bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C75: miR-7 suppresses brain metastasis of cancer stem-like cells by modulating Kruppel-like factor 4 in breast cancer
Authors: Xing Fei , Okuda Hiroshi , Kobayashi Aya , Pandey Puspa R. , Pandey Puspa R. , Sharma Sambad , Mo Yin-Yuan , Liu Yin , Wu Kerui , Watabe Kounosuke 
Published: August 2014

Abstract
The majority of cancer death of breast cancer attributed to metastatic disease. Despite this clinical importance, the exact pathological process of tumor metastasis is as yet poorly understood, and deciphering the exact molecular mechanism of this process is of paramount importance in order to identify specific therapeutic targets for this devastating disease. Recent active research in microRNA identified a series of this type of molecules that are involved in tumor progression in various tumors as oncogenes and tumor suppressors. Cancer stem-like cells (CSCs) are considered to play a role in metastatic progression of breast cancer; however, the exact pathological role of CSCs is yet to be elucidated. In this report, we found that CSCs (CD24-/CD44+/ESA+) isolated from metastatic breast cell lines are significantly more metastatic than non-CSC populations in an organ specific manner. The results of our microRNA profile analysis for these cells revealed that CSCs that are highly metastatic to bone and brain expressed significantly lower level of miR-7 and that this microRNA was capable of modulating one of the essential genes for induced pluripotent stem cell, KLF4. Interestingly, high expression of KLF4 was significantly and inversely correlated to brain- but not bone-metastasis free survival of breast cancer patients, and we indeed found that the expression of miR-7 significantly suppressed the ability of CSCs to metastasize to brain but not to bone in our animal model. We also examined the expression of miR-7 and KLF4 in brain-metastatic lesions and found that these genes were significantly down- or up-regulated, respectively, in the tumor cells in brain. Furthermore, the results of our in vitro experiments indicate that miR-7 attenuates the abilities of invasion and self-renewal of CSCs by modulating KLF4 expression. These results suggest that miR-7 and KLF4 may serve as biomarkers or therapeutic targets for brain metastasis of breast cancer.
Citation Format: Fei Xing, Hiroshi Okuda, Aya Kobayashi, Puspa R. Pandey, Puspa R. Pandey, Sambad Sharma, Yin-Yuan Mo, Yin Liu, Kerui Wu, Kounosuke Watabe. miR-7 suppresses brain metastasis of cancer stem-like cells by modulating Kruppel-like factor 4 in breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr C75.
Abstract C78: Integrin αvβ3 drives stemness in the pregnant and neoplastic mammary gland
Authors: Desgrosellier Jay , Lesperance Jacqueline , Seguin Laetitia , Cheresh David 
Published: August 2014

Abstract
Carcinoma cell expression of the integrin αvβ3 is associated with enhanced tumorigenicity and metastasis in a diverse array of human tumors. Here, we reveal αvβ3 expression in a subset of CD44+CD24-/low cancer stem cells in human breast tumor biopsies. In fact, αvβ3 is both necessary and sufficient to account for stem-like properties in breast tumor cells, suggesting that αvβ3 may contribute to mammary stem (MaSC)/progenitor cell behavior. While αvβ3 is a luminal progenitor marker in the virgin murine mammary gland, we noted a dramatic, but transient, increase in αvβ3 levels that defined the mammary stem cell pool at mid-pregnancy. Genetic deletion of β3 surprisingly had no effect on luminal progenitor behavior or ductal morphogenesis. In contrast, β3 was specifically required for MaSC clonogenicity and alveologenesis at mid-pregnancy, yet had no influence on MaSCs in the virgin gland. These findings reveal an unexpected role for αvβ3 in driving mammary stemness during pregnancy that may be related to the stem-like properties, and high metastatic potential associated with αvβ3 expression in human breast cancers.
Citation Format: Jay Desgrosellier, Jacqueline Lesperance, Laetitia Seguin, David Cheresh. Integrin αvβ3 drives stemness in the pregnant and neoplastic mammary gland. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr C78.
Abstract C83: Nicotine triggers initiation and progression of K-Ras-driven pancreatic ductal adenocarcinoma
Authors: Hermann Patrick C. , Sainz Bruno , Sancho Patricia , Heeschen Christopher 
Published: August 2014

