bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1048: Dichotomy effects of Akt signaling in breast cancer
Authors: Lin Huey-Jen L. , Peng Zhengang 
Published: May 2015

Abstract
Background: The oncogenic roles contributed by the Akt/PKB kinase family remain controversial and presumably depend on cell context, but are perceived to be modulated by an interplay and net balance between various isoforms. This study is intended to decipher whether distinct Akt kinase isoforms exert either redundant or unique functions in regulating neoplastic features of breast cancer cells, including epithelial-mesenchymal transition (EMT), cell motility, and stem/progenitor cell expansion. Results: We demonstrate that overactivation of Akt signaling in nonmalignant MCF10A cells and in primary cultures of normal human mammary epithelial tissue results in previously unreported inhibitory effects on EMT, cell motility and stem/progenitor cell expansion. Importantly, this effect is largely redundant and independent of Akt isoform types. However, using a series of isogenic cell lines derived from MCF-10A cells but exhibiting varying stages of progressive tumorigenesis, we observe that this inhibition of neoplastic behavior can be reversed in epithelial cells that have advanced to a highly malignant state. In contrast to the tumor suppressive properties of Akt, activated Akt signaling in MCF10A cells can rescue cell viability upon treatment with cytotoxic agents. This feature is regarded as tumor-promoting. Conclusion: We demonstrate that Akt signaling conveys novel dichotomy effects in which its oncogenic properties contributes mainly to sustaining cell viability, as opposed to the its tumor suppressing effects, which are mediated by repressing EMT, cell motility, and stem/progenitor cell expansion. While the former exerts a tumor-enhancing effect, the latter merely acts as a safeguard by restraining epithelial cells at the primary sites until metastatic spread can be moved forward, a process that is presumably dictated by the permissive tumor microenvironment or additional oncogenic insults.
Citation Format: Huey-Jen L. Lin, Zhengang Peng. Dichotomy effects of Akt signaling in breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1048. doi:10.1158/1538-7445.AM2014-1048
Abstract 1053: Interplay of YB-1 and IL-6 in the acquisition of EMT-like characteristics
Authors: Castellana Barbara , Aasen Trond , Cajal Santiago Ramón y 
Published: May 2015

Abstract
An important step towards tumor progression and metastasis is the activation of the epithelial-mesenchymal transition (EMT) program. This complex process confers cancer cells traits such as enhanced motility, invasiveness and resistance to therapy. EMT can be triggered by the convergence of intrinsic factors and signals from the tumor microenvironment, such as aberrant expression of cytokines. Recently, the multifunctional oncoprotein YB-1 has been shown to play an important role in malignant tumors facilitating many of the “hallmarks of cancer” proposed by Hanahan and Weinberg. In this project we focused on the alliance between YB-1 and the cytokine IL-6, which has been implicated in tumor-cell metastasis and is a well known EMT inducer. Overexpression or direct addition of IL-6 up-regulates and activates YB-1 in the epithelial breast cancer cell line MCF7, leading to an upregulation of mesenchymal markers (Snail1, N-cadherin), increased cell migration and invasion, as well as morphological changes associated with an EMT-like phenotype. Conversely, in the mesenchymal-like breast cancer cell line MDA-MB-231, RNAi-mediated downregulation of YB-1 resulted in decreased IL-6 expression and an increase in epithelial-like cell characteristics.
Our results describe a novel interplay whereby IL-6 regulates YB-1 and vice versa creating a positive feed-forward loop driving EMT during breast cancer progression. In the future we aim to delineate the exact signalling pathways linking IL-6 and YB-1, and how they converge to orchestrate important processes such as growth, invasion and metastasis. The understanding of this interplay will set the stage for new combinatorial treatments of aggressive breast cancers.
Acronyms: EMT, epithelial to mesenchymal transition; YB-1, Ybox binding protein-1; IL-6 , Interleukin-6.
Citation Format: Barbara Castellana, Trond Aasen, Santiago Ramón y Cajal. Interplay of YB-1 and IL-6 in the acquisition of EMT-like characteristics. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1053. doi:10.1158/1538-7445.AM2014-1053
Abstract 1056: COX-2/PGE2-driven lung cancer invasion/metastasis is dependent on MIG-7 and phosphorylated prohibitin
Authors: Liang Chi-Ming , Ho Ming-Yi , Liang Shu-Mei 
Published: May 2015

