bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1342: A new approach to cancer therapy based on dynamic anchor-mediated activation of tumor-specific T cells
Authors: Mao Chih-Ping , Hung Chien-Fu , Wu TC 
Published: August 2015

Abstract
Although it has been shown that T cells can play a key role in the control of tumor progression, tumor-specific T cells almost universally suffer from a poor capacity to recognize tumor antigen due to intricate mechanisms of central and peripheral immune tolerance. It has become clear that in order for immune-based cancer therapy to be successful, the major obstacle of immune tolerance to tumor self-antigen must be overcome. Here we report a strategy to accomplish this by engineering molecular events at the interface between antigen peptide-MHC (pMHC) and TCR. In particular, our approach is based on fusion of pMHC to the protein annexin V (ANXA5), which behaves as a ‘dynamic anchor’. The dynamic anchor, in a synchronized and synergistic manner, couples the early onset of TCR signaling by cognate pMHC with a boost in pMHC-TCR affinity, with serial pMHC binding, and with extensive TCR crosslinking. In our system, the dynamic anchor is linked to pMHC and strongly attaches to the plasma membrane of cognate T cells upon (and only upon) the early onset of TCR signaling. This anchor in turn exerts a mechanical force that stabilizes interactions at the pMHC-TCR interface. Furthermore, once the dynamic anchor attaches to these T cells, it facilitates repeated, serial pMHC binding and quickly arranges into uniform 2D matrices, thereby prompting TCR crosslinking. We found that fusion of ANXA5 to pMHC augments activation of cognate T cells by several orders of magnitude (&gt;1,000-fold), bypasses the need for costimulation, and breaks tolerance against a model self-antigen in vivo. Our study opens the door to a new class of vaccination that can raise a robust immune response against low affinity tumor self-antigen.
Citation Format: Chih-Ping Mao, Chien-Fu Hung, TC Wu. A new approach to cancer therapy based on dynamic anchor-mediated activation of tumor-specific T cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1342. doi:10.1158/1538-7445.AM2015-1342
Abstract 1347: Genomic stress in antigen experienced T-lymphocytes
Authors: Patel Shashank , Sukumar Madhusudhanan , Palmer Douglas , Roychoudhari Rahul , Roy Rabindra , Nussenzweig Andre , Restifo Nicholas 
Published: August 2015

Abstract
DNA damage response and repair (DDR) pathways are central to biological processes like hematopoietic stem cell maintenance, lymphocyte development and adaptive response to inflammation and cancer. However, the role of DDR in antigen experienced T-lymphocytes remains unclear.
We studied the dynamics of DDR response during CD8+ T cell proliferation and differentiation. We found that DDR gene transcripts and gamma-H2AX, a marker for DDR pathway activation, are significantly up-regulated in CD8+ T cells expanded in-vitro and in-vivo. Next we aimed to determine the consequence of the activation of DDR pathways. Based on flow cytometry measurements of gamma-H2AX phosphorylation levels, we categorized CD8+ T cells into gamma-H2AXLo and gamma-H2AXHi cells. gamma-H2AXLo CD8+ T cells actively proliferate and produce cytokines, while gamma-H2AXHi CD8+ T cells lose their ability to produce cytokines, and undergo apoptosis.
To define whether oxidative stress or replicative stress incurred in CD8+ T cell triggers this activation of DDR, we acutely treated cells with chemical agents and studied functional differences. These studies revealed that oxidative stress may be responsible for the inhibition of cytokine production and increase in cell death. Using Pmel transgenic p53-/- mouse model, we show that by deleting p53, a major signal modulator of DDR, the loss of cytokine production and cell death due to oxidative stress is reverted in CD8+ T cells. Currently, we are exploring the chemical and gene modification methods to manage oxidative stress in CD8+ T cells to improve T-cell based adoptive cell transfer therapies for cancer.
Citation Format: Shashank Patel, Madhusudhanan Sukumar, Douglas Palmer, Rahul Roychoudhari, Rabindra Roy, Andre Nussenzweig, Nicholas Restifo. Genomic stress in antigen experienced T-lymphocytes. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1347. doi:10.1158/1538-7445.AM2015-1347
Abstract 135: Associations between VEGF polymorphisms and clinical outcome in breast cancer
Authors: Furriol Jessica , Puntervoll Hanne E. , Knutsvik Gøril , Mannelqvist Monica , Aziz Sura , Wik Elisabeth , Akslen Lars A. 
Published: August 2015

