bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2589: Dissecting extrinsic and intrinsic cancer risk
Authors: Wu Song , Powers Scott , Zhu Wei , Hannun Yusuf 
Published: July 2016

Abstract
Cancers were once thought to originate from mature tissue cells that underwent dedifferentiation in response to cancer progression. Today, cancers are proposed to originate from the malignant transformation of normal tissue progenitor and stem cells, although this is not uniformly accepted. Nevertheless, recent research has highlighted a strong correlation between tissue-specific cancer risk and the lifetime population size and cumulative number of cell divisions of tissue-specific stem cells. However, there has been extensive controversy regarding the conclusion that this correlation implies that there is a very high unavoidable risk for many specific cancers that are due solely to the intrinsic baseline population size of tissue-specific stem cells. This issue has become a key public health debate with dissemination of the ‘bad luck’ hypothesis. Here we provide strong evidence that unavoidable intrinsic risk factors contribute only modestly (&lt;10-30%) to the development of many common cancer types. In an initial approach, we demonstrate that the correlation between stem-cell division and cancer risk does not distinguish between the effects of intrinsic and extrinsic factors. We then develop a novel data-driven approach to estimate intrinsic risk by considering the lower bound risk value for most cancers as a limiting condition for contribution of intrinsic processes. Furthermore, we present an independent mathematical model that capitalizes on the accumulation of endogenous mutations in stem cells. Using mutation rates as a starting point, we found that rates of intrinsic mutations are not sufficient to account for the observed lifetime cancer risk, even in the conservative estimate that all these mutations are due to intrinsic processes alone. Our results are consistent with vast epidemiological data at population level and also mutational signature data at molecular level. The consensus suggests that cancer risk is likely to be heavily influenced by extrinsic factors, and therefore is possibly modifiable and preventable. These results carry immense consequences for strategizing cancer prevention, research, and public health. [Note: this work is in press in Nature.]
Citation Format: Song Wu, Scott Powers, Wei Zhu, Yusuf Hannun. Dissecting extrinsic and intrinsic cancer risk. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2589.
Abstract 259: Modulation of doxorubicin actions on HCC cells by insulin-like growth factor-I
Authors: Carr Brian I. , Refolo Maria Grazia , D’Alessandro Rosalba , Carella Nicola , Messa Caterina , Cavallini Aldo 
Published: July 2016

Abstract
Tumor microenvironment is increasingly understood to influence tumor biology in many tumor types, including HCC. We recently showed that platelets could modulate Doxorubicin (Dox)-mediated HCC growth inhibition (Refolo MG et al. Modulation of doxorubicin mediated growth inhibition of hepatocellular carcinoma cells by platelet lysates. Anticancer Agents Med Chem. 2014;14:1154-60). Platelets contain cytokines and growth factors, including IGF-1, PDGF, FGF, EGF and serotonin. We found that Insulin-like growth factor-1 (IGF-1) shifted the Dox growth-inhibitory dose-response in the range of 0.1-1.0 μM on Hep3B, HepG2, PLC/PRF/5 human HCC lines, all of which became less sensitive to both Dox-mediated inhibition of growth and apoptosis. Similar antagonism by IGF-1 was found for Dox-mediated inhibition of cell migration (scratch assay) and invasion (Boyden chamber). This antagonism of Dox effects on cell growth, migration and apoptosis by IGF1, was blocked by GSK1838705A, an IGF-1R inhibitor. Furthermore, when platelet extracts were used to antagonize Dox inhibition of growth and migration, the platelet effects were also blocked by addition of GSK1838705A to the cultures, showing that the platelet effects were largely mediated by IGF-1. Dox caused a decrease in the levels of anti-apoptosis markers Bcl-2, Bcl-xL and survivin as seen on WB, whereas levels of all three anti-apoptosis markers were increased by IGF-1 action. These actions of IGF-1 were also blocked by GSK 1838705A. Furthermore, Dox caused a decrease in the levels of P-ERK, P-p38 and P-STAT3 (ser727). These signaling molecule decreases were also reversed by the presence of IGF-1.