Abstract
COX-2/prostaglandin E2 (PGE2) enhances lung cancer invasion/metastasis, but its mode of action is largely unclear. We showed here that PGE2 interacted with EP4 to increase phosphatidylinositol-(3,4,5)-triphosphate (PIP3), leading to increase in epithelial-mesenchymal transition and E-cadherin suppressors, notably Snail, ZEB1 and Twist. Prohibitin phosphorylated at threonine 258 (phospho-PHBT258) and MIG-7 played critical role in PGE2 effects respectively. Snail was regulated by phospho-PHBT258 via IKKα/β and Ras/Raf-1 signaling pathways, whereas ZEB1 and Twist, were regulated mainly by MIG-7 that also sustained PGE2 effects via positive feedback on phospho-AktS473. Downregulating phospho-PHBT258 and MIG-7 showed additive effect in attenuating lung cancer migration/invasion/metastasis and prolonging disease-free and overall survival of xenograft mice. Our findings highlight the potential for combination therapy targeting phospho-PHBT258 and MIG-7 to block the COX-2/PGE2 effects on cancer metastasis.
Citation Format: Chi-Ming Liang, Ming-Yi Ho, Shu-Mei Liang. COX-2/PGE2-driven lung cancer invasion/metastasis is dependent on MIG-7 and phosphorylated prohibitin. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1056. doi:10.1158/1538-7445.AM2014-1056
Abstract 1058: Grainyhead-like 2 regulates molecular subtype switching in epithelial ovarian cancer
Authors: Chung Vin Yee , Wong Meng Kang , Kuay Kuee Theng , Tan Tuan Zea , Guccione Ernesto , Thiery Jean Paul , Huang Ruby Yun-Ju 
Published: May 2015

Abstract
Epithelial ovarian cancer (EOC) is clinically heterogeneous, comprising different histological and biological subtypes. Despite tumor heterogeneity, patient stratification is lacking and targeted therapeutic options for EOC are limited. Epithelial-mesenchymal transition (EMT), an important developmental process that allows the conversion of epithelial cells to mesenchymal phenotype, has been implicated in contributing to the molecular heterogeneity in EOC. Emerging evidence suggests that EMT in EOC may be associated with tumor progression and metastasis. We aim to decipher the underlying EMT mechanisms by using a panel of 42 EMT-phenotyped EOC cell lines. We found that Grainyhead-like 2 (GRHL2), a transcription factor, was expressed exclusively in EOC cells with epithelial phenotype by using qPCR, ELISA and western blots. EOC tumors with Mesenchymal molecular subtype also showed a decrease in GRHL2 expression. These data suggest that GRHL2 is required for maintaining cell polarity or cell-cell adhesion. Therefore, manipulating the expression of GRHL2 might switch the EMT-related molecular subtypes in EOC. Here, we showed that knocking down of GRHL2 resulted in EMT changes in EOC cells with Epithelial molecular subtype, accompanied by an increase in cell motility and directional migration. GRHL2-deficient cells also showed a tendency to migrate individually instead of collectively, thus suggesting that GRHL2 might be required for collective cell migration. Knock-down of GRHL2 not only downregulates E-cadherin expression, but also interferes with the stability of E-cadherin at cell-cell junctions. Chromatin-immunoprecipitation sequencing (ChIP-seq) identified GRHL2 transcriptional targets that might be the downstream mediators for this molecular subtype switch. In conclusion, GRHL2 is an important regulator in maintaining the epithelial phenotype and crucial player in molecular heterogeneity in EOC.
Citation Format: Vin Yee Chung, Meng Kang Wong, Kuee Theng Kuay, Tuan Zea Tan, Ernesto Guccione, Jean Paul Thiery, Ruby Yun-Ju Huang. Grainyhead-like 2 regulates molecular subtype switching in epithelial ovarian cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1058. doi:10.1158/1538-7445.AM2014-1058
Abstract 1063: Inverse hormesis of cancer growth mediated by narrow ranges of tumor-directed antibodies
Authors: Pearce Oliver M.T. , Läubli Heinz , Verhagen Andrea , Secrest Patrick , Zhang Jiquan , Crocker Paul R. , Varki Nissi , Bui Jack , Varki Ajit 
Published: May 2015