Abstract
Introduction
Vascular Endothelial Growth Factor (VEGF) is a key regulator of angiogenesis and is involved in the development and progression of solid tumors. Recent advances in sequencing technologies have allowed the identification of genetic variants associated with development and progression of different diseases including breast cancer. Despite evidence suggesting that these genetic variants can be used for improved risk stratification, results are not conclusive. In this work we have evaluated the relationship between 8 VEGF SNPs (single nucleotide polymorphisms) and survival as well as clinico-pathologic characteristics in breast cancer.
Material and Methods
In this study 8 VEGF SNPs (rs3025039, rs69947, rs833070, rs2010963, rs3025010, rs25468, rs3025035 and rs833068) were selected. DNA was extracted from non-tumor FFPE-samples from a series of 367 breast cancer patients from a Norwegian population. Associations between SNPs and categorical variables were analyzed by chi-square and Fisher exact tests. We used logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI). Survival was calculated by the Kaplan-Meier method (log-rank test).
Results
Our results showed that for a subset of patients, rs3025035 CT and TT were associated with relapse (p = 0.044; OR 3.07, 95%CI 1.08-8.76). Accordingly the rs3025035 CC genotype was related to longer time to recurrence after surgery (p = 0.10). Interestingly, in patients with histologic grade 3, a trend between CC and improved survival was also found in rs3025035 (p = 0.10), whereas the CC genotype in rs3025039 was associated with worse prognosis in this group (p = 0.037). Finally, the haplotype rs3025035T-rs3025039C was associated with relapse (p = 0.015; OR 3.72, 95% CI 1.31-10.62).
Conclusions
We report for the first time an association of the rs3025035 CC genotype with disease relapse and suggest that it could be a prognostic marker in breast cancer. Independent studies are needed to confirm our result.
Citation Format: Jessica Furriol, Hanne E. Puntervoll, Gøril Knutsvik, Monica Mannelqvist, Sura Aziz, Elisabeth Wik, Lars A. Akslen. Associations between VEGF polymorphisms and clinical outcome in breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 135. doi:10.1158/1538-7445.AM2015-135
Abstract 1384: CRLX101, an investigational camptothecin-containing nanoparticle-drug conjugate, reverses the HIF-1α-mediated increase in cancer stem cells caused by bevacizumab in a preclinical model of triple-negative breast cancer
Authors: Conley Sarah J. , Baker Trenton L. , Burnet Joseph P. , Thiesen Rebecca L. , Lazarus Douglas , Peters Christian G. , Clouthier Shawn G. , Eliasof Scott , Wicha Max S. 
Published: August 2015

Abstract
Antiangiogenic agents are designed to impede the development of new tumor blood vessels, thereby starving tumors of oxygen and nutrients to ultimately block tumor growth. Despite advances made in developing antiangiogenic therapies, clinical and preclinical data suggest that these drugs have limited efficacy in breast cancer patients. Tumors inevitably develop resistance to antiangiogenic agents and patients frequently fail to demonstrate significantly better overall survival. Acquired resistance to antiangiogenic agents has been attributed in part to the induction of intra-tumoral hypoxia and the concomitant stabilization of hypoxia-inducible factor 1α (HIF-1α), a transcription factor that promotes tumor angiogenesis, invasion, metastasis, and cancer stem cell (CSC) self-renewal. In this preclinical model, we demonstrate that CRLX101, an investigational nanoparticle-drug conjugate (NDC) containing the payload camptothecin (CPT), can reverse the stimulatory effects of hypoxia on the CSC population in an orthotopic triple-negative xenograft model. The payload, camptothecin, a topoisomerase 1 inhibitor, inhibits HIF-1α protein accumulation at concentrations below those that were cytotoxic to tumor cells, and inhibits hypoxia-mediated CSC induction at these low concentrations in vitro. In an orthotopic triple-negative breast cancer model, CRLX101 is synergistic with bevacizumab. Tumor reimplantation experiments confirm that the combination therapy effectively targets both the bulk tumor cell and CSC populations. Results generated from these preclinical studies support the clinical research of combining antiangiogenic agents with CRLX101 to increase patient survival. CRLX101 is currently in phase 2 clinical trials in combination with bevacizumab in both recurrent ovarian cancer and metastatic renal cell carcinoma.
Citation Format: Sarah J. Conley, Trenton L. Baker, Joseph P. Burnet, Rebecca L. Thiesen, Douglas Lazarus, Christian G. Peters, Shawn G. Clouthier, Scott Eliasof, Max S. Wicha. CRLX101, an investigational camptothecin-containing nanoparticle-drug conjugate, reverses the HIF-1α-mediated increase in cancer stem cells caused by bevacizumab in a preclinical model of triple-negative breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1384. doi:10.1158/1538-7445.AM2015-1384
Abstract 1394: CD44 isoform expression illuminates multiple CSC subpopulations in PC3
Authors: Hernandez James R. , Mooney Steven M. , Torga Gonzalo , Verdone James E. , Pienta Kenneth J. 
Published: August 2015