Conclusions. Dox actions on HCC cells can be antagonized by platelets and specifically by platelet-associated IGF-1. IGF-1 antagonists appear to be attractive enhancers of sensitivity to Dox actions.
Citation Format: Brian I. Carr, Maria Grazia Refolo, Rosalba D’Alessandro, Nicola Carella, Caterina Messa, Aldo Cavallini. Modulation of doxorubicin actions on HCC cells by insulin-like growth factor-I. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 259.
Abstract 2595: Texture variation on a mammogram and risk of breast cancer
Authors: Rice Megan , Bertrand Kimberly , Heine John , Rosner Bernard , Tamimi Rulla 
Published: July 2016

Abstract
Mammographic density is one of the strongest risk factors for breast cancer. The most widely used measure of mammographic density is based on the percentage of dense tissue on a mammogram (percent mammographic density). However, there is additional information in mammographic images not captured by current mammographic density measurements including heterogeneity in patterns of breast density, often referred to as ‘texture’. More recent research suggests that textural features on a mammogram are associated with breast cancer risk independent of percent mammographic density. Therefore, we evaluated an automated measure called V, which measures the grayscale variation within a mammogram, in relation to subsequent breast cancer risk in 834 breast cancer cases (426 premenopausal and 408 postmenopausal) and 1805 controls (978 premenopausal and 827 postmenopausal) from a nested case-control study of breast cancer in the Nurses’ Health Studies (NHS). Among all women, V was modestly correlated with percent mammographic density (r = 0.48, p&lt;0.01); this correlation did not vary substantially by menopausal status. Among premenopausal women, those in the highest quartile of V had a significantly higher risk of breast cancer (OR = 1.84, 95%CI: 1.30-2.61) compared to those in the lowest quartile. This association was similar, though more modest, among postmenopausal women (OR = 1.54, 95%CI: 1.08-2.19). These associations somewhat attenuated after adjustment for percent mammographic density in both premenopausal women (OR comparing extreme quartiles = 1.41, 95%CI: 0.97-2.03) and in postmenopausal women (OR comparing extreme quartiles = 1.21, 95%CI: 0.81-1.81). Future work will examine the associations between V and risk of breast cancer subtypes (e.g., by ER/PR tumor expression) as well as examine the associations between other measures of texture including markovian, run-length, laws, wavelet, fourier, and power features with breast cancer risk.
Citation Format: Megan Rice, Kimberly Bertrand, John Heine, Bernard Rosner, Rulla Tamimi. Texture variation on a mammogram and risk of breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2595.
Abstract 2608: Dietary polyunsaturated fatty acids modulate adipose inflammation and the adipokine secretome to influence mammary stem cell self-renewal
Authors: Esper Raymond M. , Hill Evan , Jiang Yan , Aslam Nadeem , Simon Becky , Wicha Max , Smith William , Brenner Dean E. 
Published: July 2016

Abstract
Obesity strongly increases risk for multiple malignancies. One potential contributor may be the chronic low-grade inflammation that is likely driven by dysfunctional adipose characterized by aberrant adipokine production and macrophage activation/polarization. In adipose tissue, free fatty acids and their lipid mediators serve as important regulators of adipokine gene transcription. The adipocyte fatty acid composition is influenced by dietary availability. Here we present data demonstrating that dietary fish oil supplementation in obese rats (achieving a 2.5:1 ω6:ω3 PUFA ratio, comparable to a Mediterranean diet) attenuates adipose inflammation characterized reduction in the M1/M2 macrophage polarization ratio compared to a typical Western diet with a 20:1 ω6:ω3 PUFA ratio. We developed a novel adipose explant culture system to directly assay the secretome, and demonstrate that quenching adipose inflammation in obese animals is associated with a favorably rebalanced adipokine milieu, most notably increased adiponectin concentration and decreased leptin secretion. We previously showed that these two adipokines differentially modulate mammary stem cell self-renewal; here, we studied the effect of adipose conditioned media from obese rats on mammary stem cells using the mammosphere formation assay. Adipokines from obese rats fed the high-ω6 diet increased mammary stem cell symmetric self-renewal by 86.7 ± 7.5% (± SEM), whereas adipose-derived factors from the obese animals fed a low-ω6 diet supplemented with fish oil reduced the number of secondary mammospheres by 30.3 ± 10.1% by promoting either apoptosis, quiescence, or symmetric division-differentiation of the primary stem cells. Using a neutralizing antibody and a soluble receptor, we demonstrate that leptin contributes only 19% of the adipose-derived effect on mammary stem cell self-renewal. Taken together, our data suggests that a simple dietary intervention to modify the dietary PUFA ratio is an effective method to quench adipose inflammation and rebalance the adipokine milieu, which may modulate the mammary stem cell pool. If normal stem cells can give rise to breast cancer as has been theorized, then dietary interventions to quench adipose inflammation and reduce the rate of symmetric stem cell self-renewal might protect against the increased incidence of breast cancer seen in obese post-menopausal women.
