bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3351: NF-κB signaling between stromal macrophages and breast cancer cells
Authors: Bradford Jennifer W. 
Published: August 2015

Abstract
It has become increasingly clear that the tumor microenvironment directly interacts with tumor cells to promote tumor growth and progression. Tumor associated macrophages (TAMs) have emerged as key components of the tumor microenvironment, and their presence in breast cancer is associated with poor prognosis. There is evidence that nuclear factor -kappaB (NF-κB) is an important signaling pathway between cancer cells and the stromal compartment. Disruption of NF-κB communication between TAMs and breast tumors may weaken the pro-tumorigenic influences of TAMs, and therefore make the tumor more susceptible to standard treatments.
Our work reveals that when breast cancer cells and bone marrow derived macrophages (BMDMs) are co-cultured in transwell plates, activated canonical NF-κB and STAT3 levels dramatically increase in both cell types. This signaling interaction was confirmed by co-culturing human blood derived macrophages with breast cancer cells. BMDMs co-cultured with breast cancer cells acquire a mixed M1/M2 activation phenotype, and also have skewed inflammatory cytokine production. In basal-like mouse tumors, active NF-κB levels are much higher in the CD11b+ (TAM) fraction compared to the CD11b- fraction. Even more so than BMDMs, TAMs isolated from mouse basal-like tumors have high NF-κB activity, and can promote elevated NF-κB and STAT3 activation and cytokine production in breast cancer cells when co-cultured in transwell plates. BMDMs genetically lacking p65 have altered inflammatory cytokine production when compared to wild type BMDMs, which remains skewed when the cells are co-cultured with breast cancer cells. Because the NF-κB pathway can be targeted therapeutically, understanding how NF-κB activation influences breast tumor-TAM communication is important for developing new treatment options for aggressive cancers.
Citation Format: Jennifer W. Bradford. NF-κB signaling between stromal macrophages and breast 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 3351. doi:10.1158/1538-7445.AM2015-3351
Abstract 3364: Epithelial-mesenchymal transition is associated with a profound inflammatory tumor microenvironment in lung adenocarcinoma
Authors: Lou Yanyan , Diao Lixia , Roger Parra Cuentas Edwin , Denning Warren L. , Chen Limo , Fan Youhong , Rodriguez Jaime , Byers Lauren , Wang Jing , Papadimitrakopoulou Vassiliki , Carmen Behrens , Wistuba Ignacio I. , Hwu Patrick , Heymach John V. , Gibbons Don L. 
Published: August 2015

Abstract
Promising results in the treatment of non-small cell lung cancer (NSCLC) have been seen with immunomodulatory agents targeting immune checkpoints, such as programmed cell death 1 (PD-1) or programmed cell death 1 ligand (PD-L1). However, only a select group of patients respond to these interventions. The identification of biomarkers that predict clinical benefit to immune-based approaches, such as immune checkpoint blockade, is critical to successful translation of these agents. By using integrated gene array analysis in three large independent NSCLC patient datasets along with immunohistochemistry study (IHC), reverse phase protein array (RPPA) and in vivo animal study, we demonstrated that epithelial-mesenchymal transition (EMT) is highly associated with a profound inflammatory tumor microenvironment in lung adenocarcinoma. Our data revealed immune activation and simultaneous development of multiple immune suppressive mechanisms, including elevation of immune checkpoints such as PD-L1, PD-L2, PD-1, TIM-3, BTLA and CTLA-4, as well as an increase in tumor infiltrating CD4+Foxp3+ regulatory T cells, IL-6 and indoleamine 2,3-dioxygenase (IDO) in lung adenocarcinomas with a mesenchymal phenotype. Our data suggested that EMT might represent a potential biomarker to select the patients who will benefit from immune checkpoint blockade agents and other immunotherapies in NSCLC and possibly other cancers.
Note: This abstract was not presented at the meeting.
Citation Format: Yanyan Lou, Lixia Diao, Parra Cuentas Edwin Roger, Warren L. Denning, Limo Chen, Youhong Fan, Jaime Rodriguez, Lauren Byers, Jing Wang, Vassiliki Papadimitrakopoulou, Behrens Carmen, Ignacio I. Wistuba, Patrick Hwu, John V. Heymach, Don L. Gibbons. Epithelial-mesenchymal transition is associated with a profound inflammatory tumor microenvironment in lung adenocarcinoma. [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 3364. doi:10.1158/1538-7445.AM2015-3364
Abstract 3371: Periostin secreted by breast cancer cells inhibits macrophage phagocytosis and adhesion to fibronectin
Authors: Coleman Michelle M. , Helms Rachel S. , Dreau Didier 
Published: August 2015

