bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 720: Novel prognostic stromal subtypes in triple-negative breast cancer
Authors: Thompson Crista , Saleh Sadiq M. , Bertos Nicholas , Gigoux Mathieu , Gruosso Tina , Souleimanova Margarita , Zhao Hong , Hallett Michael T. , Park Morag 
Published: July 2016

Abstract
Breast cancer is a heterogeneous disease in terms of presentation, morphology, molecular profile and response to therapy. Gene expression profiling has identified intrinsic molecular subtypes that are associated with clinical markers (ER, PR, HER2) as well as prognosis and survival. However, it is well established that the intrinsic molecular profiles of breast tumors are not sufficient to perfectly predict disease outcome. Increasing evidence indicates that characteristics of the breast stroma influence tumor progression and response to therapy. Previous work in our lab has demonstrated that gene expression signatures in human stroma can predict outcome of breast cancer patients independently of clinical parameters and molecular subtypes. In this study, we expand our findings by focusing on a previously underrepresented subset of breast tumors that have no detectable ER, PR or HER2 (termed Triple-Negative, TN). TN tumors, which represent approximately 15% of all breast cancers, are typically associated with poor outcome. However, the contribution of the stroma to the underlying heterogeneity of TN breast cancer and its corresponding influence on therapeutic response is not well understood. To address this, we isolated TN tumor epithelial and stromal tissues by laser capture microdissection and subjected them to gene expression profiling. Class discovery revealed distinct gene-clusters (stromal properties) which are associated with prognosis in TNBC whole tumor samples. Analysis of the genes comprising each stromal property suggests that the properties primarily represent the prevalence of distinct cell types, namely T cells, B cells, activated fibroblasts, and myoepithelial cells. Importantly, these properties are not mutually exclusive, i.e. some tumors are associated with multiple stromal properties. While confirming the heterogeneity of TN-associated stroma, this also indicates that a multi-parameter classification better reflects the true nature of the tumor microenvironment. This project provides the first integrated in-depth analysis of the contribution of tumor stromal processes to TN disease heterogeneity, and positions the tumor microenvironment for therapeutic intervention.
Citation Format: Crista Thompson, Sadiq M. Saleh, Nicholas Bertos, Mathieu Gigoux, Tina Gruosso, Margarita Souleimanova, Hong Zhao, Michael T. Hallett, Morag Park. Novel prognostic stromal subtypes in triple-negative 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 720.
Abstract 721: Opposite roles of CD11b+ myeloid cells in primary and recurrent brain tumors
Authors: Sheng-Yen Wu 
Published: July 2016

Abstract
Malignant glioma is one of the toughest tumors to be treated at present due to the complexity of the tumor microenvironment and the intrinsic resistant to irradiation. Previous studies have shown that CD11b+ myleoid cells play essential role in brain tumor recurrence following radiation therapy. Here we used the CD11b-diphtheria toxin receptor (CD11b-DTR) transgenic mouse model to evaluate the role of CD11b+ myleoid cells in TK/GCV suicide gene therapy for brain tumor in a murine astrocytomal tumor model, ALTS1C1-TK. Using this transgenic mouse model, the depletion of peritoneal macrophages (CD11b+F4/80+) and blood monocyte (CD11b+Ly6G−Ly6c−) could be achieved after two injections of DT, but the neutrophil (CD11b+Gr-1+) were increased transiently. Results found that the depletion of CD11b+ myleoid cells enhanced the efficacy of TK/GCV therapy as shown by the increase of median surviving time of GCV-treated ALTS1C1-TK tumor-bearing mice from 30.6 days to 37.5 days. Interestingly, the depletion of CD11b+ myleoid cells enhanced tumor growth as shown that tumor-bearing mice had shorter surviving days and larger tumor size after receiving two doses of DT injections compared to the control PBS group (22.4 days vs 25.0 days, respectively). This indicates that depleted CD11b+ myleoid cells might have anti-tumor function for control tumor, but have pro-tumor activity during TK/GCV therapy. This study also found the effect of CD11b+ myleoid cells was only seen when the depletion was performed during the administration of GCV, but not before or after GCV treatment. Collectively, above findings suggest that CD11b+ myleoid cells might have different roles on primary and recurrent brain tumors.
