bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 716: STAT1 expression in the tumor-stroma microenvironment is influenced by loss of PTEN in prostate cancer
Authors: Vidotto Thiago , Picanço-Albuquerque Clarissa G. , Saggioro Fabiano P. , Borges dos Reis Rodolfo , Siemens David Robert , Koti Madhuri , Squire Jeremy A. 
Published: July 2016

Abstract
The prostate cancer (PCa) microenvironment is an admixture of stromal cells, such as lymphocytes, fibroblasts, myofibroblasts and blood vessel endothelium. The reactive stromal microenvironment of PCa facilitates tumor growth through cytokine and chemokine-mediated cell signaling. STAT1, a transcription factor, induces cell cycle arrest, apoptosis and modulates immune and inflammatory response through IFN-á/ã cytokine activation. IFN-á/ã may be secreted in response to PI3K/AKT activation, since this pathway is associated with JAK/STAT signaling. In addition, the PI3K/AKT pathway can become activated when the PTEN prognostic biomarker is deleted in PCa. The rationale for this project is that the immediate stromal microenvironment of PCa may become pro-tumorigenic as a result of induction of inflammatory cytokines caused by PTEN deletions and activation of PI3K/AKT. We performed FISH analysis of the PTEN gene on 172 cores on a PCa tissue microarray (TMA) derived from 43 patients with intermediate risk disease. Analysis of cytoplasmic and nuclear STAT1 in both the tumor and stromal compartments was performed on each TMA core using immunohistochemistry (IHC) to determine whether the tumor PTEN deletion status was associated with STAT1 expression. In each core, tumor and stromal cell histologies were evaluated independently to estimate the percentage area that was stained positive by IHC. The staining was graded as percentage of positive cells with 0 (negative), 1 (less than 10%), 2 (11% to 50%), and 3 (more than 51%). We found that STAT1 expression in stroma was increased when the PTEN gene in the adjacent tumor was homozygously deleted (p = 0,04). We also showed that mean STAT1 expression in benign tissue cores was reduced when compared to the average score from tumor tissue with one (p = 0.01) or two copies (p = 0.03) of the PTEN gene. STAT1 expression and PTEN gene copy numberPTEN copy numberMean STAT1 in StromaMean STAT1 in Tumor&gt;2 copies0.410.822 copies0.510.651 copy0.600.700 copies0.850.85
These results suggest that the STAT1 pathway may be influenced by PTEN loss in this tumor, suggesting that the JAK/STAT inflammatory pathway may have future clinical applications in PCa.
Citation Format: Thiago Vidotto, Clarissa G. Picanço-Albuquerque, Fabiano P. Saggioro, Rodolfo Borges dos Reis, David Robert Siemens, Madhuri Koti, Jeremy A. Squire. STAT1 expression in the tumor-stroma microenvironment is influenced by loss of PTEN in prostate 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 716.
Abstract 729: Novel role of CB2R in tuning breast tumor microenvironment, EGF/EGFR and IGF-I/IGF-IR pathways
Authors: Elbaz Mohamad , Nasser Mohd , Ravi Janani , Ahirwar Dinesh , Ganju Ramesh 
Published: July 2016