Abstract
Interactions between cancer cells and immune cells are critical to the development of breast cancer metastases. We have previously shown that breast cancer cells secrete periostin, an extracellular matrix protein implicated in tumor progression. Here we evaluated 1) the effect of macrophage secretions on 4T1 breast cancer cell production of periostin and 2) the effect of periostin on key macrophage functions. In vitro, periostin secretion by highly metastastic 4T1 mammary cancer cells was investigated by ELISA. Following a 48-hour incubation with conditioned media obtained from J774A-1 monocyte cells, 4T1 cells secreted significantly higher periostin concentrations (p&lt;0.05). Next, the effect of prolonged incubation with periostin on proliferation, adhesion and phagocytosis of macrophages was investigated using mouse J774A-1 and RAW264.7 monocyte cells and mouse primary bone marrow macrophages. In the conditions tested, periostin did not affect macrophage proliferation. Incubation with periostin significantly decreased macrophage adhesion to fibronectin-coated vessels (p&lt;0.05). Incubation with periostin also significantly inhibited macrophage phagocytosis of polymer beads (p&lt;0.05). Together, these observations indicate that the secretion of periostin by 4T1 cells is, in part, stimulated through paracrine communication with macrophages, and that periostin inhibits both macrophage adhesion and phagocytosis.
Citation Format: Michelle M. Coleman, Rachel S. Helms, Didier Dreau. Periostin secreted by breast cancer cells inhibits macrophage phagocytosis and adhesion to fibronectin. [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 3371. doi:10.1158/1538-7445.AM2015-3371
Abstract 3374: Prostate cancer bone metastases acquire resistance to androgen deprivation via WNT5A-mediated BMP6 induction
Authors: Lee Geun Taek , Kwon Seok Joo , Kim Isaac Yi 
Published: August 2015

Abstract
Prostate cancer (CaP) is the second leading cause of cancer death in American men. Traditional androgen ablation is a first-line therapy in relapsed or metastatic prostate cancer cases, but it is eventually rendered ineffective by the development of castration-resistant prostate cancer (CRPC). Once CRPC develops, treament options include taxol-based chemotherapy and second-line hormonal agents, but these have limited effectiveness. In the present study, we have investigated the role of Bone Morphogenetic Protein-6 (BMP6) in the development of castration resistant prostate cancer (CRPC) in the context of bone metastases. We initially investigated the clinical course of 158 men with advanced CaP who were treated with primary androgen deprivation therapy. To elucidate the underlying mechanism of CRPC in the context of bone metastases, we examined the impact of bone stromal cells on CaP in the absence of androgens using a co-culture model.
In these patients, we found that the median time to PSA progression was significantly shorter when bone metastases were present (14 months [95% CI, 10.2-17.8 months] vs. 57 months [95% CI, 19.4-94.6 months]). These results suggest that bone-tumor interactions may accelerate castration resistance. Mechanistically, gene expression analysis using quantitative polymerase chain reaction (Q-PCR) arrays showed a dramatic induction of BMP6 by CaP cell lines in the presence of bone stromal cells. Further studies revealed that WNT5A derived from bone stromal cells induced the expression of BMP6 by CaP cells; BMP6 in turn stimulated cellular proliferation of CaP cells in an androgen-deprived media via a physical interaction between Smad5 and β-catenin. Intracellularly, WNT5A increased BMP6 expression via PKC/NF-κB pathway in CaP cell lines. Taken together, these observations suggest that bone-CaP interaction leads to castration resistance via WNT5A/BMP6 loop. We have herein demonstrated that the bone-CaP interaction promotes resistance to androgen deprivation. At the cellular and molecular level, this castration-resistance is mediated by bone stroma-derived WNT5A that leads to the induction of BMP6; BMP6, in turn, permits CaP cells to proliferate in the absence of androgens by interacting with β-catenin. Targeting WNT5A/BMP6/β-catenin may be a viable therapeutic option in men with CaP skeletal metastases and CRPC.
Citation Format: Geun Taek Lee, Seok Joo Kwon, Isaac Yi Kim. Prostate cancer bone metastases acquire resistance to androgen deprivation via WNT5A-mediated BMP6 induction. [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 3374. doi:10.1158/1538-7445.AM2015-3374
Abstract 3399: Using protein chips to develop a highly specific HER2 antibody for HER2 amplification testing
Authors: Zhou Lixin , Yuan Kehu , Ren Fangfang , Qi Lili , Li Zhongwu , Wu Guiyin , Huang Xiaozheng , Shen Yi , Zhao Min , Fu Wei , Liu Huibo , Chu Boyang , Wang Guangli , Shu Youmin , Ma Donghui , He Wei-Wu , Chen Jian 
Published: August 2015

