bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2323: Iron chelator contributes to anti-angiogenic therapy via selective induction of VEGF-A
Authors: Ohara Toshiaki , Noma Kazuhiro , Nishitani Seishi , Watanabe Shinichiro , Tomono Yasuko , Hashimoto Yuuri , Tazawa Hiroshi , Fujiwara Toshiyoshi 
Published: August 2012

Abstract
[Introduction] Iron is essential for cancer to survive. Cancer cell is suppressed to proliferate under the iron depletion condition using iron chelator. However, only iron depletion can't suppress tumor growth completely. The reason is that cancer cell has abilities to escape the severe environment. These abilities are known as angiogenesis, migration, etc. Thus, to inhibit not only cancer cell proliferation but also these abilities are important for anti-cancer therapy. Bevacizumab, an antibody against vascular endothelial growth factor, is the first clinical anti-angiogenic drug. It's used for many kinds of cancer patients and revealed clinical benefit. According to spread widely in use, the resistance of Bevacizumab has been recognized. Recently, patients in resistance of Bevacizumab were reported to be high concentration of PIGF, VEGF-C and VEGF-D. On the other hand, we have demonstrated a synergistic therapeutic effect of iron depletion on anti-angiogenic therapy for human cancer in this meeting. In vitro study, iron chelator was used to simulate the iron depletion condition. Our result showed that iron depletion has anti-proliferative effect and induction of VEGF-A. Therefore, Bevacizumab revealed a synergistic therapeutic effect in iron depletion condition. In this study, we hypothesized that iron chelation therapy has anti-proliferative effect and induction of only VEGF-A(not PIGF, VEGF-C and VEGF-D). [Matherials and Methods] A549, H1299 NSCLC cell lines were used. Iron chelator deferasirox and deferoxamine were prepared to simulate iron depletion condition. Cell viability was determined by WST-1 assay. To determine induction of iron chelator, PIGF, VEGF-A, C, D ELISA assays were performed. In vivo Bevacizumab administration study, we used A549 subcutaneous tumor xenograft mice(n=5/group). Deferasirox(50mg/kg) was administrated orally 5days in a week. Bevaicuzmab(5 mg/kg) was administrated twice a week intravenously. [Results] Iron chelator suppressed cancer cell proliferation and induced only VEGF-A(not PIGF, VEGF-C and VEGF-D). VEGF-A was induced by iron chelator in dose dependent manner. Deferasirox revealed synergistic anti-tumor effect with Bevacizumab in vivo study. [Conclusion] Iron chelator contributes to anti-angiogenic therapy via selectively inducing VEGF-A. Iron chelator can be a new therapeutic strategy of Bevacizumab combination therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2323. doi:1538-7445.AM2012-2323
Abstract 2325: Increase in neuroblastoma metastasis after dual inhibition of VEGF and Notch
Authors: Garcia Alejandro , Banerjee Debarshi , Kitajewski Jan K. , Kandel Jessica J. , Yamashiro Darrell J. 
Published: August 2012

