bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5026: Tumor associated targeting with Manocept: HIV associated Kaposi's sarcoma as a model system
Authors: Zhang Rongzhen , Cope Frederick O. , Bracci Paige M. , McGrath Michael S. 
Published: August 2015

Abstract
Introduction
Inflammation appears to play a critical role in tumor development of HIV-associated Kaposi's sarcoma (KS). Specifically, emerging data show that KS tumor cells that co-express various macrophage (MO) antigens become resistant to current anti-viral therapies used to treat KS and AIDS. MOs also are a known source of KS tumor cell growth factors and substantial evidence suggests that tumor associated macrophages (TAMs) may represent a reservoir for HIV and its evolved retroviral variants. The MO pool driving these two pathological pathways share a common element rooted in the MOs, the CD206 human macrophage mannose receptor. Manocept, a molecular targeting agent, binds and enters MOs via pinocytosis of holo-CD206, providing a cell portal for the evaluation of Manocept as a MO and KS targeting agent.
Methods
Manocept was prepared as a synthetic molecule with a dextran backbone, and 12-20 mannose moieties. The reporter molecule (Cy3) was included as a fluorescent tracer for locating Manocept on and in MOs and KS tumor cells.
Binding and localization Cy3-Manocept was assessed through intracellular visualization and flow cytometric quantitation of Cy3-Manocept binding and uptake using in vitro generation of monocyte-derived CD206+ MOs. The fresh HIV+ KS tumor tissue culture followed by immunofluorescence staining and confocal imaging was performed to confirm Cy3-Manocept uptake in KS tumor cells and TAMs.
Results
In vitro culture showed that Cy3-Manocept binds avidly to CD206 expressing MOs. Time course studies of increasing Cy3-Manocept concentrations confirmed continuous and ongoing uptake of Manocept into CD206+ MOs at 37°C. Fresh HIV+ KS tissue culture studies showed both Manocept uptake and CD206 staining of TAMs as well as KS tumor spindle cells (HHV8+ cells). Cy3-Manocept co-localized with CD206 in nearly all KS-associated cells expressing HHV8 and/or CD68 (Tissue MO marker), confirming that CD206 acts both as a target and Manocept concentrating receptor for TAMs and KS tumor cells.
Conclusions
Our results support the potential use of CD206 macrophage mannose receptor-targeted Manocept for imaging KS tumor cells, TAMs, and more importantly, for delivery of therapeutic/diagnostic agents capable of targeting all KS-associated cells including a potential MO reservoir for HIV.
Citation Format: Rongzhen Zhang, Frederick O. Cope, Paige M. Bracci, Michael S. McGrath. Tumor associated targeting with Manocept: HIV associated Kaposi's sarcoma as a model system. [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 5026. doi:10.1158/1538-7445.AM2015-5026
Abstract 5027: Interleukin-17B promotes chemoresistance of breast tumors through ERK1/2 anti-apoptotic pathway
Authors: Laprevotte Emilie , Bastid Jeremy , Cochaud Stéphanie , Giustiniani Jerôme , Philippe Marion , Frewer Kathryn A. , Sanders Andrew J. , Jiang Wen G. , Bensussan Armand , Alberici Gilles , Eliaou Jean-François , Bonnefoy Nathalie 
Published: August 2015

Abstract
Interleukin-17B (IL-17B) is a pro-inflammatory cytokine that belongs to a family encompassing 6 interleukins (IL-17A to F) and binds to the IL-17 receptor B (IL-17RB). Little is known about the potential role of IL-17B/IL-17RB signaling pathway in cancer. Both IL-17B and IL-17RB are up-regulated in breast tumors and are associated with a poor prognosis in patients. We thus focused on their implication in breast cancer. We demonstrated that recombinant IL-17B induces resistance to conventional chemotherapeutic agents such as taxol, an effect that is totally abrogated by disrupting IL-17RB signaling. To further understand the molecular events involved in IL-17B-induced chemoresistance, we focused on signaling pathways activated under stimulation of human breast cancer cell lines by recombinant IL-17B. We observed that IL-17B induces the activation of both ERK1/2 and NFkB pathways, leading to an up-regulation of anti-apoptotic proteins of the Bcl-2 family. Interestingly we showed that the inhibition of ERK1/2 pathway totally prevents IL-17B-induced chemoresistance of breast cancer cell lines. Relevance of these data is currently under investigation in tumor mouse models. Altogether our results demonstrate the implication of the IL-17B/IL-17RB signaling pathway in breast tumors and identify IL-17B and its receptor as potential therapeutic targets for cancer.
Citation Format: Emilie Laprevotte, Jeremy Bastid, Stéphanie Cochaud, Jerôme Giustiniani, Marion Philippe, Kathryn A. Frewer, Andrew J. Sanders, Wen G. Jiang, Armand Bensussan, Gilles Alberici, Jean-François Eliaou, Nathalie Bonnefoy. Interleukin-17B promotes chemoresistance of breast tumors through ERK1/2 anti-apoptotic 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 5027. doi:10.1158/1538-7445.AM2015-5027
Abstract 5032: Acute phase liver graft injury mobilizes regulating B cells after transplantation for HCC patients through TLR4/CXCL10/CXCR3 signaling
Authors: Man Kwan , Shao Yan , Li Chang Xian , Lo Chung Mau 
Published: August 2015