Abstract
Human epidermal growth factor receptor 2 (HER2) is an orphan receptor tyrosine kinase member of the EGFR families and is found to be a key tumor driver gene. In breast cancer and gastric cancer, HER2 amplification can be effectively treated by its neutralizing antibody, trastuzumab. In clinic, the HER2 immunohistochemistry (IHC) was used as the primary screening method to diagnose HER2 amplification. However, recent evidence suggested that the frequently used rabbit HER2 antibody 4B5 cross reacted to another family member HER4. IHC staining also indicated that it has strong non-specific cytoplasmic and nucleus staining in normal gastric mucosal cells and some gastric cancer samples. Using a protein lysate array which covers 85% of the human proteome, we have successfully identified and confirmed that the 4B5 bound to HER4 and a nuclear protein ZSCAN18 besides HER2. The non-specific binding accounts for the unexpected cytoplasmic and unclear staining of 4B5 on normal gastric epithelium. Finally, we have developed a novel HER2 mouse monoclonal antibody UMAB36 with similar sensitivity to 4B5 but only reacted to HER2 across the 17,000 proteins on the protein chip. In 129 breast cancer and 158 gastric cancer samples, UMAB36 showed 100% sensitivity and specificity comparing to the HER2 FISH reference results with no unspecific staining in the gastric mucosa layer. UMAB36 could provide an alternative high specific IHC reagent for HER2 amplification testing in gastric cancer population.
Citation Format: Lixin Zhou, Kehu Yuan, Fangfang Ren, Lili Qi, Zhongwu Li, Guiyin Wu, Xiaozheng Huang, Yi Shen, Min Zhao, Wei Fu, Huibo Liu, Boyang Chu, Guangli Wang, Youmin Shu, Donghui Ma, Wei-Wu He, Jian Chen. Using protein chips to develop a highly specific HER2 antibody for HER2 amplification testing. [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 3399. doi:10.1158/1538-7445.AM2015-3399
Abstract 3406: Enhancer of zeste homolog 2 (EZH2) expression and proliferation index (Ki-67) in neuroendocrine tumors of the gastrointestinal tract and pancreas
Authors: Qin Jia , Agrawal Raag , Echevarria Miguel G. , Martello LAura A. , Haseeb M.A , Gupta Raavi 
Published: August 2015