Citation Format: Raymond M. Esper, Evan Hill, Yan Jiang, Nadeem Aslam, Becky Simon, Max Wicha, William Smith, Dean E. Brenner. Dietary polyunsaturated fatty acids modulate adipose inflammation and the adipokine secretome to influence mammary stem cell self-renewal. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2608.
Abstract 2609: Epigenetic reactivation of TIMP-3 in human prostate cancer cells by green tea polyphenols
Authors: Deb Gauri , Thakur Vijay S. , Shankar Eswar , Gupta Sanjay 
Published: July 2016

Abstract
Metastasis is responsible for more than 90% of prostate cancer-associated mortality in the United States. Metastasis is facilitated by remodeling of the extracellular matrix by a family of proteolytic enzymes known as matrix metalloproteinases (MMPs). These zinc-dependent proteases elicit pivotal role in the proteolytic degradation of structural components of extracellular matrix contributing to the metastatic process. High levels of MMP-2/9 in the plasma and urine has been correlated with metastasis. MMPs are produced in a latent form (pro-MMP) that require activation and are inhibited by tissue inhibitors of matrix metalloproteinases (TIMPs). TIMPs inhibit MMPs by binding in a 1:1 stoichiometry through strong noncovalent interactions. In prostate cancer, low levels of TIMP3 has been associated with aggressive tumor phenotype and poor disease-free survival. Loss of TIMP3 in prostate cancer is attributed to epigenetic silencing tipping the balance towards active MMPs driving metastasis. Green tea polyphenols (GTP) and its major constituent, epigallocatechin-3-gallate (EGCG) has been shown to suppress prostate cancer metastasis, however the mechanism has not been fully elucidated. We determined whether treatment with GTP/EGCG has ability to restore induction of TIMP3 and play a key role in suppressing invasiveness in prostate cancer. Treatment of prostate cancer LNCaP and DUPRO cells with 10μg/mL GTP and 20μM EGCG for 72 h significantly induced TIMP3 mRNA and protein levels. Silencing of enhancer of zeste homolog 2 (EZH2) and class I histone deacetylases (HDACs) significantly increased the expression of TIMP3 which was independent of DNA hypermethylation. Treatment of prostate cancer cells with GTP/EGCG significantly reduced EZH2 and class I HDAC protein levels; H3K27 trimethylation activity; and transcriptional activation of TIMP-3 was found to be associated with decreased EZH2 localization and H3K27 trimethylation enrichment at the TIMP3 promoter with a concomitant increase in histone H3K9/18 acetylation. EGCG/GTP treatment also caused a global reduction in histone methylation thereby increasing histone acetylation to revive and activate TIMP3 levels. Furthermore, EGCG/GTP exposure significantly reduced MMP2/9 gelatinolytic activity and abrogated invasive and migration capabilities in prostate cancer cells. Taken together, our findings suggests that TIMP-3 induction could be a key epigenetic event modulated by GTPs in restoring MMP: TIMP balance to delay prostate cancer invasion and metastasis.
Citation Format: Gauri Deb, Vijay S. Thakur, Eswar Shankar, Sanjay Gupta. Epigenetic reactivation of TIMP-3 in human prostate cancer cells by green tea polyphenols. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2609.