Abstract
Cannabinoid receptor-2 (CB2R) is an integral part of the endocannabinoid system. It is upregulated in the primary breast cancer lesions and in different types of immune cells however; its functional role in breast tumorigenesis is not well understood. The present study was aimed at evaluating the mechanistic anti-tumor role of CB2R activation on breast cancer cells and immune cells within the breast tumor microenvironment. First, we analyzed the anti-tumorigenic mechanisms of CB2R activation in ERá- and ERá+ breast cancer cells. Our studies showed that CB2R specific agonist (JWH-015) inhibits EGF and IGF-I-induced migration and invasion of ERá+ and ERá- breast cancer cells. At the molecular level, JWH-015 inhibits EGFR and IGF-IR activation and their downstream targets STAT3, AKT, ERK, NF-kB and MMP-9/MMP-2. Interestingly, We found that JWH-015 significantly reduces breast cancer growth in vivo and the tumors that were derived from CB2R agonist treatment showed reduced activation of EGFR and IGF-IR and their downstream targets compared to control group. Since CB2R is overexpressed in immune cells, we assessed for the role of CB2R activation on modulation of immune cells present in tumor stroma. We observed increased tumor weight, more myeloid derived suppressor cells (MDSCs) (CD11b+/Gr-1+) and less CD3+/CD8+ cells in orthotopically injected CB2R knock out mice compared to wild type mice. Furthermore, we found that JWH-015-treated wild type mice have reduced tumor growth and metastasis, more CD3+/CD8+ cells and less MDSCs within the tumor stroma. For the first time, we show that CB2R activation might suppress breast tumor growth and metastasis through novel mechanisms of inhibiting EGFR and IGF-IR signaling axes on tumor cells and modulating the immune cells’ compositions within the breast tumor microenvironment.
Citation Format: Mohamad Elbaz, Mohd Nasser, Janani Ravi, Dinesh Ahirwar, Ramesh Ganju. Novel role of CB2R in tuning breast tumor microenvironment, EGF/EGFR and IGF-I/IGF-IR pathways. [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 729.
Abstract 731: Transcriptional control of inflammatory signaling in the megakaryocyte and erythroid lineages: implications for the tumor microenvironment
Authors: Trinh Bon Q. , Barengo Nicolas , Kim Sang Bae , Lee Ju-Seog , Zweidler-McKay Patrick A. , Naora Honami 
Published: July 2016

Abstract
Thrombocytosis, characterized by high platelet counts, and anemia, caused by low numbers of red blood cells, are associated with poor outcomes in various solid tumors and also occur in several myeloid disorders. The megakaryocyte and erythroid lineages give rise to platelets and red blood cells, respectively, but the mechanisms that cause increased megakaryopoiesis and concurrently decreased erythropoiesis in malignancies are poorly understood. We and others have previously identified that DLX4, a developmental transcription factor encoded by a homeobox gene, is aberrantly expressed in several types of solid tumors and myeloid malignancies but the mechanisms of DLX4 are poorly understood. In this study, we identified that DLX4 expression increases during megakaryopoiesis and decreases during erythropoiesis. Overexpression and knockdown experiments using normal CD34+ stem/progenitor cells and bipotent K562 cells demonstrated that DLX4 induces lineage markers and morphologic features of megakaryocytes, and concomitantly represses erythroid marker expression and hemoglobin levels. Gene Ontology and Gene Set Enrichment Analyses of genome-wide changes in gene expression induced by DLX4 showed that DLX4 induces a megakaryocytic transcriptional program and inhibits an erythroid transcriptional program. Bioinformatic analysis also revealed that DLX4 induces gene signatures that are associated with NF-kappaB signaling. The ability of DLX4 to promote megakaryocyte development and to inhibit erythroid differentiation was diminished by blocking NF-kappaB activity or by repressing IL1B, a transcriptional target of DLX4. These findings indicate that DLX4 promotes megakaryocyte development at the expense of erythroid generation in part by inducing inflammatory signaling. Studies are ongoing to investigate the transcriptional control by homeobox genes of inflammatory signaling in thrombocytosis and anemia that are associated with solid tumors and myeloid disorders.
Citation Format: Bon Q. Trinh, Nicolas Barengo, Sang Bae Kim, Ju-Seog Lee, Patrick A. Zweidler-McKay, Honami Naora. Transcriptional control of inflammatory signaling in the megakaryocyte and erythroid lineages: implications for the 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 731.
Abstract 751: Secreted anterior gradient-2 is a potential tumor-microenvironment-related therapeutic target
Authors: Guo Hao , Zhu Qi , Wu Zhenghua , Mangukiya Hitesh B. , Yu Xiaoyan , Li Dawei 
Published: July 2016