Abstract
Smoking has been identified as a leading risk factor for pancreatic ductal adenocarcinoma. Nicotine is an important active ingredient of tobacco smoke and replacement products, but does not bear carcinogenic properties. While nicotine has been shown to induce proliferation, invasion and metastasis of fully transformed pancreatic cancer cells, its role in pancreatic cancer development and/or progression has not been determined yet. First, our in vivo studies showed a marked acceleration of carcinogenesis in two distinct genetically engineered mouse models for pancreatic cancer. Moreover, nicotine promoted tumor progression as evidence by enhancing the cancer stem cell signature and invasiveness via epithelial-to-mesenchymal-transition. This translated into increased numbers of circulating cancer cells and metastatic lesions. Using two independent model systems, i.e. pharmacological nAChR inhibition and knockout of the alpha7-nAChR, we demonstrate that nicotine activates the pancreatic progenitor compartment resulting in their subsequent expansion and enhanced susceptibility for K-Ras induced pancreatic carcinogenesis. Mechanistically, we found that nicotine-medicated Ca2+ influx induced mitochondrial ROS production and activation of the non-canonical Wnt pathway. Intriguingly, co-treatment with metformin prevented the accelerated pancreatic carcinogenesis and progression independent of AMPK. In conclusion, our findings reveal for the first time that nicotine promotes activation of the pancreatic (cancer) stem cell compartment and subsequently drives K-Ras-initiated pancreatic cancer development and progression.
Citation Format: Patrick C. Hermann, Bruno Sainz, Jr., Patricia Sancho, Christopher Heeschen. Nicotine triggers initiation and progression of K-Ras-driven pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr C83.
Abstract IA1: Metastasis and diversity in breast cancer
Authors: Polyak Kornelia 
Published: August 2014

Abstract
Genetic and phenotypic heterogeneity of cancer cells within tumors underlies metastatic progression and therapeutic resistance, thus, it is a major clinical problem. We have characterized intratumor genetic and phenotypic heterogeneity by immunoFISH (iFISH) in primary tumor, lymph node, and distant metastases from the same patient and breast tumor biopsies before and after treatment. We found that distant metastases were highly divergent in some patients and that intratumor diversity associated with tumor subtype and response to treatment. We have also developed preclinical models to assess the functional relevance of intratumor heterogeneity in breast cancer and found cooperative clonal interactions that may promote metastatic progression and contribute to therapeutic resistance. In addition, our analyses of associations between clonal frequency and drivers of tumor growth have revealed some unexpected findings. Our results highlight the importance of exploring and understanding tumors at the single cell level to be able to predict and overcome disease progression and therapeutic resistance.
Citation Format: Kornelia Polyak. Metastasis and diversity in breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr IA1.
Abstract PR1: The role of the microenvironment protein cathelicidin LL-37 in pancreatic ductal adenocarcinoma
Authors: Sainz Bruno , Frias Javier , Cioffi Michele , Alcala Sonia , Heeschen Christopher 
Published: August 2014

Abstract
The tumor-associated microenvironment does not only provide structural support for tumor development, but more importantly the microenvironment provides cues to cancer initiating cells [i.e. cancer stem cells (CSC)] that regulate their self-renewal capacity and metastatic potential. Recent evidence also suggests that inflammatory molecules at the tumor-stroma interface may also play critical roles in the development and progression of numerous tumors, such as pancreatic cancer, and their effects may also be paracrine-mediated. Along these lines, we have discovered that the immuno-modulatory cationic antimicrobial protein 18 (hCAP-18 or LL-37) is highly expressed in microenvironment resident cells (cancer-associated fibroblasts, infiltrating immune cells, and pancreatic stellate cells) of patients with pancreatic cancer. It is also secreted by primary human macrophages co-cultured with pancreatic CSCs. Intriguingly, LL-37 was not detectable in tissue from patients with chronic pancreatitis or pancreatic intraepithelial neoplasia (PanIN) suggesting a bilateral crosstalk between LL-37 producing cells and fully transformed cancer (stem) cells. As we have recently shown a strong role for the tumor stroma and microenvironment-secreted factors in pancreatic CSC self-renewal and invasiveness, LL-37 may represent a new and uncharacterized PDAC microenvironment factor that may play a critical role in pancreatic cancer progression and metastasis. Indeed, treatment of pancreatic CSCs with LL-37 increased CSC pluripotency-associated gene expression, self-renewal, and invasion in vitro as well as tumorigenicity and metastasis in vivo. LL-37 exerted its biological functions through interaction with the G protein—coupled receptor, formyl peptide receptor—like 1, P2X(7) purinergic receptor. In addition, receptor independent activity was mediated by stabilization of the CXCR4 receptor in the cell membrane. Taken together, our data expands our understanding of the tumor microenvironment and the tumor host interactions that perpetuate pancreatic ductal adenocarcinoma. Even more importantly, these studies identify a new tumor-specific factor for identifying malignant lesions in the pancreas and predicting patient outcome. Targeting of LL-37 could improve our therapeutic armamentarium against this deadly disease.
This abstract is also presented as Poster A18.
Citation Format: Bruno Sainz, Jr., Javier Frias, Michele Cioffi, Sonia Alcala, Christopher Heeschen. The role of the microenvironment protein cathelicidin LL-37 in pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr PR1.
Abstract A18: Mouse models of autochthonous cancer to study local immune subversion.
Authors: Bransi Ali , Yagita Hideo , Knuth Alexander , Broek Maries van den 
Published: August 2014