Abstract 2660: A renal CpG island methylator phenotype (R-CIMP) in kidney tumors associated with germline mutations of FH and SDHB
Authors: Ricketts Christopher , Killian J. Keith , Vocke Cathy D. , Sourbier Carole , Yang Youfeng , Merino Maria J. , Meltzer Paul S. , Linehan. W. Marston 
Published: July 2016

Abstract
Germline mutations of the genes encoding the Krebs cycle enzymes fumarate hydratase (FH) and succinate dehydrogenase (SDHB, SDHC, SDHD) have both been associated with an increased risk of renal cell carcinoma (RCC). These renal tumors demonstrate complete loss of enzyme activity and significantly increased levels of intracellular fumarate or succinate that are predicted to infer with the actions of multiple cellular processes primarily through the inhibition of 2-oxoglutarate-dependent dioxygenases, such as the prolyl hydroxylases that regulate the HIF pathway and the TET enzymes that regulate DNA methylation.
This study evaluated and compared the genome-wide methylation profiles of 33 tumor samples (including 9 FH -/- and 7 SDHB -/- tumors), 10 associated normal samples and 13 cell-lines (including cell-line models derived from FH -/- and SDHB -/- tumors) using the Illumina HumanMethylation450 BeadChip arrays. Tumors derived from patients
with germline FH or SDHB mutations demonstrated a distinct pattern of hypermethylation across the genome with enrichment for hypermethylation within the CpG island regions. SDHB mutation associated tumors demonstrated that was more variable and less extensive pattern of hypermethylation than the tumors associated with germline FH mutations. Cell-line models derived from HLRCC or SDHB tumors demonstrated patterns of hypermethylation similar to the patterns observed in the tumors, yet re-expression of either wild-type FH or SDHB within these cell-line models did not alter the methylation profiles. All the HLRCC and SDHB-RCC cell lines, including the cell-line re-expressing of either wild-type FH or SDHB, demonstrated growth inhibition and reduced invasion rates in response to treatment with 5-aza-2′-deoxycytidine.
Thus, renal cell carcinomas associated with FH or SDHB germline mutation demonstrate a specific R-CIMP hypermethylation profile that differentiates these tumors from tumors derived from other RCC susceptibility syndromes. These tumors represent the most aggressive
types of familial-associated RCC and this could provide a useful biomarker for identifying these tumors and de-methylating agents, such as 5-aza-2′-deoxycytidine, may be effective as part of a therapeutic regime for the treatment of these tumors.
Citation Format: Christopher Ricketts, J. Keith Killian, Cathy D. Vocke, Carole Sourbier, Youfeng Yang, Maria J. Merino, Paul S. Meltzer, W. Marston Linehan. A renal CpG island methylator phenotype (R-CIMP) in kidney tumors associated with germline mutations of FH and SDHB. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2660.
Abstract 2667: Platelet microparticles infiltrating solid tumors transfer miRNAs and modulate tumor angiogenesis and growth
Authors: Michael James V. , Wurtzel Jeremy G.T. , Mao Guang Fen , Rao A. Koneti , Hoffman Nicholas E. , Rajan Sudarsan , Madesh Muniswamy , Jana Fabian , Nieman Marvin , Rowley Jesse W. , Weyrich Andrew S. , Goldfinger Lawrence E. 
Published: July 2016

Abstract
Platelet-derived microparticles are associated with enhancement of metastasis and poor cancer outcomes. Platelet microparticles can transfer platelet microRNAs (miRNAs) to vascular cells upon co-incubation in vitro, but the contributions of platelet microparticles and miRNAs to tumor progression are still poorly understood. Tumor vasculature is highly permeable, allowing the possibility of platelet microparticle-tumor cell interaction in primary solid tumors. Here we show that platelet microparticles infiltrate solid tumors in humans and mice, attach to tumor cells, and transfer platelet-derived RNA, including miRNAs, to tumor cells in vivo as well as in vitro. MiR-24 was a major species in this transfer. We identified RNA targets of platelet-derived miR-24 in lung carcinoma cells, which included mt-Nd2, a mitochondrial mRNA which lacks a 3’-UTR, and Snora75, a non-coding small nucleolar RNA. These RNAs were depleted in platelet microparticle-treated tumor cells, resulting in mitochondrial dysfunction and tumor cell growth inhibition, in a miR-24-dependent manner. Blockade of miR-24 in tumor cells accelerated tumor growth in vivo, and prevented tumor growth inhibition by platelet microparticle transfusion. Thus, platelet microparticles inhibit lung carcinoma cell proliferation and solid tumor growth via transfer of miR-24. However, global depletion of platelet miRNAs by platelet-specific deletion of Dicer1 inhibited tumor angiogenesis, platelet microparticle infiltration, and delayed tumor growth in mice. Thus, platelet-derived miRNAs transfer in vivo to tumor cells in solid tumors via microparticles, regulate tumor cell gene expression, and modulate tumor progression, whereas platelet miRNAs promote tumor angiogenesis. These findings shed novel insight onto mechanisms of horizontal gene transfer and add multiple layers to the regulatory roles of miRNAs and platelet microparticles in tumor progression.