Citation Format: Wu Sheng-Yen. Opposite roles of CD11b+ myeloid cells in primary and recurrent brain tumors. [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 721.
Abstract 725: HMGB1-mediated RAGE activation mechanism in M2 macrophages
Authors: Rojas Armando , Araya Paulina , Romero Jacqueline , Delgado-López Fernando , Pérez-Castro Ramón , González Ileana , Añazco Carolina , Morales Erik , Llanos Jorge , Vidal-Vanaclocha Fernando 
Published: July 2016

Abstract
Tumor-associated macrophages display M2 phenotype and promote immunosuppression, tumor growth, angiogenesis and metastasis. We have previously reported that M2 macrophages express the receptor of advanced glycation end-products (RAGE) and their protumoral activities enhanced by HMGB1, a RAGE ligand highly abundant at the cancer microenvironment. However, RAGE is highly expressed by M1 macrophages and it is unknown if proinflammatory and antitumor cytotoxicity of M1 macrophages become skewed from classical antitumor activities to a tumor permissive profile when M2 macrophages are induced by HMGB1.
In order to clarify whether RAGE contributes to inflammatory response inhibition in M2 macrophages, we look at some microRNAs, a tolerance-like state as well as to some epigenetic changes. Polarized M1 and M2 macrophages were derived from wild-type and RAGE-targeted knock-down THP-1 cells and treated with HMGB1 at different times. NFkB activation was assessed by p65, IKBalpha western blots, and p50 and p65 Transcription Factor Assay. Additionally, we analyzed changes of chromatin activity related to HMGB1 treatment by quantitative chromatin immunoprecipitation (ChIP) with antibodies against acetylated or methylated histone H3 at the IL-10 promoter.
We showed that RAGE activation by HMGB1 did not produce NFkB activation, as assessed by either IKB alpha and phospho p65 western blots or by p65 and p50 trascription factor assays. In addition, HMGB1 did not modify M2 macrophage expression profile of relevant microRNAs for macrophage polarization such as miR-155, miR-21 and miR-125b. However, ChIP analysis showed that HMGB1 induced a transcription-prone histone modification at the IL-10 promoter in M2 macrophages and this epigenetic imprinting correlated with HMGB1-induced IL-10 production, leading to immunosupression. These results demonstrate that RAGE activation on M2 macrophages did not induce NFkB activation and suggest that epigenetic changes are a major mechanism by which activities described for M1 macrophages upon RAGE activation have become skewed during macrophage polarization.
Citation Format: Armando Rojas, Paulina Araya, Jacqueline Romero, Fernando Delgado-López, Ramón Pérez-Castro, Ileana González, Carolina Añazco, Erik Morales, Jorge Llanos, Fernando Vidal-Vanaclocha. HMGB1-mediated RAGE activation mechanism in M2 macrophages. [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 725.
Abstract 738: Correlation between tumor infiltrating lymphocytes and CCL5 gene expression in chemotherapy-resistant triple negative breast cancer
Authors: Pinto Joseph A. , Morante Zaida D. , Salgado Roberto , Cardenas Nadezhda , Araujo Jhajaira , Ponce Jaime , Doimi Franco , Balko Justin , Gomez Henry 
Published: July 2016

Abstract
Background:
The presence of tumor infiltrating lymphocytes (TILs) have been associated with a better outcome in triple negative breast cancer (TNBC). In the other hand, we have found that CCL5, a chemokine involved in the recruitment of immune cells to the tumor microenvironment is an independent prognostic marker for distant-recurrence free survival (DFRS) in TNBC. The aim of this work was to evaluate the relationship between these two immunological prognostic markers in chemotherapy-resistant TNBC.
