha6 in almost all cell lines. In addition, integrin alpha5 was also detected in not only CCA cell lines but also in immortalized non-tumorigenic biliary epithelial cell. For beta subunit integrin, the result revealed high expression levels of integrins beta1 and beta4 in CCA and non-tumorigenic cells. These results implied high level of integrins alpha5/beta1 and alpha6/beta4 in CCA cells. Flow cytometry and immunocytochemistry analysis confirmed intact molecules of these 2 integrin receptors on the membrane of M213 CCA cell line. Cell adhesion on periostin-coated surface was significantly decreased after integrin alpha5/beta1, but not alpha6/beta4, was blocked with the corresponding neutralizing antibodies. This result indicated that CCA cells preferred to use integrin alpha5/beta1 to bind with periostin. Moreover, cells treated with a neutralizing antibody against integrin alpha5/beta1 showed attenuated effect of periostin-induced invasion as similar to cells exposed to siRNA against integrin alpha5. Furthermore, we found that integrin alpha5-knocked down cells had decreased level of intracellular pAKT compared to negative control cells after activation with periostin. Taken these results together, it is likely to say that periostin activates CCA invasion through integrin alpha5/beta1 and AKT-dependent signal transduction pathway. This study suggests fibroblast-derived periostin, the stromal cell-derived substance, in promotion of CCA progression. Importantly, the obtained data highlight the potential of using the mechanism underlying stroma-driven cancer progression as an alternative target in the treatment of CCA patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 419. doi:10.1158/1538-7445.AM2011-419
Abstract 4190: ADAM23: Biomarker for nonmelanoma skin cancer disease progression
Authors: Peng Lisan S. , Regan Suzanne 
Published: July 2012

Abstract
The ADAMs (A Disintegrin and Metalloproteinase) comprise a family of multidomain transmembrane and secreted proteins involved in cytokine and growth factor release, proteolysis and cell adhesion. Multiple family members have been shown to play a role in cancer formation and disease progression. Decreased ADAM23 expression has been demonstrated in human breast, colon, gastric, head and neck, brain and pancreatic cancers and is believed to be associated with a more malignant or metastatic phenotype. Substantially more than 1 million cases of non-melanoma skin cancer (NMSC) occur annually in the United States according to the American Cancer Society. Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the two major types of NMSC and most are related to chronic sun exposure. We have demonstrated by microarray analysis that ADAM23 expression is decreased in human keratinocytes chronically irradiated with a solar-simulated light source. Using a human SCC skin carcinogenesis model, we have demonstrated that decreased ADAM23 expression correlates with disease progression. Preliminary immunohistochemical analysis of human SCC samples also demonstrates decreased ADAM23 expression. We believe that ADAM23 may serve as a biomarker of human skin SCC disease progression. This may be important for earlier detection and for the possible development of targeted therapy that may serve as an alternative to potentially disfiguring surgical treatment.
This work was supported in part by PHS grant CA27502 and CA23074 from the National Cancer Institute and the National Institutes of Health. It was also supported in part by start-up funds supplied by the Department of Medicine at the University of Arizona School of Medicine.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4190. doi:10.1158/1538-7445.AM2011-4190
Abstract 4191: Prognostic impact of phosphohistone H3 in cutaneous nodular melanoma
Authors: Ladstein Rita G. , Bachmann Ingeborg M. , Straume Oddbjorn , Akslen Lars A. 
Published: July 2012

Abstract
Aims: The mitotic marker Phosphohistone H3 (PHH3) is considered to facilitate counting of mitosis. The aim of this study was to evaluate the prognostic significance and strength of PHH3 expression in a series of nodular cutaneous melanoma in comparison with other proliferation markers.
Materials and methods: Standard sections of paraffin embedded tumor tissue from 345 cases of cutaneous melanoma of the nodular type were examined by immunohistochemistry, and PHH3 staining of tumor cells were recorded in an area of 1 mm2.
In 92 cases, data on mitotic count and Ki-67 expression was available for comparison. The mitotic count was assessed on standard H&E as number of mitoses per mm2, the immunohistochemical staining of Ki-67 was given as a percentage of positive tumour cells.
Results: Increased PHH3 was strongly associated (p&lt;0.001) with increased tumor thickness, presence of ulceration and tumor necrosis. Furthermore, high expression of PHH3 was correlated with increased mitotic count (p&lt;0.001) and high Ki-67 expression (p=0.001). Univariate survival analysis showed significantly worse outcome in the cases with high PHH3 count (p&lt;0.001). Increased PHH3 and tumor thickness were significant prognostic factors in multivariate survival analysis when included together with ulceration. In multivariate survival analysis of the subset of 92 cases, high PHH3 was a stronger predictor of patient outcome than Ki-67 expression and mitotic count.
Conclusion: In this series of nodular melanomas, high PHH3 count was a significant predictor of poor prognosis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4191. doi:10.1158/1538-7445.AM2011-4191
Abstract 4196: MSH3 mediates sensitization of colorectal cancer cells to cisplatin, oxaliplatin and a poly(ADP-ribose) polymerase inhibitor
Authors: Takahashi Masanobu , Koi Minoru , Balaguer Francesc , Boland C. Richard , Goel Ajay 
Published: July 2012