Abstract
We aim to investigate the impact of acute-phase small-for-size graft injury on mobilization of circulating regulating B cells (Bregs) in HCC patients after liver transplantation and to explore the molecular mechanism therein.
Methods
From May 2000 to November 2009, 115 HCC recipients were included. The intragraft gene expression profile and Bregs infiltration of the grafts greater (Group 1) and less than 60% (Group 2) of standard liver weight (SLW) were detected by RT-PCR and immunostaining. Circulating Bregs (CD19+CD24hiCD38hi) were compared by FACS analysis after transplantation. Clinical-pathological data including the incidence of tumor recurrence and metastasis were compared.
The direct roles of TLR4, CXCL10 and CXCR3 on circulating Bregs mobilization were investigated in TLR4-/-, CXCL10-/- and CXCR3-/- mice models, respectively.
The association of intragraft Bregs infiltration and tumor invasiveness were also examined in a rat liver transplantation for liver cancer model. The role of Bregs on liver tumor growth and invasiveness were further studied in a series of in vitro and in vivo functional experiments.
Results
The patients were grouped into Group 1 (&gt; = 60% SLW, n = 37) and Group 2 (&lt;60% SLW, n = 78). Much more patients in Group 2 developed tumor recurrence and lung metastasis [19/78(24.4%) vs 3/37(8%), p = 0.04]. Level of circulating Bregs was significantly higher in Group 2 (Week1: 7.02 vs 1.31/10^5PBMC, p = 0.03; month3: 5.7 vs 1.3/10^5PBMC, p = 0.03). There was more intragraft Bregs infiltration in group 2 indicated by CD20/IL10 staining. Intragraft gene expression of TLR4, CXCL10 and CXCR3 were significantly higher in Group 2 at early phase after transplantation. In rat liver transplantation model, more
Bregs infiltration at early phase after transplantation correlated with late phase invasive tumor growth. Levels of circulating Bregs were significantly lower in the mice model with major hepatectomy and hepatic I/R injury using TLR4-/-, CXCL10-/- and CXCR3-/- mice, respectively. Bregs also promoted liver cancer cell proliferation and migration in vitro, and tumor growth in vivo.
Conclusion
A significantly higher population of circulating Bregs, which are mobilized by small-for-size graft injury, may lead to a higher incidence of tumor recurrence and metastasis after LDLT.
TLR4/CXCL10/CXCR3 signaling may play important roles on Bregs mobilization.
Citation Format: Kwan Man, Yan Shao, Chang Xian Li, Chung Mau Lo. Acute phase liver graft injury mobilizes regulating B cells after transplantation for HCC patients through TLR4/CXCL10/CXCR3 signaling. [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 5032. doi:10.1158/1538-7445.AM2015-5032
Abstract 5038: Role of the short isoform of the progesterone receptor in hormone-regulated invasiveness of breast cancer cells at pre- and post-menopausal levels of estrogen and progesterone
Authors: McFall Thomas B. , Patki Mugdha , Rosati Rayna , Ratnam Manohar 
Published: August 2015