Abstract
The tumor environment delivers suppressive signals to the immune system, which impair the effector function of tumor-infiltrating lymphocytes. The identity of these signals, their targets and their mode of action, however, are largely unresolved.
We use TRAMP mice, a well-known autochthonous murine model for prostate cancer, to study the interaction of the adaptive immune system and cancer cells in order to investigate which cell types and molecules are crucial in deviating immune surveillance. Tumorigenesis in TRAMP mice is driven by SV40 large T (SV40LT), which allows monitoring of specific CD8 T cell responses to the tumor.
We analyzed quantitative and qualitative aspects of the tumor-specific T cell response in the spleen, the draining and non-draining lymph nodes and in the tumor of TRAMP mice. Interestingly, this mouse model shows CD8 T cell tolerance towards epitope IV but not epitope I of SV40LT when infected with recombinant vaccinia viruses expressing these epitopes. However, when transferring TCR transgenic CD8 T cells specific for epitope I, we observed rapid local and peripheral immune subversion of adoptively transferred cells in tumor-bearing animals. Homing and proliferation were not affected, but effector functions of these cells were greatly impaired. Furthermore, this immunosuppression was more severe locally at the tumor site than in the periphery. When using a combination of blocking antibodies for co-inhibitory molecules (PD-1, CTLA-4 and TIM-3), we could restore to some extent the function of transferred cells in the periphery, but not at the tumor site.
In parallel, we are in the process of generating an inducible CreERT/LoxP-based model to express the immunologically well-characterized oncogene SV40LT with the luciferase in a tissue specific fashion. This model will allow sensitive detection of arising tumors and precise dissection of tumor-specific immunity over time. By comparing fundamentally different target tissues, we may find mechanisms that are active in every malignancy and some that are organ-specific.
Citation Format: Ali Bransi, Hideo Yagita, Alexander Knuth, Maries van den Broek. Mouse models of autochthonous cancer to study local immune subversion. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr A18.
Abstract A24: Enhancing chemotherapy efficacy and antitumor immune activity by combined antisense downregulation of TS and IDO.
Authors: Vareki Saman Maleki , Koropatnick James 
Published: August 2014

Abstract
Chemotherapy plays a major role in treatment of many common cancers. However, it is limited by intrinsic and/or acquired tumor cell resistance to anticancer drugs, often mediated by increased expression of genes mediating that resistance. An approach to increase chemotherapy effectiveness is to reduce expression of such genes using small molecules or RNAi to silence specific targets that cancer cells rely on for escape from death due to exogenous treatment or immune cell attack. We have previously shown that siRNA downregulation of thymidylate synthase (TS), the enzyme responsible for the de novo synthesis of thymidylate and a common target for some anti-cancer drugs (5FUdR, pemetrexed, and others) enhances the activity of these drugs in vitro. Using lower concentrations of anticancer drugs has the potential to decrease deleterious side effects, including therapy-induced toxicity to T cells capable of recognizing and killing tumor cells. In addition, certain tumor proteins including indoleamine 2,3-dioxygenase [IDO] can regulate immunosurveillance by inhibiting antitumor T and NK cell activity. IDO can also mediate tumor cell resistance to some anticancer drugs, such as imatinib. To assess the capacity of combined siRNA knockdown of TS and IDO in human tumor cells to increase sensitivity to anticancer drugs, we report that: a) TS siRNA downregulates TS by 90% in HCT-15 colon carcinoma cells, over 90% percent in A549 lung carcinoma cells, and by 80% in H441 lung carcinoma cells, b) shRNA expression vectors stably expressing IDO siRNA in multiple clonally-derived populations of A549 reduces IFNγ-induced IDO protein expression by over 95%. Transiently-transfected TS siRNA is being used, alone and in combination with stable shRNA-mediated reduction in IDO, to assess the utility of targeting both mRNAs to enhance sensitivity to TS-targeting drugs (5-FU, 5-FUdR, pemetrexed), DNA-damaging anticancer drugs (cisplatin, melphalan) and both, both in vitro and against human A549-derived tumour xenografts in immunocompromised mice without T cells but competent with respect to NK cell activity. Combined antisense targeting of both TS and IDO in human tumor cells has the potential to increase the effectiveness of anti-TS and other drugs, both by increasing tumor cell drug sensitivity and by combined enhancement of sensitivity to drug treatment and reduced inhibition of NK cell activity.
Citation Format: Saman Maleki Vareki, James Koropatnick. Enhancing chemotherapy efficacy and antitumor immune activity by combined antisense downregulation of TS and IDO. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr A24.
Abstract A3: Enhanced effector responses in CAR-redirected CD8+ T cells deficient in diacylglycerol kinases.
Authors: Riese Matthew , Wang Liang-Chuan , Ranganathan Anjana , Koretzky Gary , Albelda Steven 
Published: August 2014