Material and Methods:
We evaluated a retrospective cohort (n = 74) of TNBC patients with residual disease after neoadjuvante chemotherapy. Residual tumors were profiled with Nanostring for genes previously related to TNBC aggressiveness. Gene expression values for CCL5 were log2 transformed and median centered. TIL count was performed according to the methods published by Salgado et al (2015). Values of TILs count were log2 transformed (values with 0% were removed from the cohort; n = 1). Spearman's rank correlation analysis and proportional hazards regression was used to investigate the relationship and impact in the outcome between these two markers.
Results: The median TIL count was 10% (interquartile range: 21.25). A total of 59.5% of cases had TILs &lt;15%. There was a significant correlation between TILs and CCL5 (ñ = 0.345, P = 0.032). In univariate analysis (as continuous variable), TILs (HR = 0.968 per unit of change; 95%IC: 0.946-0.990; P = 0.006) and CCL5 (HR = 0.95 per unit of change; 95%IC: 0.635-0.996; P = 0.046) were both associated with outcome. After adjusting to CCL5 expression, TIL's count, was the only significant marker with a P-value = 0.007 (HR = 0.702 per unit of change; 95%IC: 0.54-0.909), in contrast to CCL5 (HR = 0.925, CI95%:0.717-1,194; P-value = 0.550).
Conclusions: TILs and CCL5 gene expression are significantly correlated in chemotherapy-resistant TNBC. However, although CCL5 expression is strongly associated with the progression of BC, particularly TNBC, TIL assessment remains the stronger and more significant prognostic immunological marker.
Citation Format: Joseph A. Pinto, Zaida D. Morante, Roberto Salgado, Nadezhda Cardenas, Jhajaira Araujo, Jaime Ponce, Franco Doimi, Justin Balko, Henry Gomez. Correlation between tumor infiltrating lymphocytes and CCL5 gene expression in chemotherapy-resistant triple negative 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 738.
Abstract 739: The role of obesity on inflammation markers in the prostate tumor microenvironment
Authors: Zeigler-Johnson Charnita M. , Morales Knashawn H. , Lal Priti , Rebbeck Timothy R. , Feldman Michael 
Published: July 2016

Abstract
Background: Obesity reflects a chronic inflammatory environment that may contribute to prostate cancer progression and poor treatment outcomes. However, it is not clear which mechanisms drive this association within the tumor microenvironment. The aim of this pilot study was to examine prostatic inflammation via tumor infiltrating lymphocytes and macrophages characterized by obesity and cancer severity.
Methods: We studied paraffin-embedded prostatectomy tissue from 99 participants (63 non-obese and 36 obese) from the Study of Clinical Outcomes, Risk and Ethnicity (University of Pennsylvania) Pathologists analyzed the tissue for type and count of lymphocytes and macrophages, including CD3, CD8, FOXP3, and CD68. Pathology data were linked to clinical and demographic variables. Statistical analyses included frequency tables, Kruskal-Wallis tests, Spearman correlations, and multivariable models.
Results: We observed positive univariate associations between the number of CD68 cells and tumor grade (p = 0.019), as well as biochemical failure (p = 0.033). In multivariable analysis, CD3 and CD8 counts were associated with time to biochemical failure (HR = 0.93, 95% CI = 0.88-0.99; HR = 1.08, 95% CI = 1.01-1.17, respectively.) Preliminary results suggested differences in lymphocytes by race. There were no differences in lymphocytes or macrophages by obesity status or BMI.
Conclusions: The number of lymphocytes and macrophages in the tumor microenvironment did not differ by obesity status. However, these inflammation markers were associated with poor prostate cancer outcomes. Further examination of underlying mechanisms that influence obesity-related effects on prostate cancer outcomes is warranted. Such research will guide immunotherapy protocols and weight management as they apply to diverse patient populations and phenotypes.