Abstract
Compelling evidence for naturally occurring immunosurveillance against malignancies informs and justifies some current approaches towards cancer immunotherapy. However, some types of immune reactions have also been shown to facilitate tumor progression. For example, our previous studies showed that experimental tumor growth in mice can be enhanced by low levels of circulating antibodies directed against the non-human sialic acid N-glycolyl-neuraminic acid (Neu5Gc, which accumulates in human tumors from dietary sources). However, tumor growth could instead be inhibited by anti-Neu5Gc antibodies from a different source, in a different model. Thus, anti-Neu5Gc antibodies appeared to be showing differential effects on tumor growth. However it remains generally unclear whether the immune responses that mediate cancer immunosurveillance versus those responsible for inflammatory facilitation are qualitatively and/or quantitatively distinct. Here, we address this question using multiple murine tumor growth models in which polyclonal antibodies against tumor antigens such as Neu5Gc can alter tumor progression. We found that while growth was stimulated at low antibody doses it was inhibited by high doses, over a linear and remarkably narrow range, defining an immune response curve (IRC), i.e., inverse hormesis. Moreover, modulation of immune responses against the tumor by altering antibody avidity or by enhancing innate immunity shifted the IRC in the appropriate direction. Thus, the dualistic role of immunosurveillance versus inflammation in modulating tumor progression can be quantitatively distinguished in multiple model systems, and can occur over a remarkably narrow range. We also reproduced the biphasic IRC in a model using the monoclonal anti-CD20 antibody rituximab. Furthermore, depletion of macrophages abrogated the growth promotion at low antibody concentrations and depletion of NK cells reduced growth inhibition at high antibody concentrations. These findings may have implications for the etiology and prevention of cancer, and for immunotherapeutic approaches utilizing antibodies.
Citation Format: Oliver M.T. Pearce, Heinz Läubli, Andrea Verhagen, Patrick Secrest, Jiquan Zhang, Paul R. Crocker, Nissi Varki, Jack Bui, Ajit Varki. Inverse hormesis of cancer growth mediated by narrow ranges of tumor-directed antibodies. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1063. doi:10.1158/1538-7445.AM2014-1063
Abstract 1064: IL-6 secreted by tumor-associated macrophages promotes DLBCL chemoresistance via expansion of the CSCs population
Authors: Bai Nan 
Published: May 2015

Abstract
Cancer stem-like cells (CSCs), a highly tumorigenic subpopulation of cells found in developmentally diverse tumors, are highly resistant to chemotherapeutic drugs. Tumor-associated macrophages (TAMs) are known to promote progression of tumors and chemoresistance of DLBCL (Diffuse Large B cell Lymphoma). Here, we report that TAMs promote a CSC-like phenotype in DLBCL cells. This was characterized by increased ALDH1A1, Sox-2, Oct-4, Nanog and KLF-4 gene expression. In in vitro studies, we found that co-culture with monocyte cell lines enhanced the chemoresistance and CSC-like phenotypes of DLBCL cells. RNA-seq revealed high levels of IL-6 expression following co-culture with DLBCL, and in fact IL-6 was sufficient to promote the chemoresistance and CSC-like phenotypes of DLBCL cells. Surprisingly, patients exhibited elevated IL-6 after chemotherapy relative to patients pre-chemotherapy, suggesting that chemotherapy may elicit a host response favoring chemoresistance. High levels of serum IL-6 were associated with poor prognosis. In agreement with these results, tumor infiltration by TAMs directly correlated with disease severity. Therefore, IL-6 may be a prognostic marker for outcome in DLBCL.
Citation Format: Nan Bai. IL-6 secreted by tumor-associated macrophages promotes DLBCL chemoresistance via expansion of the CSCs population. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1064. doi:10.1158/1538-7445.AM2014-1064
Abstract 1068: Socs3 deficiency in myeloid cells promotes prostate tumor development
Authors: Yu Hao , Qin Hongwei 
Published: May 2015