Abstract
Purpose: Vascular endothelial growth factor (VEGF) inhibition is a validated cancer treatment. However, even in responsive tumors, acquired resistance is common. Notch proteins also function as key angiogenic effectors, and cross-regulate VEGF expression, raising the question of whether combined treatment would enhance tumor suppression. We hypothesized that dual VEGF/Notch blockade would inhibit tumor growth in experimental SY5Y neuroblastoma. Methods: SY5Y neuroblastoma cells were lentivirally transfected to express Notch1-decoy (N1D) or GFP (control). Proliferation was assessed in vitro under both hypoxia and normoxia using BrdU assays. To examine the effect of N1D on tumor growth, 10[6] cells were xenografted intrarenally in nude mice and treated with placebo or bevacizumab (BV) twice a week. Tumor progression was monitored by bioluminescence. Metastatic burden in target organs was quantified by bioluminescence and histology. Vascular disruption due to N1D and BV treatment was evaluated by immunostaining. IACUC approval was obtained for all experiments. Results: Expression of soluble N1D was confirmed by immunoblotting conditioned media. SY5Y+N1D cells proliferated more rapidly in hypoxia than control SY5Y+GFP cells (p&lt;0.01). In vivo, BV treatment alone significantly reduced tumor growth as compared to placebo (p=0.026). However, combined treatment (N1D + BV) did not further reduce SY5Y tumor growth as compared to BV treatment alone (p=0.684). Interestingly, dual-treated mice developed higher metastatic burdens in liver than mice treated with either agent alone or controls by bioluminescence (p=0.006). By histology, dual-treated mice displayed a higher incidence of liver metastasis (7/9 mice) vs. mice treated with BV only (3/10 mice). Immunostaining demonstrated disruption of tumor vessel architecture in BV- and N1D + BV-treated mice. Conclusion: Dual VEGF/Notch targeting of SY5Y tumors resulted in increased metastatic burden, without affecting primary tumor growth, as compared to either treatment alone. Recent data indicates that tumoral hypoperfusion can promote progression, potentially by selecting for biologically aggressive behaviors. Our results suggest that dual Notch/VEGF blockade causes an enhanced propensity to metastasize. These data warrant further preclinical investigation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2325. doi:1538-7445.AM2012-2325
Abstract 2326: Antiangiogenic effects associated with the inhibition of HSP90 in colorectal cancer
Authors: Mahaseth Hemchandra , Nagaraju Ganji Purnachandra , Diaz Roberto , Taliaferro-Smith LaTonia D. , Landry Jerome C. , Saba Nabil F. , El-Rayes Bassel F. 
Published: August 2012

Abstract
Purpose/Objectives: Angiogenesis has a central role in tumor growth and metastasis. Inhibition of angiogenesis has been shown to improve outcomes of patients with advanced stage colorectal cancer receiving standard chemotherapy regimens. HSP90 has a central role in the regulation of transcription factors that modulate the expression of angiogenic cytokines. Ganetespib is a small molecule functional inhibitor of HSP90. We tested the hypothesis that HSP90 inhibition by ganetespib can inhibit angiogenesis in colorectal cell lines. Methods: Two colorectal cancer (CRC) cell lines were used, HCT-116 and HT-29. Cells were either untreated (control) or treated with ganetespib at 50 nM for 24 hours. Western blot and RT-PCR analyses were carried out to determine the effect of ganetespib on HIF-1alpha and vascular endothelial growth factor (VEGF) expression. ELISA for VEGF expression was performed on the medium of CRC cells to evaluate the effects of ganetespib on VEGF secretion. Tube formation assays and chicken egg chorioallantoic membrane (Egg CAM) assay were also performed. Results: Western blot analyses demonstrated significant (p&lt;0.001) inhibition of HIF-1alpha and VEGF expression in both cell lines treated with ganetespib. RT-PCR demonstrated significant (p&lt;0.0001) downregulation of VEGF transcription. Similarly, ELISA assay demonstrated significant inhibition of VEGF expression in the culture medium in both CRC cell lines. The HUVEC tube formation and the egg CAM assays further confirmed that treatment of the cell lines with ganetespib inhibited angiogenesis. Conclusions: HSP90 inhibition has significant antiangiogenic effects in preclinical models. Evaluating HSP90 inhibitors in conjugation with chemotherapy in colorectal cancer is a rational approach that could have a significant impact on the outcome of this deadly and common disease.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2326. doi:1538-7445.AM2012-2326
Abstract 2334: Anti-angiogenic activity of anthrax lethal toxin using the mouse retina as a model system
Authors: Bromberg-White Jennifer L. , Boguslawski Elissa , Duesbery Nicholas S. 
Published: August 2012