Abstract
The secreted anterior gradient-2 (AGR2) orthologs in amphibians are critical signaling proteins in anterior specification and limb regeneration. It is also overexpressed in diverse human cancers especially adenocarcinomas. Although tumor-related functions of intracellular AGR2 have been intensively investigated and several AGR2-related signaling pathways have been identified, the full scope of secreted AGR2 functions, especially the exact mechanism of actions, remain insufficiently explored. Here we report that AGR2 induction after SKOV3 xenograft inoculation is tumor microenvironment (TME) dependent. This phenomenon can be mimic in vitro through serum deprivation but not hypoxia treatment. In addition, the secreted AGR2 may in turn influence the development of TME. It scatters the tumor cells and guides the nearby vascular endothelial cells and fibroblasts toward the source of AGR2 through various degrees of crosstalk with VEGF and bFGF pathways. Blocking the AGR2 inhibits the tumor growth and decreases the blood vessel density in SKOV3 xenograft model. Our results show that exogenous AGR2 binds specifically with VEGF and bFGF, and promotes their dimerization. This binding enhances the phosphorylation signals, such as ERK phosphorylation, induced by VEGF and bFGF, and promotes the VEGF- and bFGF- dependent angiogenesis. We also find that heparin may reverse the binding between bFGF and AGR2, indicating that dimerized bFGF that promoted by AGR2 would be released when it is close to the cell surface where heparin sulfate is abundant. Taken together, the present results suggest that tumor-secreted AGR2 may activate the specific growth factors surrounding the tumor cells to promote the angiogenesis and tumor growth, and also act as a short-range chemoattractant to guide surrounding vascular endothelial cells and fibroblasts toward tumor cells in building the TME. This mechanism of action directly links the secreted AGR2 with the cell signaling networks well-known in building TME. This may help to further explain how tumor cells interact with and attract nearby fibroblasts and blood vessel cells to form their microenvironment and support their growth, suggesting a potential anti-TME target.
Citation Format: Hao Guo, Qi Zhu, Zhenghua Wu, Hitesh B. Mangukiya, Xiaoyan Yu, Dawei Li. Secreted anterior gradient-2 is a potential tumor-microenvironment-related therapeutic target. [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 751.
Abstract 755: ￼Antagonistic effect of M-MDSC and N-MDSC during astrocytoma progression
Authors: Huang. Chin-NIng 
Published: July 2016

Abstract
The traditional dogma holds that tumor size has a positive correlation with tumor progression. However, on murine orthotopical astrocytoma model ALTS1C1, we found that the tumor growth is not a linear function instead a shrinkage and regrowth wave was noticed. To examine the un-characteristic tumor growth behavior, the relative relationship among tumor cells, brain resident cells, such as astrocytes and microglia, and infiltrating cells, such as monocytic (CD45+CD11b+) or lymphocytic (CD45+CD11b-) lineage cells, was analyzed by flow cytometry and immunohistochemistry (IHC). Not only tumor area, peripheral organs, including spleen, blood, and lymph nodes were also examined. The preliminary data showed that in tumor shrinkage stage, CD3+ lymphocytes increased dramatically, while CD11b+CD45low microglia decreased. Furthermore, we found that the change of two subtypes of myeloid derived suppressor cells (MDSCs), Ly6G+ neutrophilic MDSC (N-MDSC) and Ly6G- monocytic MDSC (M-MDSC), was in opposite direction during tumor progression. The increase of M-MDSCs is associated with the increase of tumor size while the N-MDSC is decreased. More interestingly, the flow cytometry data shows that the total amount of CD11b+ macrophages was constant during tumor growth phase, but IHC shows the different distribution pattern of macrophage subsets within different tumor regions (invasion tumor front vs tumor core). Currently, we are examining the dynamic change of these cells following irradiation to identify the cells that are responsive for tumor shrinkage and re-growth following radiation therapy for brain tumor. These results will be presented in the meeting.
Citation Format: Chin-NIng Huang. ￼Antagonistic effect of M-MDSC and N-MDSC during astrocytoma progression. [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 755.
Abstract 765: The manipulation of FAP expression and its role in SDF-1 and IL-6 secretion by fibroblasts and melanoma cells
Authors: Fisher Zachary B. , Miyamoto Yuko J. 
Published: July 2016