Abstract
Suppressor Of Cytokine Signaling (SOCS) proteins are negative regulators of the JAK/STAT pathway, and have been implicated as functioning as tumor suppressors, particularly SOCS3. We have previously demonstrated that specific deletion of SOCS3 in myeloid cells leads to heightened activation of STAT3 and downstream STAT3 target gene expression. STAT3 activation has been strongly implicated in contributing to prostate cancer progression and metastasis. STAT3 signaling in myeloid cells has been demonstrated to attenuate anti-tumor immunity. Thus, we evaluated the impact of SOCS3 deletion in myeloid cells in a murine prostate tumor model. We demonstrate that prostate tumor growth is significantly enhanced in myeloid-specific SOCS3-deficient mice, which correlates with elevated levels of Myeloid Derived Suppressor Cells (MDSC) in both the spleen and tumor microenvironment, and less CD8+ T-cell infiltration in tumors. Furthermore, SOCS3-deficient bone-marrow-derived mononuclear cells exhibit heightened STAT3 activation and are preferentially differentiate into MDSC phenotype. Importantly, we identify granulocyte-colony stimulating factor (G-CSF) as a critical factor secreted by the prostate tumor microenvironment that promotes development of Gr-1+CD11b+ cells via a STAT3-depentent pathway. Abrogation of tumor-derived G-CSF reduced the proliferation and accumulation of Gr-1+CD11b+ cells and inhibited prostate tumor growth. Therefore, the tumor-derived cytokine, G-CSF, is a prospective candidate upstream of the STAT3/SOCS3 pathway in MDSC differentiation from the bone marrow. These findings highlight the critical function of SOCS3 as a negative regulator of MDSC development and function, which may contribute to tumor suppressor attributer of SOCS3.
Citation Format: Hao Yu, Hongwei Qin. Socs3 deficiency in myeloid cells promotes prostate tumor development. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1068. doi:10.1158/1538-7445.AM2014-1068
Abstract 1072: TAM and CD44 in medullary thyroid carcinoma
Authors: MIYAZAWA MARTA , SANTOS MARIA JOSE C. P. , BIM LARISSA V. , ORTI-RADUAN ERIKA S. L. , VALENTE FLÁVIA O. F. , NUNES ADAUTO F. , DELCELO ROSANA , MACIEL RUI M. B. , CERUTTI JANETE M. 
Published: May 2015

Abstract
Background: Tumor-associated macrophages (TAMs) are alternatively activated or M2 macrophages that infiltrate cancer tissues. It has been suggested that TAMs exert several pro-tumor functions by releasing several growth factors and proangiogenic cytokines that favor tumor progression. In fact, TAM density has been associated with poor prognosis. Although it is well known the pro-tumor roles of TAM in several tumor types, its role in medullary thyroid cancer (MTC) is still unknown. We here evaluated the M2 macrophage marker CD163 in MTC and correlated with RET mutational status and clinical and pathological features. Because it has been suggested TAMs could interact with CD44-positive tumor cells to during tumorigenesis process, we also investigated the expression of CD44 in MTC.
Patients and Methods: CD163 and CD44 expression we investigated in 78 MTC by immunohistochemistry (IHC). Because hereditary form is caused by germline mutations in the RET gene, all patients were screened for RET mutations (exons 8, 10, 11, 13-16) in the DNA isolated from blood samples. Those MTC that were negative for RET germline mutations, were also screened for somatic mutations in the RET gene (exons 10, 11 e 16).
Results: Germline mutation in the RET gene were identified in 29 patients (p.G533C, p.C609Y, p.C611Y, p.C620Y, p.C634R, p.C634Y/Y791F, p.S891A and p.M918V). Approximately 49 cases are sporadic cases in which somatic RET mutations were identified in about 6 cases (p.M918T, p.C634R and p.C634Y). CD163 expression was mainly found in sporadic MTC when compared to hereditary MTC (p=0.021), suggesting that TAM may play a role in the progression of sporadic MTC. On the other hand CD44 expression was mainly found in hereditary MTC than in sporadic cases (p=0.017), particularly in patients with RET germlime mutation at codon C634.
Conclusion: TAM seems to be more important for sporadic MTC tumorigenesis when compared to hereditary MTC. On the other hand, CD44 expression correlated with hereditary MTC, particularly in patients with mutation at codon C634.
Citation Format: MARTA MIYAZAWA, MARIA JOSE C. P. SANTOS, LARISSA V. BIM, ERIKA S. L. ORTI-RADUAN, FLÁVIA O. F. VALENTE, ADAUTO F. NUNES, ROSANA DELCELO, RUI M. B. MACIEL, JANETE M. CERUTTI. TAM and CD44 in medullary thyroid carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1072. doi:10.1158/1538-7445.AM2014-1072
Abstract 1076: Antagonists of the chemokine receptor CCR4 reverse the tumor-promoting microenvironment of renal cancer
Authors: Berlato Chiara , Kahn Moddasar N. , Schioppa Tiziana , Thompson Richard , Maniati Eleni , Canosa Monica , Kulbe Hagen , Sheldon Chris , Wreggett Keith , Hagemann Urs , Duncan Alexander , Fletcher Laura , Wilkinson Robert W. , Powles Thomas , Quezada Sergio , Balkwill Frances 
Published: May 2015