Abstract
The concept of the cancer stem cell (CSC) is neither new nor without controversy. It is important to study these cells since they are often hypothesized to be androgen insensitive and resistant to chemotherapeutics. Therefore, finding reliable markers for identifying and targeting these cells has become increasingly attractive. The hyaluronic acid receptor, CD44, is associated with a wide variety of cell types, including CSCs. CD44 has many different isoforms which can be categorized as belonging to one of two groups; one expressing different combinations of 10 variant extracellular exons (CD44v), and the other only expressing standard exons found in all isoforms, but none of the 10 variant exons (CD44s). CD44s is typically associated with the mesenchymal stem cell niche, while the various CD44v forms are related to hematopoietic stem cells and increased cell adhesion. However, both CD44s and CD44v have been linked to the CSC niche and cancer progression. Similar to CD44, the aldehyde dehydrogenases (ALDH) superfamily expression is also associated with CSCs and cancer progression. Previously, our laboratory demonstrated that epithelial cancer cells undergo an EMT upon exposure to M2 macrophages. In order to obtain a purely epithelial PCa population, our laboratory isolated a single cell clone of PC3 that had high E-cadherin expression, denoted PC3-Epi. PC3-Epi cells were then incubated with M2 macrophages, which caused a stable EMT to occur after only a few days in culture, denoted PC3-EMT. Our finding demonstrate that these PC3 clones exhibit numerous CSC characteristics, such as high ALDH activity, CD44 expression and cell plasticity. FACS analysis of CD44 isoform expression show distinct CSC subpopulations within these PC3-Epi and PC3-EMT cell types. These subpopulations showed the ability to recapitulate the presorted parental population after being returned to culture. This data suggests not only that the PC3 cell line displays numerous CSC characteristics, but also that distinct CSC subpopulations may exist.
Note: This abstract was not presented at the meeting.
Citation Format: James R. Hernandez, Steven M. Mooney, Gonzalo Torga, James E. Verdone, Kenneth J. Pienta. CD44 isoform expression illuminates multiple CSC subpopulations in PC3. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1394. doi:10.1158/1538-7445.AM2015-1394
Abstract 1397: Identification of a hepatocellular carcinoma cell line capable of monitoring the differentiation of CD13(+)CD166(-) cancer stem cells and effects of sorafenib
Authors: Yamada Takeshi , Abei Masato , Danjoh Inaho , Shirota Ryoko , Yamashita Taro , Endo Shinji , Hyodo Ichinosuke , Nakamura Yukio 
Published: August 2015