Abstract
EZH2 is a polycomb group protein that is involved in the progression of multiple human cancers including prostatic, endometrial, and colonic adenocarcinomas. Its expression has been shown to increase from typical carcinoid to atypical carcinoid and further to small cell/large cell neuroendocrine carcinomas of the lung. Here we examine the EZH2 expression and the proliferation index (PI) by Ki-67 expression in neuroendocrine tumors of the gastrointestinal tract (GI) and pancreas.
We retrieved 72 cases of GI and pancreatic neuroendocrine tumors of grades G1 (n = 56), G2 (n = 6) and G3 (n = 10) which were graded according to the WHO classification. Expression of EZH2 and Ki-67 was analyzed by immunohistochemistry using monoclonal antibodies (EZH2 at 1:200; Ki-67 at 1:70). Expression of EZH2 was determined to be low (10%), and was compared with the respective PI.
All G1 tumors had low EZH2 expression and a low PI (20%). In G2 tumors, EZH2 expression was intermediate (1-10%) and PI was between 0-8%. One of the G2 tumors had a low PI of 0, however, the EZH2 expression was intermediate (3%). There was increased EZH2 expression relative to increasing tumor grade from G1 to G3 (p &lt;0.05).
EZH2 expression increases incrementally from G1 neuroendocrine tumors to G2 and further to G3 tumors, suggesting an association or a role in progression of neuroendocrine tumors. There is strong correlation between the expression of EZH2 and PI in G1, G2 and G3 tumors. EZH2 appears to be a better predictor of tumor grade in G2 tumors as compared to PI. Thus, EZH2 could be used as an additional diagnostic marker in examining atypical GI neuroendocrine tumors.
Citation Format: Jia Qin, Raag Agrawal, Miguel G. Echevarria, LAura A. Martello, M.A Haseeb, Raavi Gupta. Enhancer of zeste homolog 2 (EZH2) expression and proliferation index (Ki-67) in neuroendocrine tumors of the gastrointestinal tract and pancreas. [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 3406. doi:10.1158/1538-7445.AM2015-3406
Abstract 3408: Nedd4-1 is an exceptional prognostic biomarker for gastric cardia adenocarcinoma and functionally associated with metastasis
Authors: Sun Aiqin , Yu Guanzhen , Dou Xiaoyan , Yan Xiaowei , Yang Wannian , Lin Qiong 
Published: August 2015

Abstract
Background: Gastric cardia adenocarcinoma (GCA) is the most aggressive subtype of gastric carcinoma. New molecular markers and therapeutic targets are needed for diagnosis, prognosis and treatment of GCA. This study is to establish the E3 ubiquitin ligase Nedd4-1 as a prognostic biomarker to predict the survival and guide the treatment of GCA patients.
Methods: Expression of Nedd4-1 in 214 GCA tumor samples was detected by immunohistochemistry staining (IHC) using tissue microarray assay (TMA). Association of Nedd4-1 with cumulative survival of the TNM stages I-III patients and clinicopathological characteristics was statistically analyzed. The role of Nedd4-1 in gastric cancer cell migration and invasion were determined by transwell and wound healing assays.
Results: Nedd4-1 is overexpressed in 83% of the GCA tumors. The 5-year survival rate in Nedd4-1 negative GCA patients is as high as 96%. Log-rank analysis indicated that overexpression of Nedd4-1 is inversely correlated with cumulative survival (χ2 = 21.885, p&lt;0.001). Multivariate logistic regression analysis showed that overexpression of Nedd4-1 is associated with an extremely low GCA survival rate with a hazard ratio (HR) = 0.068 (p = 0.008) in TNM stages I-III patients. Statistical analysis of association of Nedd4-1 overexpression with clinicopathological characteristics revealed that overexpression of Nedd4-1 is tightly associated with TNM stage (p&lt;0.001). Knockdown of Nedd4-1 in gastric cancer cell lines AGS and N87 dramatically inhibited the gastric cancer cell migration and invasion.
Conclusions: Our results indicate that Nedd4-1 is an exceptional prognostic biomarker for GCA and suggest that Nedd4-1 may play an essential role in GCA metastasis.
Citation Format: Aiqin Sun, Guanzhen Yu, Xiaoyan Dou, Xiaowei Yan, Wannian Yang, Qiong Lin. Nedd4-1 is an exceptional prognostic biomarker for gastric cardia adenocarcinoma and functionally associated with metastasis. [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 3408. doi:10.1158/1538-7445.AM2015-3408
Abstract 3410: Onodera's prognostic nutritional Index predicts survival in patients with unresectable advanced or recurrent colorectal cancer
Authors: Ikeya Tetsuro 
Published: August 2015