Abstract
Our laboratory has previously shown that inhibition of MKK pathways by anthrax lethal toxin (LeTx) inhibits tumor growth and angiogenesis, reduces VEGF secretion, and results in rapid cessation of blood flow to tumors in melanoma and sarcoma xenograft model systems. To gain insight into the anti-angiogenic nature of LeTx, we utilized both developmental and pathological models of vascularization in the murine retina. By immunoblotting and immunofluorescence microscopy we observed that MAPK activation occurs in a spatially and temporally regulated manner during retinal vascular development. Intravitreal administration of LeTx caused an early delay in retinal vascular development followed by the formation of abnormal vascular tufts that co-stained with phosphorylated MAPK in the outer retinal region. Using a model of oxygen-induced retinopathy, western analysis revealed that MAPK activation preceded the onset of hypoxia and development of neovascularization in this model system. Intravitreal injection of LeTx during hypoxia resulted in a persistent lack of development and progression of all pathologic aspects of neovascularization, while having minimal effect on macrophage recruitment. VEGF levels remained at an elevated level even with the persistent lack of neovascular growth and continued hypoxic environment, implying a VEGF-independent mechanism for the effects of MKK inhibition. Additionally, immature retinal vasculature during normal development was persistently destroyed following MAPK inhibition, while mature vessels from adult animals were unaffected. Our studies not only reveal that MKK signaling plays a key role in retinal angiogenesis but also that perturbation of MKK signaling by LeTx can profoundly alter vascular morphogenesis. The persistent destruction of immature vessels during normal vascular development in the retina and in the model of oxygen-induced retinopathy suggests an extreme sensitivity of immature vessels to MKK signaling inhibition. Since MKK inhibition prevents oxygen-induced retinopathy by a mechanism independent of the VEGF-targeting strategies, this approach may be used in conjunction with existing strategies utilizing VEGF inhibitors to prevent pathologic angiogenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2334. doi:1538-7445.AM2012-2334
Abstract 234: Snapshot of MAP kinase and related signal transduction pathways from biopsied cells using a novel non-optical assay technology - a proof of concept study
Authors: Dickerson W. Matthew , Alderman Edward M. , Beausang Lee Ann , Leong Kristen , Saab Ashley 
Published: August 2012

Abstract
Aberrant activity of the MAP and PI3 kinases is implicated in many forms of cancer. The ability to gather quantifiable information on the activation-state of these kinases from limited in-vitro and in-vivo tumor samples would accelerate drug development and ultimately, the treatment of cancer. Here non-optical, AMMP (acoustic membrane microparticle) technology is used to quantitate the activity state of multiple kinases including EGFR, c-RAF, MEK, ERK, AKT, p38 and JNK in a single assay plate. Lysates from multiple unstimulated tumor cell lines were compared with those from the same cell lines specifically stimulated with ligands to several well-known surface receptors for expressed changes in their phosphorylation states. The data show that the AMMP assay technology can be used to monitor the MAP Kinase pathway activation from EGFR stimulation through ERK phosphorylation following EGF stimulation. Additionally, the activation states of PI3 kinase, p38 and JNK were determined from the same lysate samples. Subsequently, assays were developed to monitor kinase dimerization (e.g., MEK-ERK) by rearranging the pairing of antibodies from the kinase activity assays described above. Using fewer than 2000 cells per assessment, multiple kinases were measured, in their native states, in a single assay using AMMP technology.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 234. doi:1538-7445.AM2012-234
Abstract 2343: Establishment of patients’ primary non-small cell lung cancer xenograft models for test of anticancer drugs
Authors: Liu Changnian , Sun Daqiang , Li Wenwei , Zhou Wen , He Fang , Zhou Rui , Zhang Xun 
Published: August 2012