Abstract
Introduction:The MSH3 gene is one of the DNA mismatch repair (MMR) genes that has undergone somatic mutation frequently in MMR-deficient cancers. MSH3, together with MSH2 forms the MutSβ heteroduplex, which interacts with interstrand crosslinks (ICLs) induced by drugs such as cisplatin and psoralen. However, the precise role of MSH3 in mediating the cytotoxic effects of ICL-inducing agents remains poorly understood. MethodsIn this study, we first examined the effects of MSH3 deficiency on cytotoxicity caused by cisplatin and oxaliplatin, another ICL-inducing platinum drug. Results: Using isogenic HCT116-derived clones in which MSH3 expression is controlled by shRNA expression in a tet-off system, we discovered that MSH3 deficiency sensitized cells to both cisplatin and oxaliplatin at clinically relevant doses. Interestingly, siRNA-induced down-regulation of the MLH1 protein did not affect MSH3-dependent toxicity of these drugs, indicating that this process does not require participation of the canonical MMR pathway. Furthermore, MSH3-deficient cells maintained higher levels of pH2AX after oxaliplatin treatment in comparison to MSH3-proficient cells, suggesting that MSH3 plays an important role in repairing DNA double strand breaks (DSB). This role of MSH3 was further supported by our findings that MSH3-deficient cells were sensitive to olaparib, a Poly(ADP-ribose) polymerase inhibitor. Moreover, the combination of oxaliplatin and olaparib exhibited more than 10-fold increase in toxicity compared to either treatment individually. Conclusion:Collectively, our results provide novel evidence that MSH3 deficiency contributes to the cytotoxicity of platinum drugs through deficient DSB repair. These data lay foundation for the development of effective prediction and treatments for cancers with MSH3 deficiency.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4196. doi:10.1158/1538-7445.AM2011-4196
Abstract 4197: A DNA damage checkpoint response to unrepaired ultraviolet radiation-induced lesions which is defective in melanoma
Authors: Wigan Matthew , Pavey Sandra , Brooks Kelly , Giles Nichole , Burgess Andrew , Sturm Rick , Gabrielli Brian 
Published: July 2012

Abstract
Ultraviolet radiation (UVR) is a major environmental risk factor in the development of skin cancer. Here we describe a G2 phase cell cycle checkpoint response to suberythemal doses of UVR that is defective in a majority of melanoma cell lines tested. The majority of cells in the basal layer of the epidermis are quiescent, and exposure to suberythemal doses of UVR produces not only DNA damage but also provides a mitogenic stimulus to drive cells into the cell cycle. The majority of UVR-induced DNA lesions are rapidly repaired by NER mechanisms, but a small number of DNA lesions fail to be repaired during G1 phase and are encountered by the replication fork during S phase. This triggers Werner helicase (Wrn) dependent lesion bypass, allowing replication to continue relatively unhindered, but producing gaps in the newly replicated DNA strand opposite the lesions. These single stranded DNA gaps recruit replication protein A (RPA) and components of the ATR-Chk1 checkpoint signaling responsible for the G2 phase arrest observed. The RPA foci also co-localise components of the error free RAD18-RAD51 post replication repair pathway which are essential for repair of the gaps and checkpoint signaling. This checkpoint mechanism ensures detection and repair of all UVR induced DNA damage before proceeding into mitosis. Loss of this checkpoint response increases the rate of UVR induced mutation. Thus this checkpoint response is critical for maintaining genomic stability in the epidermal melanocytes and keratinocytes, and loss of this checkpoint mechanism may account for the increased UVR signature DNA mutations found in melanomas.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4197. doi:10.1158/1538-7445.AM2011-4197
Abstract 4198: Mismatch repair polymorphisms and breast cancer risk in the Metropolitan New York Breast Cancer Family Registry
Authors: Kappil Maya A. , Delgado-Cruzata Lissette , Liao Yuyan , Terry Mary-Beth , Santella Regina M. 
Published: July 2012