Abstract
Tumor microenvironments posses complex chemokine networks that contribute to the extent and phenotype of the host infiltrate. Malignant cells may gain functional chemokine receptors, often as a consequence of oncogenic mutations, allowing them to respond to distant chemokine gradients during metastasis. The chemokine receptor CCR4 was highly expressed in human renal cell carcinoma, RCC, biopsies and RCC patient plasma had abnormal levels of CCR4 ligands. However, during pre-clinical evaluation of CCR4 as a target in RCC, we found that both a small molecule CCR4 inhibitor and an anti-CCR4 antagonistic antibody had unexpected and novel anti-tumor activity in the mouse RCC RENCA model. CCR4 antagonists did not reduce the proportion of infiltrating leukocytes in the tumor microenvironment but altered the phenotype of myeloid cells, increased NK cells and Th1 cytokine levels, as well as reducing splenic MDSC infiltrate, and blood chemokine levels. Although the most prominent changes were in the myeloid compartment, anti-tumor activity was lost in athymic mice, supporting a role for the adaptive immune system in CCR4 antagonist action. CCR4 antagonists, alone, or in combination with other immune modulators, may be of interest in human cancers with high levels of tumor CCR4 and abnormal plasma CCR4 ligand levels.
Citation Format: Chiara Berlato, Moddasar N. Kahn, Tiziana Schioppa, Richard Thompson, Eleni Maniati, Monica Canosa, Hagen Kulbe, Chris Sheldon, Keith Wreggett, Urs Hagemann, Alexander Duncan, Laura Fletcher, Robert W. Wilkinson, Thomas Powles, Sergio Quezada, Frances Balkwill. Antagonists of the chemokine receptor CCR4 reverse the tumor-promoting microenvironment of renal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1076. doi:10.1158/1538-7445.AM2014-1076
Abstract 108: Consequences of hepatic JAK2 deficiency for liver metabolism and hepatocarcinogenesis
Authors: Themanns Madeleine , Friedbichler Katrin , Kessler Sonja M. , Schlederer Michaela , Kenner Lukas , Wagner Kay-Uwe , Haybaeck Johannes , Moriggl Richard 
Published: May 2015

Abstract
The metabolic syndrome is a frequent disease in the western world due to increased prevalence of obesity and diabetes mellitus. Non-alcoholic fatty liver disease (NAFLD) is a hepatic manifestation of the metabolic syndrome associated with primary stages of hepatocellular carcinoma (HCC). Hepatic JAK2-STAT5 signaling is mainly activated by growth hormone (GH) which controls cellular metabolism.
To address the role of hepatic JAK2 in lipid homeostasis and hepatocarcinogenesis, we crossed a mouse model of inflammatory liver cancer caused by hyperactivated GH signaling (GHtg) to mice harboring the hepatocyte-specific deletion of JAK2 (J2KO; using AlfpCre). While excess of GH caused chronic hepatitis, as well as pathologic alterations such as big hepatocytes with large polymorphic nuclei, severe and progressive hepatosteatosis was evident in GHtg:J2KO and J2KO mice as soon as 12 weeks of age. Hepatosteatosis in JAK2 deficient mice, independent of GH overexpression, was due to increased hepatic lipid synthesis and peripheral lipolysis associated with elevated unsaturated fatty acid (FA) and triglyceride (TG) amounts in the liver. However, microvesicular steatosis, which is associated with a more severe pathology, was more abundant in GHtg:J2KO livers accompanied by significantly elevated liver/body weight ratios. Surprisingly, loss of hepatic JAK2 proteins led to delayed hepatocarcinogenesis in aged mice. Currently, we are investigating the involvement of NAFLD in the pathogenesis of HCC development by genetic and histo-pathologic profiling. We will provide molecular and cellular insights responsible for delayed hepatocarcinogenesis in GHtg:J2KO and J2KO mice.
Citation Format: Madeleine Themanns, Katrin Friedbichler, Sonja M. Kessler, Michaela Schlederer, Lukas Kenner, Kay-Uwe Wagner, Johannes Haybaeck, Richard Moriggl. Consequences of hepatic JAK2 deficiency for liver metabolism and hepatocarcinogenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 108. doi:10.1158/1538-7445.AM2014-108