Abstract
BACKGROUND Human xenograft tumor models established by transplantation of human tumor cell lines into immunodifficient mice have been routinely used for preclinical test of anticancer agents. But tumor cell lines have a relatively low transplantability and resulted in a limited number of tumor models available for selection of right models for preclinical testing novel agents based on their antitumor mechanism. Recently, we have developed a large number of patient primary non-small cell lung cancer (NSCLC) xenograft models by transplanting patients’ fresh tumor tissues into nude mice, which have been employed for preclinical test of anticancer agents. METHODS The fresh NSCLC tissues were collected from local hospitals. The tumor fragments of 1-2 mm were subcutaneously implanted in the flanks of the nude mice by trocar needle. Sixteen tumor fragments were grafted into four mice from one patient tumor tissue (passage 1). All therapeutic efficacy experiments used female mice bearing passage 5 xenografts. The test drugs included cisplatin, carboplatin, paclitaxel, docetaxel, gemcitabine, tarceva, and iressa. RESULTS A total of 142 patient primary NSCLC samples were implanted into nude mice, and 71 primary tumor models were established with a tumor taking rate of 50% for the first passage. The tumor taking rates were higher (80-100) in the later passages. The therapeutic efficacy of the test drugs in these models is consistent with their clinical findings. The histopathology and gene sequence of the established primary tumor xenografts were analyzed; their architecture, histopathological morphology, and genomic mutation status from five generations of xenografts retained the patients’ original tumor characteristics. CONCLUSIONS The patient primary NSCLC models have been employed for preclinical test of standard clinically used and novel anticancer agents. The primary tumor models retain a similarity in histology and genomic mutation status to their patients’ original tumors. They may predict more relevant clinical response rate and higher correlation with clinical findings than use of traditional xenograft models established from long-term cultured cancer cell lines. Especially, they have advantages for test of target-oriented therapeutics in new drugs development programs.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2343. doi:1538-7445.AM2012-2343
Abstract 2346: Lung cancer progression by efficient cre-mediated deletion of Pten and Smad4
Authors: Akkanti Bindu , Cho Sung-Nam , Jin Nili , Matzuk Martin , Wistuba Ignacio , DeMayo Francesco 
Published: August 2012

Abstract
Introduction: Lung cancer is the leading cause of cancer death in the world and the incidence of pulmonary adenocarcinoma, the most common type of lung cancer in the United States has been increasing in recent years. Mouse models have played a crucial role in understanding the tumor biology and progression of disease. The need for more clinically relevant preclinical mouse models for lung cancer is clear. Most mouse models for lung cancer use adenoviral delivery or cre recombinase models that result in development of cancers of the distal air ways. The tumors resulting from these mouse models are usually a mixed phenotype with mice developing adenocarcinoma, squamous cell carcinoma and benign adenomas depending on the combination of genetic alterations. We wanted to study lung cancer in the setting of more efficient cre that is present in the proximal as well as the distal lung epithelium. Utilizing this cre-system, we created a double knockout murine model with conditional ablation of pten and smad4 genes and wanted to compare tumor development and progression in these mice when compared to wildtype or smad 4 d/d or pten d/d mice. Methods: All mice were maintained at our core facility under approved protocols. The efficient cre system was accomplished by inserting the iCre recombinase into the Clara Cell Secretory protein locus. Tissues were collected at the time of sacrifice and compared to wild-type mice. Methods include Microarray analysis, RT-PCR, Immunohistochemistry and CHIP-Seq. Results: When compared with wildtype mice, smad 4 d/d or pten d/d alone mice, we have recognized that this particular mouse model has reproducibly developed proximal lung cancers that stain negative for SPC, a marker for distal airways. Additionally, this mouse model has developed metastatic disease, with metastasis to stomach. The immunohistochemistry results confirmed that the metastasis site was positive for TTF-1. Immunohistochemistry for EMT makers show that there is gradual loss of E-Cadherin. Conclusions: We have successfully created a mouse model with CCSPicre/Pten/Smad4 that results in proximal lung tumor development that advances to metastatic disease. Previous studies showed that tissue specific knockout of Smad 4 results in malignancy including gastric polyposis, pancreatic cancer, mammary gland epithelial hyperproliferation and SCC of the skin. Our results add to the previous findings in that loss of Smad4 in conjunction Pten may provide a novel platform to study lung cancer especially as it relates to proximal lung cancers that metastasize.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2346. doi:1538-7445.AM2012-2346
Abstract 2348: Suppression of metastasis of intratesticular inoculation of B16FO melanoma cells by a novel nutrient mixture in male athymic nude mice
Authors: Roomi M. Waheed , Roomi Nusrath W. , Rath Matthias , Niedzwiecki Aleksandra 
Published: August 2012