Abstract
Suboptimal DNA repair capacity is believed to contribute to genomic instability and, thereby, onset of carcinogenesis. In fact, deficient repair has been reported to account for up to a five-fold increase in breast cancer risk. Major cancer susceptibility genes involved in repair, including BRCA1 and BRCA2 among breast cancer cases, have been identified. However, mutations in these genes are thought to account for only 5-10% of familial cases. Additional genetic susceptibility factors may play a role in the remaining cases, including polymorphisms in DNA repair pathway genes. Microsatellite instability, a commonly observed marker of mismatch repair (MMR) defects, has been observed in skin samples from breast cancer patients, suggesting a putative role for MMR in breast cancer. In this study, we investigated polymorphisms in mismatch repair genes and their association with breast cancer risk among participants of the Metropolitan New York Registry of Breast Cancer Families (N=744). Of the 313 sister-sets included in the registry, 306 sister-sets consisted of sisters discordant for disease. A total of twelve SNPs were chosen and assayed using Taqman SNP genotyping kits from Applied Biosystems. Using conditional logistic regression, an association with breast cancer was observed for two of the twelve SNPs assayed. A significant association with breast cancer risk was observed for MutY (H335Q,C/G) while a borderline association was observed for MSH2 (IVS12-6, T/C): OR = 2.24 (1.11-4.52) and OR = 1.71 (0.99-2.95), respectively. Future studies will focus on replicating these findings in a larger study population.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4198. doi:10.1158/1538-7445.AM2011-4198
Abstract 4202: Hair follicles disruption leads to enhanced UVB-induced cutaneous inflammation and basal cell carcinoma development
Authors: Xu Jianmin , Athar Mohammad , Kopelovich Levy 
Published: July 2012

Abstract
Hairless mice carrying homozygous mutations in hr gene manifest disrupted hair follicles (HFs) and develop more squamous cell carcinomas (SCCs) than their haired littermates, suggesting that HFs act as tumor suppressor for cutaneous SCCs. However, the role of HFs in the pathogenesis of BCCs remains elusive. Here, we show that HF disruption alters susceptibility to both BCCs and SCCs. For this, we bred ptch+/-/C57BL6 mice with SKH-1 hairless mice followed by brother-sister crossing to get F2 homozygous mutant or wild-type mice. These animals were UVB-irradiated for 44 weeks. UVB-induced inflammation was less pronounced in shaved haired than in hairless mice. In hairless mice, inflammatory infiltrate was histologically associated around the epidermal cyst and rudimentary HFs suggesting that HF disruption enhances UVB-induced inflammation. Tumor onset in hairless mice begins 10 weeks earlier than in shaved haired littermates. 100% of hairless developed &gt;15 tumors/mouse after 32 weeks while haired mice developed &lt;3 tumors/mouse following 44 weeks irradiation. The tumor spectrum in hairless and haired animals was also different. Spindle cell carcinomas only appeared in haired mice. Hairless animals developed more squamous papillomas and SCCs. The incidence of BCCs was significantly higher in hairless animals (p&lt;0.001). UVB-induced skin tumors in hairless mice were more aggressive than those in haired shaved littermates. Molecular typing of these tumors showed decreased E-cadherin expression and enhanced mesenchymal proteins, snail, slug, fibronectin and vimetin. These data suggest that the disruption of HF enhances susceptibility to epidermal carcinogenesis by augmenting inflammation and epithelial-mesenchymal transition.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4202. doi:10.1158/1538-7445.AM2011-4202
Abstract 4206: Tumorigenic polyploid cells contain elevated levels of reactive oxygen species and are selectively targeted by antioxidant treatment
Authors: Roh Meejeon , Van der Meer Riet , Abdulkadir Sarki 
Published: July 2012

Abstract
Polyploidy has been linked to the tumorigenicity mainly due to the chromosomal aberrations. Elevated reactive oxygen species (ROS) generation, on the other hand, has also been associated with oncogenic transformation in most cancer cells. However, a possible link between ploidy and ROS is largely not known. Here we have explored the role of ROS in the tumorigenicity of polyploid cells. We show that polyploid prostate and mammary epithelial cells contain higher levels of ROS due to their higher mitochondrial contents. ROS levels and mitochondrial mass are also higher in dihydrocytochalasin B (DCB)-induced polyploid cells, suggesting that higher levels of ROS observed in polyploid cell is due to cytokinesis failure. Interestingly, polyploid cells were more sensitive to the inhibitory effect of the antioxidant, N-Acetyl-L-cysteine (NAC), than control diploid cells. Treatment of polyploid/diploid cells with NAC led to the selective elimination of polyploid cells over time and abrogated the tumorigenicity of polyploid cells. This was partially mediated via the Akt signaling pathway. We next explored a possible role for ROS in promoting chromosomal instability by analyzing the effects of ROS on the mitotic stage of the cell cycle. Enhancing ROS levels by treatment of cells with hydrogen peroxide delayed not only entry into and but also exit from mitosis. Furthermore, increasing ROS levels significantly increased taxol resistance. Our results indicate that increased ROS in polyploid cells can contribute to tumorigenicity and illuminates therapeutic potential of antioxidant by selectively targeting the tumorigenic polyploidy cells and reversing taxol resistance.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4206. doi:10.1158/1538-7445.AM2011-4206
Abstract 4207: DHA enhances genotoxic stress in prostate cancer cells through suppression of NF-κB
Authors: Cavazos David A. , deGraffenried Linda A. 
Published: July 2012