Abstract
Background: Recent cancer stem cell (CSC) research has highlighted the necessity to develop drugs targeting CSCs. However, only few in vitro models are available which show CSC hierarchy and allow monitoring of CSC differentiation and screening of drugs targeting CSC.
Aim: In the present study, we aimed to identify such hepatocellular carcinoma (HCC) cell line(s).
Methods: Based on a hypothesis that the proportion of CSCs would decrease during culture because of their differentiation into progenitors (population switch), we tested the positivity of several markers (CD13, EpCAM, CD133, CD44, CD90, CD24, CD166) in HCC cell lines (HuH-7, Li-7, PLC/PRF/5, HLF, HLE) before and after 2 months culture.
Results: Only Li-7 cells showed relevant population switch: the proportion of CD13 decreased, while that of CD166 increased during the culture. High tumorigenicity of Li-7 was lost after the population switch. CD13(+)/CD166(-) cells showed slow growth and reconstructed the bulk Li-7 populations composed of CD13(+)/CD166(-), CD13(-)/CD166(-) and CD13(-)/CD166(+) fractions, while CD13(-)/CD166(+) cells showed rapid growth but could not reproduce any other cell populations. CD13(+)/CD166(-) cells showed high ALDH activity, spheroid forming ability and resistance to 5FU. Microarray analysis demonstrated higher expression of stemness-related genes in CD166(-) than CD166(+) fraction. These results indicated the hierarchy of Li-7 cells, in which CD13(+)/CD166(-) and CD13(-)/CD166(+) cells serve as slow growing CSCs and rapid growing progenitors, respectively. Interestingly, sorafenib selectively targeted CD166(-) fraction including CD13(+) CSCs, which exhibited higher mRNA expression of FGF3 and FGF4, candidate biomarkers for sorafenib. 5-FU followed by sorafenib inhibited the growth of bulk Li-7 cells more effectively than reverse sequence or either alone.
Conclusions: We identified an useful cell line Li-7 capable of monitoring the CD13 (+) CSC differentiation and screening the drugs targeting the CSCs of HCC and found that sorafenib preferentially targeted CD13(+) CSCs in vitro. Screening cell lines for “population switch” may be useful to identify novel candidate model systems for screening drugs targeting CSCs.
Citation Format: Takeshi Yamada, Masato Abei, Inaho Danjoh, Ryoko Shirota, Taro Yamashita, Shinji Endo, Ichinosuke Hyodo, Yukio Nakamura. Identification of a hepatocellular carcinoma cell line capable of monitoring the differentiation of CD13(+)CD166(-) cancer stem cells and effects of sorafenib. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1397. doi:10.1158/1538-7445.AM2015-1397
Abstract 1429: Contribution of membrane-bound carboxypeptidase M to tumor growth and metastasis by regulating epithelial mesenchymal transition in esophageal squamous carcinoma
Authors: Kudo Yuji , Fukuda Junki , Harigai Ritsuko , Kato Kazunori 
Published: August 2015

Abstract
Carboxypeptidase M (CPM) is a membrane-bound exopeptidase that recognizes the arginine (Arg) and lysine (Lys) residues in a C-terminal of polypeptide chain or protein. The cleavage of some soluble factors such as SDF-1 and EGF by CPM leads to the alteration of binding affinity to their receptors. In this study, we examined the properties of CPM for tumor growth and metastasis in human esophageal carcinoma cells. In order to investigate the expression of CPM on human tumor cells, we established the monoclonal antibody specific for human CPM and found the constitutive expression of CPM on various human carcinomas by flow cytometry and confocal laser microscopy. Treatment of cancer cells with EMT-mediated cytokines, including TGF-beta, IL-6 and OSM, increased CPM expression on their cell surface followed by enhancement of cell migration and change of cell shapes from epithelial to mesenchymal type. Silencing CPM expression by small interfering RNA (siRNA) specific for CPM in esophageal and breast carcinoma cells were confirmed by flow cytometry. We found that CPM-silenced carcinoma exhibited reduced cell proliferation not only in 2D culture flask but also in 3D spheroid culture plate. Importantly, the treatment of siRNA for CPM inhibited the expression of EMT-related genes such as snail and slug which are important for cancer motility. Consistently, we found that CPM-silenced carcinoma exhibited reduced motility of cell in wound healing assay. Taken together, these data indicate that CPM contributes to cell growth and EMT and might be a therapeutic target in esophageal carcinoma.
Citation Format: Yuji Kudo, Junki Fukuda, Ritsuko Harigai, Kazunori Kato. Contribution of membrane-bound carboxypeptidase M to tumor growth and metastasis by regulating epithelial mesenchymal transition in esophageal squamous carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1429. doi:10.1158/1538-7445.AM2015-1429
Abstract 1440: Mitochondrial superoxide dismutase (Sod2) modulates ovarian clear cell carcinoma transcoelomic metastatic pathway
Authors: Hemachandra L.P.Madhubhani P. , Dier Usawadee , Hempel Nadine 
Published: August 2015