Abstract
Introduction: High expression of the progesterone receptor (PR) isoform A, relative to PR isoform B, is clinically associated with progression to invasiveness in estrogen receptor (ER)-positive breast cancer and lower disease free survival. This is apparently at odds with in vitro studies implicating PR-B in mediating progestin-induced invasiveness. As the in vitro studies were conducted in the absence of estrogen (E2) signaling, we considered the possibility that modulation of E2 action may comprise a distinct aspect of the regulation of invasiveness by progestins.
Methods: Standard ER+/PR+ and ER+/PR+/HER2+ breast cancer cell line models were studied, as well as recombinant cells expressing a single PR isoform. For the progestin hyper-sensitization studies, PR-A was over-expressed by lentiviral infection. Hormonal influence on invasiveness was studied using the Boyden chamber assay. Gene expression was examined by Illumina DNA microarray analysis and by Taq-Man real time RT-PCR assays.
Results: E2 strongly suppressed invasiveness of ER+ breast cancer cells at concentrations below 0.01nM. At low (&lt; 1 nM) concentrations, progesterone, R5020 and medroxyprogesterone acetate completely abrogated the inhibition of invasiveness by E2. It was only in a higher (5nM - 50 nM) concentration range that progestins induced invasiveness in the absence of E2. The ability of progestins to rescue invasiveness from E2 regulation was exclusively mediated by PR-A whereas PR-B mediated the E2-independent component of progestin-induced invasiveness. Overexpression of PR-A in PR-A+/PR-B+ cells lowered the progestin concentration needed to completely rescue invasiveness (to &lt; 0.2 nM). Progesterone opposed E2 regulation of a distinctive set of genes, exclusively through PR-A.
Conclusion: At relatively low concentrations, progesterone influences breast cancer cell invasiveness by rescuing it from E2 regulation via PR-A, whereas at higher concentrations the hormone also induces invasiveness independent of E2 signaling, through PR-B. The findings establish a direct functional link between PR-A and progression of luminal breast cancer in the context of the entire range of pre- and post-menopausal plasma and breast tissue estrogen and progesterone levels.
Citation Format: Thomas B. McFall, Mugdha Patki, Rayna Rosati, Manohar Ratnam. Role of the short isoform of the progesterone receptor in hormone-regulated invasiveness of breast cancer cells at pre- and post-menopausal levels of estrogen and progesterone. [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 5038. doi:10.1158/1538-7445.AM2015-5038
Abstract 5043: ERβ decreases the invasiveness of triple-negative breast cancer cells by regulating mutant p53 gain-of-function
Authors: Bado Igor , Nikolos Fotis , Rajapaksa Gayani , Gustafsson Jan-Ake , Thomas Christoforos 
Published: August 2015

Abstract
Triple-negative breast cancers (TNBCs) display distinct metastatic potential and a poor prognosis despite a relative chemosensitivity. Most (80%) of these highly aggressive tumors express mutant p53 proteins that are known to elicit oncogenic activities that contribute to metastasis and chemoresistance. Despite the lack of estrogen receptor α (ERα), TNBCs express wild-type ERβ (ERβ1). We previously showed that ERβ1 impedes epithelial to mesenchymal transition (EMT) in TNBC cells by repressing epidermal growth factor receptor (EGFR) signaling. Our recent findings indicate that ERβ1 regulates EGFR expression and decreases the invasiveness of TNBC cells by interacting with mutant p53 and inhibiting its function. Suppression of a mutant p53 transcriptional program and induction of p63 activity are essential for the anti-migratory activity of ERβ1 in TNBC cells. These results describe an ERβ1/mutant p53 interaction that disturbs oncogenic signals to inhibit aggressiveness in TNBC.
Citation Format: Igor Bado, Fotis Nikolos, Gayani Rajapaksa, Jan-Ake Gustafsson, Christoforos Thomas. ERβ decreases the invasiveness of triple-negative breast cancer cells by regulating mutant p53 gain-of-function. [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 5043. doi:10.1158/1538-7445.AM2015-5043
Abstract 5046: Amphiregulin is a key effector of estrogen receptor in breast cancer
Authors: Peterson Esther A. , Chandiramani Natasha , Aranda Jaque Evelyn J. , Jenkins E. Charles , Kenny Paraic A. 
Published: August 2015