Abstract
Excess levels of omega-6 fatty acids, commonly consumed in Western diets, are heavily implicated in contributing to prostate cancer incidence and tumor cell proliferation. Omega-6 fatty acids may promote worse outcome through the chronic production of eicosanoids that promote inflammation and oxidative stress. As omega-3 fatty acids competitively interact with some of the same rate-limiting enzymes to diminish inflammation and oxidative stress, epidemiologic studies have sought to determine if diets high in omega-3 fatty acids may impart beneficial effects on prostate cancer rates and progression. Pre-clinical observations indicate that omega-3 fatty acids suppress prostate tumor cell growth and induce cancer cell death, supporting a beneficial role of omega-3 fatty acids in delaying time to PSA failure and reducing the aggressiveness of advanced prostate cancer. As omega-3 fatty acids possess known pro-oxidant and antioxidant properties, we investigated the effects of docosahexaenoic acid (DHA-22:6n-3) in modulating oxidative DNA damage in normal and prostate cancer cells. Preliminary data demonstrates that prostate cancer cells (LNCaP) pretreated with DHA and pulsed with physiologic levels of H2O2 encounter a sustained G2 checkpoint arrest and exhibit decreased colony formation potential when compared to normal prostate epithelial cells (PrEC). LNCaP cells pulsed with 32 uM H2O2 exhibit DNA breaks associated with translocation of NF-κB into the nucleus, whereas pretreatment with DHA precluded NF-κB translocation, selectively sensitizing LNCaP cells, but not PrEC, to cell death. Further, DHA suppresses degradation of the NF-κB inhibitor, IκB, and attenuates NF-κB transcriptional activity as well as expression of the NF-κB downstream target, survivin. To conclusively demonstrate the critical role of NF-kB signaling in LNCaP cells after exposure to H2O2, we induced a 50% knockdown of p65 by siRNA and observe a complete ablation of colony formation relative to scrambled siRNA control vector. Here we describe one potential mechanism by which DHA may selectively increase genotoxicity in prostate cancer cells after exposure to oxidizing agents, ultimately setting the stage for Phase II clinical trials.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4207. doi:10.1158/1538-7445.AM2011-4207
Abstract 4210: Oxidative stress, DNA damage, and apoptosis mediated by arsenic trioxide in lung carcinoma cells
Authors: Walker Alice M. , Stevens Jacqueline J. , Tchounwou Paul B. 
Published: July 2012

Abstract
Lung cancer is one of the most lethal and common of cancers in the world, causing up to 3 million deaths annually. Arsenic trioxide (ATO) has been used in the treatment of relapsed/refractory acute promyelocytic leukemias. However, its effects on lung cancer are not known. We hypothesize that ATO may also have a bioactivity against lung cancer, and its mechanisms of action may involve apoptosis, DNA damage and changes in stress-related proteins in lung cancer cells. Using lung cancer (A549) cells as test model, mthe effects of ATO were examined by 6-diamidine-2 phenylindole (DAPI) nuclear staining for apoptosis, commet assay for genotoxicity ane western blotanalysis for stress protein (Hsp 70 and cfos) expression. Morphological changes of apoptosis (condensed chromatin and apoptotic bodies) were observed with DAPI and cell shrinkage and membrane blebbing without DAPI at 4 and 6µg/ml of ATO. The comet assay data revealed that DNA damage was significant as indicated by increased of the precent of DNA damage, tailmoment and tail length. There was significant increase in Hsp70 expression and significant decrease in cfos in ATO-treated cells compared to controls. ATO is cytotoxic to lung cancer cells and its toxicity is mediated via oxidative stress and DNA damage leading to apoptosis. However, further studies are warranted to understand its specific molecular mechanisms of toxicity.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4210. doi:10.1158/1538-7445.AM2011-4210