Abstract
Testicular cancer (TC) is rare, but still represents one of the most common diseases in young men between the ages of 20-45. However, men of any age can develop this disease. The incidence in Caucasians is greater than in African Americans. Risk factors include undescended testis, Klinefelter syndrome, and HIV positive patients. If left untreated, it is almost certainly fatal. Metastasis is the major cause of cancer death. The most common place for TC to spread in the body is to the lung. In this investigation, we studied the effect of a novel nutrient mixture (NM) containing ascorbic acid, amino acids and green tea extract that has been shown to exhibit anti-cancer activity, on inhibition of B16FO melanoma cells inoculated intratesticularly. Male athymic mice (n=12), 10-12 weeks of age, were inoculated with half a million B16FO melanoma cells in 100 µL of PBS into the right testis; the left testis was left untreated. After inoculation, the mice were randomly divided into two groups. Group A (n=6) was fed a regular mouse chow diet, while the mice in Group B (n=6) were fed the same diet but supplemented with 0.5% NM. Four weeks later the mice were sacrificed and the abdominal cavity was opened. Mice in the control group (Group A) exhibited extensive metastasis in the peritoneal cavity, which was totally masked by B16FO melanoma cells. The testis was severely enlarged and replaced by invading malignant melanoma cells. The remaining testicular tissue was represented by necrotic seminiferous tubules. The capsular region of the testis was severely infiltrated with a population of mixed cells. In contrast, in the NM fed group (Group B), there was no evidence of peritoneal metastasis, but the testes were enlarged. Seminiferous tubules in the area of invasion showed evidence of degeneration. In all groups, there was no metastasis to liver, kidney and spleen. However, severe lung metastasis was observed in the control group (2 out of 6) and mild in the test group (2 out of 6). In conclusion, these results suggest that NM has potential to suppress tumor metastasis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2348. doi:1538-7445.AM2012-2348
Abstract 2352: Molecular profiles of head and neck cancer tumorgrafts
Authors: Kimple Randall J. , Blitzer Grace C. , Torres Alexandra D. , Yang Robert Z. , Lorenz Laurel D. , Armstrong Eric A. , Soriano Benjamin J. , Lambert Paul F. , Harari Paul M. 
Published: August 2012

Abstract
Purpose: We have developed a primary tumorgraft system of squamous cell carcinoma of the head and neck with relevance for investigating mechanisms of therapeutic resistance, understanding differential responses to standard therapy in HPV-positive and HPV-negative cancers, and testing novel therapeutics. To better understand the power, limitations and relevance of our tumorgraft system, we have initiated molecular characterization of these tumors. Methods: Patients with newly diagnosed or recurrent HNSCC were consented for donation of tumor at the time of surgery. Tumor tissue was obtained, washed in antibiotic rich media, manually disaggregated, and subcutaneously implanted into mice (NOD.Cg-Prkdc scid Il2rgtm1Wjl/SzJ) for initial tumorgraft establishment. Subsequent mouse-to-mouse passages were performed and formalin-fixed/paraffin embedded as well as flash frozen tissue was harvested for subsequent molecular analyses. Expression of p16(Ink4a), p53, pRB, and EGFR was assessed by immunohistochemistry(IHC). HPV status and subtype was assessed using MY09/MY11 and GP5/GP6 degenerate nested polymerase chain reaction and Sanger sequencing. Transcriptionally active HPV infection was assessed by qRT-PCR for the HPV oncogenes E6 and E7. Mutation status of p53 was assessed by PCR-based exon amplification and Sanger sequencing. Results: To date, thirty primary tumorgrafts have been established with robust growth in eighteen (60%). p16(INK4A) expression was identified in approximately one-third. The majority of HPV-positive tumorgrafts contained HPV-16 and were transcriptionally active by mRNA expression profiling. HPV-positive tumors showed low p53 and RB expression by IHC. As anticipated, mutations in p53 were seen more frequently in HPV-negative tumors. Conclusions: These primary human tumorgrafts represent a diverse range of head and neck cancers. Both HPV-positive tumors and HPV-negative tumors have been successfully propagated with a diverse range of molecular characteristics. These primary tumorgrafts will provide a valuable platform for testing novel therapeutics as well as radiation and chemotherapy response profiles.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2352. doi:1538-7445.AM2012-2352