Abstract
Estrogen is an essential hormone for mammary gland development and is a key driver of proliferation during the development of estrogen receptor positive breast tumors. The actions of estrogen are primarily mediated by its receptor, the ERα transcription factor, which regulates several hundred estrogen-responsive genes in breast cancer cells. However, despite much investigation, the identity of the key effectors of this proliferative signal in breast cancer remains unclear. Amphiregulin (AREG) is a ligand of the Epidermal Growth Factor Receptor. It is transcriptionally regulated by estrogen and is required for estrogen-dependent mouse mammary gland development. In this study, we have tested whether Amphiregulin is a key effector of estrogen in breast cancer.
shRNA-mediated knockdown of Amphiregulin in MCF7 cells strongly attenuated ER+ breast cancer cell line growth in vivo. Conversely, expression of Amphiregulin from an estrogen-insensitive promoter allowed MCF7 xenografts to escape the therapeutic effects of tamoxifen. Thus, Amphiregulin expression is both necessary and sufficient for the proliferative response to estrogen in MCF7 cells in vivo, and downregulation of Amphiregulin in response to tamoxifen is required for a therapeutic benefit.
After initially responding to endocrine therapy, many ER+ tumors progress to resistance to these therapies. Our model predicts that breast tumors which either (1) express AREG in an estrogen-insensitive manner or (2) have elevated levels of alterative ERBB family ligands, will be endocrine resistant. We present experimental and clinical evidence demonstrating that these features contribute to at least some examples of endocrine resistance. Firstly, in MCF7 cells selected for resistance to fulvestrant, we show that AREG expression is no longer regulated by estrogen or its antagonists, but the cells remain AREG-dependent. Secondly, in a series of 52 ER+ breast cancer patients treated with neo-adjuvant letrozole, we show that the downregulation of Amphiregulin in response to endocrine therapy observed in our mouse studies is recapitulated in human breast cancer patients, and that tumors in which alternate ERBB ligands (TGFalpha, Epiregulin, and Neuregulins 1 & 2) are expressed at high levels are least likely to respond to letrozole.
In summary, these data underline the importance of ERBB signaling in estrogen receptor positive breast cancer and implicate Amphiregulin as the primary ERBB ligand in mediating the effects of estrogen in these tumors.
Citation Format: Esther A. Peterson, Natasha Chandiramani, Evelyn J. Aranda Jaque, E. Charles Jenkins, Paraic A. Kenny. Amphiregulin is a key effector of estrogen receptor 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 5046. doi:10.1158/1538-7445.AM2015-5046
Abstract 5049: Checkpoint kinase 2 is a novel regulator of prostate cancer cell growth
Authors: Ta Huy Q. , Ivey Melissa L. , Frierson Henry F. , Conaway Mark R. , Dziegielewski Jaroslaw , Larner James M. , Gioeli Daniel 
Published: August 2015

Abstract
Prostate cancer (PCa) is the second leading cause of cancer death in American men, and the cure for metastatic disease remains a significant challenge. While nearly all patients with disseminated PCa initially respond to androgen deprivation therapy (ADT), virtually every patient will relapse and develop incurable castration-resistant prostate cancer (CRPC). Androgen receptor (AR) signaling pathways continue to play a crucial role in CRPC progression. Previous studies have shown that signal transduction pathways can stimulate AR activation, suggesting that the ability of signaling cascades to influence AR function may have a significant role in CRPC progression, and that CRPC may not be effectively treated by ligand-directed therapy alone. A high-throughput RNAi screen identifying signaling pathways that regulate PCa cell growth led to our discovery that knockdown of Checkpoint Kinase 2 (CHK2) dramatically increased PCa proliferation in the presence and absence of androgen. Furthermore, CHK2 depletion hypersensitized cells to castrate androgen levels. These CHK2-mediated effects on growth were dependent on the downstream signaling proteins CDC25C and CDK1 and could be blocked by the AR antagonist MDV3100. Immunohistochemical analysis of CHK2 in patient samples demonstrated that reduced CHK2 expression significantly correlated with increased Gleason score indicating the clinical relevance of CHK2 in PCa. Moreover, CHK2 expression is lower in castration-resistant C4-2 and CWR22Rv1 cells compared to androgen-sensitive LNCaP cells consistent with loss of CHK2 expression during PCa progression. CHK2 depletion increased AR transcriptional activity on both androgen-activated and androgen-repressed genes, substantiating that CHK2 affects PCa growth through the AR. Remarkably, quantitative PCR, chromatin immunoprecipitation, and western blot analyses revealed that CHK2 is a novel AR-repressed gene, suggesting a negative feedback loop between CHK2 and the AR. Furthermore, we show that CHK2 physically associates with the AR, and that cellular stress, such as DNA damage and serum starvation, increases this association. Based on these data, we propose that CHK2 is a negative regulator of androgen sensitivity and PCa growth. Thus, alterations to CHK2 signaling may sensitize CRPC to ADT and radiation.
Citation Format: Huy Q. Ta, Melissa L. Ivey, Henry F. Frierson, Mark R. Conaway, Jaroslaw Dziegielewski, James M. Larner, Daniel Gioeli. Checkpoint kinase 2 is a novel regulator of prostate cancer cell growth. [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 5049. doi:10.1158/1538-7445.AM2015-5049
Abstract 5052: The association between estrogen receptor alpha and platinum sensitivity in ovarian cancer cells
Authors: Matsumura Sohei , Ohta Tsuyoshi , Takahashi Toshifumi , Takahashi Kazuhiro , Nagase Satoru 
Published: August 2015