Abstract
Ovarian clear cell carcinoma (OCCC) is a highly aggressive histological subtype that represents approximately 10% of all ovarian cancer cases and displays high expression of mitochondrial superoxide dismutase (Sod2), a major mitochondrial antioxidant enzyme. In the female body ovarian cancer cells metastasize via the transcoelomic route, where cells detach from the primary tumor into the intraperitoneal (IP) cavity and survive as unattached single cells or spheroid aggregates until they get carried via ascites fluid to the omental wall and surrounding organs for metastatic colonization. Ovarian cancer spheroids evade anoikis and display strong resistant to most anti-proliferative cancer drugs. This may contribute to the high recurrence rate and chemoresistance of ovarian cancer. The present study suggests that Sod2 is critically important for the key events of this transcoelomic metastatic route of OCCC. Levels of Sod2 are further increased in OCCC cell lines when these are cultured as anchorage-independent spheroid aggregates, suggesting that Sod2 may play a major role in spheroid stability and survival. When Sod2 levels are reduced using RNA interference, spheroid morphology of ES-2 OCCC cell line is compromised, suggesting a potential correlation between anoikis resistant and Sod2 levels in OCCC. Sod2 knockdown compromises mitochondrial metabolism, as a consequence of reduced superoxide scavenging, and enhances spheroid sensitivity to cisplatin. In addition, Sod2 is necessary for spheroid attachment and outgrowth on extracellular matrix components, representing the invasion of spheroids into the omental wall. Further, tumor cell metastasis is attenuated with reduced Sod2 levels when ES-2 spheroids are placed on the vasculature of the Chorioallantoic membrane (CAM). Scavenging H2O2 by exogenous addition of catalase inhibits the migration of OCCC and our data suggest that high levels of Sod2 in OCCC shift the intracellular redox balance to drive H2O2-dependent pro-metastatic signaling. These results indicate that Sod2 plays a major role in OCCC tumor metastasis, by regulating survival and chemoresistance of tumor spheroids in the IP cavity and by supporting attachment and migration at secondary metastatic sites. Inhibition of Sod2 can be a potential therapeutic target against OCCC transcoelomic metastasis.
Citation Format: L.P.Madhubhani P. Hemachandra, Usawadee Dier, Nadine Hempel. Mitochondrial superoxide dismutase (Sod2) modulates ovarian clear cell carcinoma transcoelomic metastatic pathway. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1440. doi:10.1158/1538-7445.AM2015-1440
Abstract 1445: Overexpression of angiotensin II type 1 receptor induces epithelial-mesenchymal transition and promotes tumorigenesis of human breast cancer cells
Authors: Oh Eunhye , Kim Ji Young , Cho Youngkwan , Lee Nahyun , An Hyunsook , Kim Jun Suk , Seo Jae Hong 
Published: August 2015

Abstract
Propose: Accumulating evidence suggests that angiotensin II type 1 receptor (AGTR1) is involved in tumorigenesis and metastasis in many types of cancer, however little is known about its role in breast cancer. Our objective of the present study is to investigate the effect of AGTR1 overexpression on cell proliferation, epithelial-mesenchymal transition (EMT), migration, invasion, angiogenesis and tumorigenesis of human breast cancer.
Methods: To determine the role of AGTR1, MCF7 cells were stably transfected with an expression construct carrying the GFP cDNA for AGTR1. MTS assay, Matrigel invasion assay, wound healing assay, Western blotting and immunofluorescence were used. For in vivo study, parental MCF7 or AGTR1-MCF7 cells were subcutaneously injected into the left and right flanks of nude mice. Tumor growth and angiogenesis were determined.
Results and conclusion: AGTR1-MCF7 cells, expressing high level of AGTR1 exhibited significant increases in cell proliferation, migration and invasion capacities compared with parental MCF7 cells. Furthermore, AGTR1-MCF7 cells displayed the mesenchymal phenotype, as evidenced by elongated spindle morphology, decreased E-cadherin level, increased N-cadherin and snail, and nuclear accumulation of smad3 and smad4. Interestingly, blockade of smad4 using small interfering RNA strongly induced mesenchymal to epithelial transition (MET) and restoration of E-cadherin expression in AGTR1-MCF7 cells, suggesting that AGTR1-induced EMT is ultimately mediated by smad4 activation. Finally, we showed that AGTR1 overexpression enhanced tumor volume (p&lt;0.001, n = 10) and weight (p&lt;0.01) as well as increased angiogenesis in human breast cancer xenograft in vivo. In summary, we demonstrate that AGTR1 overexpression promotes cell proliferation, EMT, angiogenesis and tumorigenic properties of breast cancer cells. Our findings suggest that AGTR1 could be a useful target of therapy in breast cancer.
Citation Format: Eunhye Oh, Ji Young Kim, Youngkwan Cho, Nahyun Lee, Hyunsook An, Jun Suk Kim, Jae Hong Seo. Overexpression of angiotensin II type 1 receptor induces epithelial-mesenchymal transition and promotes tumorigenesis of human breast cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1445. doi:10.1158/1538-7445.AM2015-1445