Abstract
The cancer microenvironment surrounds tumors and primarily consists of fibroblasts and immune cells that cancer cells utiliaze to support their growth and invasion. Cancer-associated fibroblasts (CAFs) are the most prominent cell type in the microenvironment. They are attracted to tumors and activated by signals from cancer cells, including transforming growth factor-â (TGF-â). Following activation, CAFs display FAP on their surface, which breaks bonds in the extracellular matrix (ECM), creating space for cancer cells to migrate. CAFs also secrete cytokines, including stromal cell-derived factor-1 (SDF-1) and interleukin-6 (IL-6), to initiate this migration. This study seeks to determine if there is a link between the expression of fibroblast activation protein (FAP) and the specific production of SDF-1 and IL-6. Flow cytometry was used to verify the expression of FAP by the Malme-3 fibroblast cell line at an average rate of 50.6% and in the Malme-3M melanoma cell line at 4.8%. TGF-â treatment increased FAP expression in Malme-3M melanoma cells (50% increase), indicating a prominent role in cell transformation. siRNA transfection was also used to reduce FAP expression in both the fibroblasts (48.4% decrease) and the melanoma cells after initial TGF-â activation (11.6% decrease). Preliminary data from intracellular staining and ELISA analysis suggest that SDF-1 and IL-6 production both increased in melanoma cells in direct correlation to FAP expression in, but may be inversely related in fibroblasts. Future studies will further analyze the FAP expression levels and cytokine secretion of both cell types in different microenvironments to elucidate the relationship between FAP expression in cancer and the secretion of SDF-1 and IL-6.
Citation Format: Zachary B. Fisher, Yuko J. Miyamoto. The manipulation of FAP expression and its role in SDF-1 and IL-6 secretion by fibroblasts and melanoma cells. [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 765.
Abstract 791: Examining the roles of deleterious and potentially damaging variant alleles in African and Caucasian ancestral populations
Authors: Gibert Myron K. , Ricks-Santi Luisel , McDonald John T. 
Published: July 2016

Abstract
The purpose of this study was to analyze the overlap between potentially damaging Single Nucleotide Polymorphisms (SNPs) for coding gene regions across African American and Caucasian populations. Allele frequency and genotype data from the International HapMap Project was acquired for ancestral groups from Utah Residents with Northern and Western European Ancestry (CEU), Yoruba in Ibadan, Nigeria (YRI) and African Americans from the Southwest (ASW) resulting in 34,844 unique variants. Using the Variant Effect Predictor, non-synonymous SNPs in overlapping transcripts were filtered and found in 12,367 unique genes. SIFT or Polyphen-2 scores were used to determine which variants were likely to prove damaging to protein function, resulting in 10,917 variants. Functional annotation of biological pathways in genes affected by these variants was analyzed using DAVID. There was enrichment in olfactory pathways/g-protein coupled receptor function, cell membrane function and epidermal growth factor activity. Comparisons of genes affected by these deleterious variants were overlapped with the catalog of published genome-wide association studies (GWAS) with SNP-traits associated with cancer. There were 90 of 463 genes in common with this data that were examined for linkage disequilibrium with the damaging variants. Finally, SNPs with a variant allele frequency differences &gt;±5% between CEU versus YRI or ASW resulted in with 2,381 SNPs with 55.7% overlap between groups. Analysis of patient genotypes found those in the CEU population were more likely to possess a homozygous allele. Using Chi-Squared tests, populations were examined for risk allele frequencies by genotype. This study demonstrated variants with potentially damaging consequences in cancer pathways are disproportionally represented in different ancestral populations.
Citation Format: Myron K. Gibert, Luisel Ricks-Santi, John T. McDonald. Examining the roles of deleterious and potentially damaging variant alleles in African and Caucasian ancestral populations. [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 791.
Abstract 805: The molecular mechanisms of obesity driving breast cancer etiology and prognosis in post-menopausal women
Authors: Heng Yu Jing Jan , Wang Jun , Hazra Aditi , Hunter David J. , Eliassen A. Heather , Tamimi Rulla M. , Hankinson Susan E. , Beck Andrew H. 
Published: July 2016