Abstract
[Objective] The objective of this study was to examine whether estrogen receptor alpha (ERα) is associated with the sensitivity to cisplatin in ovarian cancer cells.
[Methods] Using two human ovarian cancer cell lines (Caov-3, Ovcar-3) which express ERα, we investigated the effect of cisplatin on ERα activation. We evaluated the association between ERα activation and Erk cascade in the cells treated with cisplatin. We next examined the antitumor effects of estradiol (E2) with cisplatin by using MTS [3-(4, 5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt], and Western blot assay. Then, ERα expression was down-regulated in Caov-3 and Ovcar-3 by using lentiviral shRNA against ERα, and we generated batch clonal lines. The nontarget shRNA (NTS) served as control. Finally, we determined the effect of ERα down-regulation on the sensitivity to cisplatin.
[Results] Cisplatin induced the phosphorylation of ERα at serine 118 via Erk cascade. Pretreatment with E2 antagonized cisplatin-induced cytotoxicity, and decreased the expression of cleaved PARP induced by cisplatin. Pretreatment of E2 followed by cisplatin increased the expression of Bcl-2, which is anti-apoptotic protein. The shRNA- mediated down-regulation of ERα increased the sensitivity to cisplatin compared with NTS.
[Conclusions] These results indicate that E2 promotes resistance to cisplatin via ERα, and down-regulation of ERα may increase efficacy of cisplatin in ovarian cancer.
Citation Format: Sohei Matsumura, Tsuyoshi Ohta, Toshifumi Takahashi, Kazuhiro Takahashi, Satoru Nagase. The association between estrogen receptor alpha and platinum sensitivity in ovarian 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 5052. doi:10.1158/1538-7445.AM2015-5052
Abstract 5055: Role of insulin-like growth factor 1 receptor in pancreatic cancer pathogenesis
Authors: Subramani Reddy Ramadevi , Arumugam Arunkumar , Nandy Sushmita Bose , Gonzalez Elizabeth , Gonzalez Viviana , Bonkoungou Sandrine , Ortega Andrew , Lakshmanaswamy Rajkumar 
Published: August 2015

Abstract
Pancreatic cancer incidence and the associated mortality are increasing worldwide. This indicates that there is a clear lack of understanding about pancreatic cancer pathogenesis. This can be attributed to the lack of specific symptoms to diagnose the disease at an early stage. Various growth factor receptors are known to play a vital role in the development of pancreatic cancer. In the present investigation, we have attempted to target insulin-like growth factor-1 receptor (IGF-1R) due to its well-established role in progression of pancreatic cancer. RNA interference (small interfering RNA [siRNAs]) approach targeted to IGF-IR was used to study the effect of IGF-1R silencing on pancreatic cancer growth and metastasis. For this we used HPAC and PANC-1 pancreatic cancer cell lines and primary pancreatic cancer tissue array. Our results demonstrated that silencing IGF-1R remarkably inhibited pancreatic cancer growth and metastasis. Silencing IGF-1R significantly altered key signaling molecules such as PI3K, AKT, MAPK, ERK1/2, mTOR, PTEN, p70S6K, JAK2 and STAT3. Further IGF-1R silencing also reduced epithelial to mesenchymal transition (N-Cad, Notch, Snail, Slug and Vimentin). In addition, silencing IGF-1R inhibited cell viability, invasive and migratory capabilities of PANC-1 and HPAC pancreatic cancer cell lines. Colony forming ability was also drastically reduced in IGF-1R silenced cells. Flow cytometric analysis revealed the induction of apoptosis in IGF-1R silenced cells. Interestingly, silencing IGF-1R decreased the expression of Kras, which is altered in almost 95% of pancreatic cancers. Overall, our data clearly demonstrates the significance of IGF-1R in pancreatic cancer pathogenesis and also identifies IGF-1R as a potential target for pancreatic cancer treatment and therapy.
Citation Format: Ramadevi Subramani Reddy, Arunkumar Arumugam, Sushmita Bose Nandy, Elizabeth Gonzalez, Viviana Gonzalez, Sandrine Bonkoungou, Andrew Ortega, Rajkumar Lakshmanaswamy. Role of insulin-like growth factor 1 receptor in pancreatic cancer pathogenesis. [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 5055. doi:10.1158/1538-7445.AM2015-5055