Citation Format: Charnita M. Zeigler-Johnson, Knashawn H. Morales, Priti Lal, Timothy R. Rebbeck, Michael Feldman. The role of obesity on inflammation markers in the prostate tumor microenvironment. [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 739.
Abstract 749: Betaglycan-mediated regulation of mesenchymal stromal cell behavior in the prostate tumor-bone microenvironment
Authors: Cook Leah M. , McGuire Jeremy J. , Lynch Conor C. 
Published: July 2016

Abstract
Prostate cancer frequently metastasizes to bone, resulting in increased risk of fractures and severe pain that significantly impacts patient quality of life. Bone metastatic prostate cancer is currently incurable with standard of care therapies being mainly palliative. In bone, prostate cancer generates extensive osteogenic lesions by promoting osteoblast activity. Osteoblasts are specialized bone forming cells derived from mesenchymal stem cells. In a bid to find new molecular targets through which prostate cancer induces osteogenesis, we incubated naïve MSCs with osteogenic bone metastatic prostate cancer cell line C4-2B conditioned media. Gene expression analysis revealed a 3-fold increase in expression of the TGFâ co-receptor, betaglycan. Given the critical role of TGFâ in the context of bone metastatic disease, we examined the role of betaglycan in MSC behavior. To this end, we utilized shRNA to knockdown betaglycan gene expression in mouse bone marrow-derived primary MSCs. Reduced betaglycan expression in knockdown (KD) MSCs had little to no impact on the expression of TGFâ signaling receptors, TGFâRI and TGFâRII, or pan-TGFâ ligand expression. However, using PAI promoter activity, a readout for TGFâ signaling, we observed a 3-fold increase in luminescence in KD-MSCs compared to controls. Likewise, phosphorylated Smad 2 was significantly increased in Betaglycan KD-MSCs in response to TGFâ treatment, collectively demonstrating increased TGFâ signaling in MSCs with reduced betaglycan expression. Using modified Boyden chamber assays, we found that 50% more Betaglycan-KD MSCs migrated towards recombinant TGFâ than controls (100 KD-MSCs cells migrated towards recombinant TGFâ vs. 50 control cells); this change was reversed with the addition of recombinant betaglycan. Using osteogenic differentiation assay, we found that Betaglycan KD-MSC differentiation was reduced by approximately 70% compared to control MSCs as measured by alizarin red staining. Addition of recombinant TGFâ further suppressed differentiation in both KD-MSCs and Control MSCs. This phenomenon was rescued by the addition of recombinant betaglycan, suggesting that MSC-derived betaglycan is critical for driving the osteogenic program. We are currently determining the impact of betaglycan on MSC behavior in the tumor bone microenvironment using in vivo models of bone metastatic prostate cancer. Collectively, these findings suggest that prostate cancer-induced MSC osteogenic programs are regulated in part via the induction of betaglycan.
Citation Format: Leah M. Cook, Jeremy J. McGuire, Conor C. Lynch. Betaglycan-mediated regulation of mesenchymal stromal cell behavior in the prostate tumor-bone microenvironment. [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 749.
Abstract 753: The use of proteomics to analyse whole tumors and identify unique stroma cell targets for antibody-based therapeutics
Authors: Ackroyd James , Allen Jason , Berry Jo , Roesch Lisa , Barnes Martin , Bisht Arnima , Rohlff Christian , Wilson Keith , Aud Dee , Boyd Robert 
Published: July 2016

Abstract
Solid tumors comprises of two distinct compartments: cancer cells and the stroma that the cancer cells induce and are dispersed in. This stroma contains stromal (Fibroblasts, endothelial and pericyte cells) and infiltrating immune cells (Lymphocytes, macrophages, granulocytes and myeloid derived suppressor cells). Recent oncology research has implicated these stroma cells as promoters of tumor progression and there is thus a strong need to profile the cell membrane proteins present on these cells. For tumors which do not contain infiltrating T cells (non-immunogenic tumors) it has been recognized that it will be necessary to employ therapeutic agents to disrupt the tumor micro-environment (TME); allowing the release and processing of tumor antigens by antigen presenting cells, entry and migration T cells into intrastromal sites and potent activation of T cell responses to tumor antigens.