Abstract
This study aims to gain insights into the molecular mechanisms of obesity driving breast cancer etiology and prognosis as post-menopausal women with high body mass index (BMI) have increased breast cancer risk and poorer prognosis.
We examined the differential gene expression of breast tumors from 441 post-menopausal women part of the Nurses’ Health Studies. Primary analysis was performed between women with BMI of &lt;25, ≥25 to &lt;30, ≥30 to 35 and ≥35 while secondary analysis was performed using BMI as a continuous variable. Analyses were adjusted for age of diagnosis, year of diagnosis, post-menopausal hormone therapy, alcohol consumption, microarray batch and ER status.
In the primary analysis, differentially expressed genes associated with BMI were identified in pairwise analyses comparing women with BMI ≥35 with women in lower BMI categories (&lt;25 vs. ≥35, n = 58 significant genes; ≥25 to &lt;30 vs. ≥35, n = 29; ≥30 to 35 vs. ≥35, n = 12; FDR&lt;0.05); no significant genes were identified in the other pairwise comparisons. In the secondary analysis which considered BMI as a continuous value, two genes, NCOA3 and PTPN1, were significantly up-regulated in breast tumors with increasing BMI (FDR&lt;0.05). Gene set enrichment analyses suggested that tumors from post-menopausal women with increasing BMI have increased inflammation and decreased carcinogen/anti-cancer drug metabolism.
These molecular insights have further elucidated breast cancer etiology in post-menopausal women with high BMI.
Citation Format: Yu Jing Jan Heng, Jun Wang, Aditi Hazra, David J. Hunter, A. Heather Eliassen, Rulla M. Tamimi, Susan E. Hankinson, Andrew H. Beck. The molecular mechanisms of obesity driving breast cancer etiology and prognosis in post-menopausal women. [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 805.
Abstract 808: Microsatellite instability in metastatic colorectal cancer (mCRC)
Authors: KIM Jee Hung , Kim Chang-gon , Ahn Joong Bae , Jung MinKyu , Beom Seung Hoon , Kim Joo Hoon , Heo Soo Jin , Shin Sang Joon 
Published: July 2016

Abstract
Background: Although early stage colorectal cancer (CRC) with microsatellite instability (MSI) phenotype has a more favorable prognosis, impact on outcome of MSI status in metastatic CRC (mCRC) is rarely known. We aim to explore patterns of metastatic spread and prognosis of CRC with MSI-H (high-level MSI) in comparison to MSI-L (low-level of MSI)/MSS.
Methods: Patients with mCRC who underwent testing for MSI were identified using retrospective cohort of Yonsei Cancer Center. Patients were categorized to MSI status (MSI-H vs. MSS-L/MSS). Patterns of metastatic spread, surgical resection after recurrence and outcome between two groups were compared.
Results: A total of 944 patients were evaluated. Of all, 34 patients (3.6%) had MSI-H tumors. A distinct pattenrs of metastatic spread was observed in MSI-H tumors, namely higher rates of peritoneal metastasis (41% vs 10%, P &lt; 0.001), intraabdominal lymph node metastasis (14.7% vs 4.8%, P = 0.011), and lower rates of lung metastasis (8.8% vs 24.6%, P = 0.034), liver metastasis (20.6% vs 53.6%, P &lt; 0.001). Patients with MSI-H tumors were less likely to receive metastectomy (24.8% vs 55.9%, P &lt; 0.001). Median overall survival was inferior in MSI-H tumor compared with MSI-L/MSS tumor (16.3 months vs 38.1 months, P = 0.005).
Conclusions: Different patterns of metastatic spread and receipt of surgical resection in MSI-H mCRC is demonstrated in this study. In addition, MSI-H phenotype is associated with poorer survival in mCRC on the contrary to early stage disease. Future studies focusing on deeper understanding of tumor biology and therapeutic response in this rare disease entity are warranted.
Citation Format: Jee Hung KIM, Chang-gon Kim, Joong Bae Ahn, MinKyu Jung, Seung Hoon Beom, Joo Hoon Kim, Soo Jin Heo, Sang Joon Shin. Microsatellite instability in metastatic colorectal cancer (mCRC). [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 808.