Citation Format: James V. Michael, Jeremy G.T. Wurtzel, Guang Fen Mao, A. Koneti Rao, Nicholas E. Hoffman, Sudarsan Rajan, Muniswamy Madesh, Fabian Jana, Marvin Nieman, Jesse W. Rowley, Andrew S. Weyrich, Lawrence E. Goldfinger. Platelet microparticles infiltrating solid tumors transfer miRNAs and modulate tumor angiogenesis and growth. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2667.
Abstract 2679: Induction of β-globin protects circulating tumor cells from oxidative stress during dissemination
Authors: Zheng Yu , Miyamoto David T. , Wittner Ben S. , Sullivan James P. , Aceto Nicola , Vincent Jordan Nicole , Yu Min , Karabacak Nezihi Murat , Comaills Valentine , Morris Robert , Desai Rushil , Desai Niyati , Emmons Erin , Lee Richard J. , Wu Chin-Lee , Sequist Lecia V. , Haas Wilhelm , Ting David T. , Toner Mehmet , Ramaswamy Sridhar , Maheswaran Shyamala , Haber Daniel A. 
Published: July 2016

Abstract
Identification of candidate metastasis genes has traditionally resulted from comparison of primary and metastatic tumor specimens. However, Circulating Tumor Cells (CTCs) contain metastatic precursors that are present transiently in the bloodstream and their analysis may reveal additional pathways that are induced for a limited time, as they invade and survive within the vasculature. By comparing transcriptome profiles of CTCs from breast, prostate and lung cancers with their primary tumor of origin, we observed consistent and significant induction of the β-globin gene (HBB) within CTCs. In contrast, expression of α-globin, its binding partner within hematopoietic cells, is not coordinately upregulated. The tumor-specific origin of HBB was further confirmed by analysis of human xenografts-derived CTCs in mice, where human-specific HBB polymorphisms are readily distinguishable in the murine background. In cultured cancer cells, we further demonstrate that induction of HBB is triggered by exposure to reactive oxygen species (ROS), and we identify KLF-family transcriptional regulators that mediate this effect. To investigate the function of aberrant β-globin expression within CTCs, we performed shRNA-mediated knockdown of HBB in breast CTC-derived cultures. Cells with depleted HBB expression displayed elevated intracellular ROS levels, increased sensitivity to hydrogen peroxide, and impaired metastatic potential in mouse models. Taken together, these observations suggest that β-globin, a component of functional hemoglobin in red blood cells, is deregulated in disseminated tumor cells, where it may function as a ROS scavenger, reducing oxidative stress and facilitating cancer metastasis.
Citation Format: Yu Zheng, David T. Miyamoto, Ben S. Wittner, James P. Sullivan, Nicola Aceto, Nicole Vincent Jordan, Min Yu, Nezihi Murat Karabacak, Valentine Comaills, Robert Morris, Rushil Desai, Niyati Desai, Erin Emmons, Richard J. Lee, Chin-Lee Wu, Lecia V. Sequist, Wilhelm Haas, David T. Ting, Mehmet Toner, Sridhar Ramaswamy, Shyamala Maheswaran, Daniel A. Haber. Induction of β-globin protects circulating tumor cells from oxidative stress during dissemination. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2679.