We have conducted in-depth proteomic profiling of tumors from 14 different solid cancer indications with varying degrees of stroma involvement to characterize their immune and stromal cell composition. The data from this work was analyzed in OGAP®; a unique proteomic database that integrates information at the tissue, disease and protein isoform level across diseases, indications, and normal tissues to clarify membrane protein expression levels and profiles. It is one of the world's largest proprietary cell-membrane focused proteomic database, with data on over 5000 cancer membrane proteins. Purified stroma cell populations were also profiled to facilitate the interpretation of whole tumor proteomic data.
Cell membrane proteins present in tumors from different cancer indications were analyzed by mass spectrometry. We classified tumors as immunogenic or non-immunogenic using validated T cell markers (CD3, CD4, CD8 and CD69). We then profiled the non-immunogenic tumors for fibroblast, macrophage and B cell type markers to try and identify strong stroma cell expression patterns not detected in normal tissues. Importantly, most current antibody therapeutic stroma cell targets (CSF-1R, FAP and VEGF-A) were re-discovered. Several novel stroma cell therapeutic targets were identified which if targeted by a therapeutic antibody have the potential to enhance the T cell immune response in tumors resistant to current immunotherapy.
Citation Format: James Ackroyd, Jason Allen, Jo Berry, Lisa Roesch, Martin Barnes, Arnima Bisht, Christian Rohlff, Keith Wilson, Dee Aud, Robert Boyd. The use of proteomics to analyse whole tumors and identify unique stroma cell targets for antibody-based therapeutics. [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 753.
Abstract 757: p16INK4A negatively regulates Leptin through miR-141 and miR-146b-5p in breast stromal adipocytes
Authors: Alkhalaf Huda H. , Aboussekhra Abdelilah 
Published: July 2016

Abstract
Obesity, a disease linked to increased number of adipocytes in various tissues, is increasingly recognized as a risk factor for the development of breast cancer. Obesity has been reported to be associated with the occurrence of larger, more advanced tumors and aggressive cancer pathological features, including lymph node metastasis, advanced tumor stage, and high grade. Accumulating recent evidence highlights the tumor-surrounding adipose tissue as a key component of breast cancer progression. However, the molecular basis of adipocyte-related breast carcinogenesis remains elusive. To shed light on this important phenomenon, we investigated the autocrine and paracrine roles of the tumor suppressor p16 INK4A protein in adipocytes. We have found that down-regulation of p16INK4A by specific shRNA in breast adipocytes enhanced their migration/invasion abilities and increased the expression/secretion levels of various adipokines including leptin. In addition, we have shown that p16INK4A protein inhibits the pro-carcinogenic effects of breast stromal adipocytes in vitro and in tumor xenografts through repressing the expression/secretion of Leptin. Indeed, p16INK4A suppresses Leptin at the mRNA level. This effect is mediated trough miR-141 and miR-146b-5p, which inhibits Leptin expression through a specific sequence at the Leptin 3’UTR. In addition, we present clear evidence that down-regulation of p16INK4A is sufficient to trans-activate breast stromal adipocytes, which promote epithelial-to-mesenchymal-transition in normal breast luminal cells in a leptin-dependent manner.
These results provide the first indication that p16INK4A and miR-141 and miR-146b-5p represses Leptin and its procarcinogenic effects in breast stromal adipocytes. This indicates that p16 pathway has non-cell-autonomous tumor suppressor function.
Citation Format: Huda H. Alkhalaf, Abdelilah Aboussekhra. p16INK4A negatively regulates Leptin through miR-141 and miR-146b-5p in breast stromal adipocytes. [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 757.