Abstract
Background: Nutrition and immunity significantly affect the progression of cancer in cancer patients. Therefore, the evaluation of the nutritional and immune status would be useful as a prognostic factor and to determine the optimal treatment strategy for patients with unresectable metastatic colorectal cancer who are receiving chemotherapy. The aim of this retrospective study was to evaluate the prognostic significance of the nutritional and immune status in patients with unresectable metastatic colorectal cancer treated with chemotherapy. Methods: We retrospectively reviewed 80 patients with colorectal cancer. A total of 22 patients had metachronous unresectable cancer and 58 patients had synchronous unresectable cancer. All patients underwent combination chemotherapy with oxaliplatin or irinotecan plus 5-fluorouracil/leucovorin as first-line chemotherapy for unresectable metastatic colorectal cancer. We then examined the correlations between the Onodera's Prognostic Nutritional Index (OPNI) and the patients’ clinicopathological features. The OPNI was calculated as follows: 10 × serum albumin (g/dl) + 0.005 × total lymphocyte count (per mm3). According to the receiver operating characteristic (ROC) curve analysis, the cut-off value for OPNI was 44.5. Results: Patients with a pretreatment OPNI of ≧44.5 demonstrated a longer OS than those with a pretreatment OPNI of &lt;44.5. Moreover, we categorized these patients into four groups according to the combination of the pre- and post-treatment OPNI. The patients in the group with both OPNIs ≥ 44.5 exhibited a better prognosis compared to the other group (p = 0.001). Conclusion: The OPNI is considered to be a useful marker for predicting the long-term outcome in patients who receive chemotherapy for unresectable metastatic colorectal cancer.
Citation Format: Tetsuro Ikeya. Onodera's prognostic nutritional Index predicts survival in patients with unresectable advanced or recurrent colorectal 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 3410. doi:10.1158/1538-7445.AM2015-3410
Abstract 3425: Overexpression of TRIM44 contributes to malignant outcome in upper GI tract cancer
Authors: Kawaguchi Tsutomu 
Published: August 2015

Abstract
Recent studies have shown that some members of the tripartite motif-containing protein (TRIM) family, which function as important regulators for carcinogenesis. In this study, we tested whether TRIM44 (11p13) acts as a cancer-promoting gene through overexpression in gastric cancer (GC) and esophageal squamous cell carcinoma (ESCC). We analyzed 7 GC and 14 ESCC cell lines for in vitro analysis. We also analyzed 113 GC and 68 ESCC primary tumors, which were curatively resected in our hospital between 1998 and 2008. As the results, expression of the TRIM44 protein was detected in GC and ESCC cell lines (2/7 cell lines; 29% and 8/14; 57%, respectively) and primary tumor samples of GC and ESCC (24/113 cases; 24% and 39/68; 57%, respectively). Knockdown of TRIM44 expression using several specific siRNAs inhibited cell proliferation and migration and invasion in TRIM44-overexpressing GC cell, and inhibited cell migration and invasion in TRIM44-overexpressing ESCC. Using immunohistochemical analysis, overexpression of the TRIM44 was significantly correlated with an advanced type of macroscopic appearance, lymphatic invasion, and higher recurrence rate in GC, and with the status of the lymph node metastasis in ESCC. TRIM44-overexpressing tumors had a worse overall rate of survival than those with non-expressing tumors in GC and ESCC tumors. Moreover, TRIM44 positivity was independently associated with worse outcome in multivariate analysis in GC tumors. These findings suggest that TRIM44 plays a crucial role in tumor progress through its overexpression, and highlight its usefulness as a novel predictor and potential therapeutic target in GC and ESCC.
Citation Format: Tsutomu Kawaguchi. Overexpression of TRIM44 contributes to malignant outcome in upper GI tract 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 3425. doi:10.1158/1538-7445.AM2015-3425