Abstract
The use of chimeric antigen receptor (CAR)-redirected CD8+ T cells in the treatment of malignancy is a novel strategy that has shown tremendous promise; however, it remains likely this strategy could be enhanced when combined with additional approaches. We hypothesized that deletion of signaling mediators that negatively regulate TCR signal transduction might enhance CAR signaling and function, since CARs utilize the same machinery that transduces TCR signals. We tested CAR activity and function in T cells that lacked one or both lymphocyte-specific isoforms of diacylglycerol kinase (dgk), proteins that metabolize the second messenger DAG and limit Ras/ERK activation. We found that primary murine T cells transduced with CARs specific for the human tumor antigen mesothelin demonstrated greatly enhanced cytokine production and cytotoxicity when co-cultured with a murine mesothelioma line that stably expresses mesothelin. Additionally, we found that dgk-deficient CAR transduced T cells were more effective in limiting the growth of implanted tumors, both concurrent with and after establishment of tumor. These results suggest that deletion of negative regulators of TCR signaling enhances the activity and function of CAR-expressing T cells, and identify dgks as a potential target for improving the clinical potential of CARs.
Citation Format: Matthew Riese, Liang-Chuan Wang, Anjana Ranganathan, Gary Koretzky, Steven Albelda. Enhanced effector responses in CAR-redirected CD8+ T cells deficient in diacylglycerol kinases. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr A3.
Abstract A38: T cell costimulation by TNFRSF4, TNFRSF18, and TNFRSF25 in the context of vaccination.
Authors: Schreiber Taylor H. , Gonzalez Louis , Wolf Dietlinde , Bodero Maria , Podack Eckhard R. 
Published: August 2014

Abstract
TNFRSF4 (OX40, CD134), TNFRSF18 (GITR) and TNFRSF25 are costimulatory receptors that influence CD4+ and CD8+ T cell responses to cognate-antigen. Independently, these receptors have been described to stimulate overlapping functions including enhanced proliferation and activation for both regulatory (CD4+FoxP3+, Treg) and conventional (CD4+FoxP3- or CD8+FoxP3-) T cells. To determine the relative functionality of TNFRSF4, TNFRSF18 and TNFRSF25 in T cell immunity, the activity of TNFRSF4, TNFRSF18 and TNFRS25 agonistic antibodies was compared in the context of both traditional protein/adjuvant (ovalbumin/alum) and CD8+ specific heat shock protein based (gp96-Ig) vaccine approaches. These studies demonstrate that both TNFRSF4, TNFRSF18 and TNFRSF25 independently and additively costimulate vaccine induced CD8+ T cell proliferation following both primary and secondary antigen challenge. In contrast, the activity of TNFRSF4 and TNFRSF25 were observed to be divergent in the costimulation of CD4+ T cell immunity. TNFRSF4 and TNFRSF18 agonists were potent costimulators of ova/alum induced CD4+ conventional T cell proliferation but only weakly costimulated Treg proliferation and IgG2a production, while TNFRSF25 agonists were strong costimulators of Treg proliferation, production of IgG1, IgG2a and IgG2b and weak costimulators of CD4+ Tconv proliferation. Interestingly, antigen-specific cellular and humoral responses were uncoupled upon secondary immunization, which was dramatically effected by the presence of TNFRSF4, TNFRSF18 or TNFRSF25 costimulation. These studies highlight the overlapping but non-redundant activities of these three TNF receptors in T cell immunity, which may guide the application of receptor agonistic agents as vaccine adjuvants for infectious disease and tumor immunity.
Citation Format: Taylor H. Schreiber, Louis Gonzalez, Dietlinde Wolf, Maria Bodero, Eckhard R. Podack. T cell costimulation by TNFRSF4, TNFRSF18, and TNFRSF25 in the context of vaccination. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr A38.