bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4662: YYFZBJS ameliorates the progression of colon carcinogenesis in ApcMin/+ mice by inhibiting regulatory T-cell generation
Authors: Sui Hua , Gu Kaijuan , Ren Junze , Wen Haotian , Wang Ting , Hu Jing , Yang Liu , Ji Qing , Li Qi 
Published: August 2019

Abstract
Colorectal cancer (CRC) is the third most common solid tumor in the world and shows resistance to several immunotherapies, particularly immune checkpoint blockade which has therapeutic effects on many other types of cancer. T cell (Treg) represents one of the main populations of effector immune cells in antitumor immunity, has been considered as a double-edged sword during the progression of colon carcinogenesis. Our previous studies showed that traditional Chinese herbs had potential anticancer effects in improving the quality of life and therapeutic effect. However, little is known whether the mechanism of TCM formula is depended on the Treg-mediate innate immunity. Here, we used C57BL/6 ApcMin/+ mice, an animal model of human intestinal tumorigenesis, to investigate tumor-associated lymphocyte subsets and the mechanisms of their accumulation into gastrointestinal adenomas, and to evaluate the effects of YYFZBJS on the progression of colon carcinogenesis in vivo and in vitro. Compared to unaffected spleen, intestinal lymphatic, and mesenteric lymph nodes (MLN), accumulated CD4+CD25+ FoxP3 positive Treg cells were reduced after YYFZBJS treatment in ApcMin/+ mice. Treatment with YYFZBJS blocked tumor initiation and progression in the transgenic mouse models (ApcMin/+) with less change of body weight and survival rates. Moreover, YYFZBJS significantly reduced the expression of IL-6, IL-10, TGF-β, and other oncogenes markers such as MMP-2, MMP-9, cyclinD1 and c-Myc in Peripheral Blood and adenomatous tissue. In conclusion, we show that the Treg is involved in CRC development and progression and we identify YYFZBJS as a new potential drug target for the treatment of CRC.
Note: This abstract was not presented at the meeting.
Citation Format: Hua Sui, Kaijuan Gu, Junze Ren, Haotian Wen, Ting Wang, Jing Hu, Liu Yang, Qing Ji, Qi Li. YYFZBJS ameliorates the progression of colon carcinogenesis in ApcMin/+ mice by inhibiting regulatory T-cell generation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4662.
Abstract 4670: The molecular mechanisms of EpCAM in regulating tumor progression in colon cancer cells
Authors: Liang Kang-Hao , Tso Hsien-Cheng , Hung Shao-Hsi , Liao Mei-Ying , Wu Han-Chung 
Published: August 2019

Abstract
Epithelial cell adhesion molecule (EpCAM) is highly expressed in advanced epithelial cancers and tumor-initiating cells, but its role in cancer progression remains to be elucidated. Here, we show that the extracellular domain of EpCAM (EpEX) acts through its EGF-like domain I to bind EGFR and activates downstream ERK1/2 and AKT signaling. Inhibition or shRNA knockdown of EGFR ablated EpEX-induced ERK1/2 and AKT phosphorylation in colon cancer cells. EGFR signaling, stimulated by either EpEX or EGF, then induces regulated intramembrane proteolysis of EpCAM, releasing both EpEX and EpCAM intracellular domain (EpICD). MEK inhibitor, U0126, prevented EpEX-induced EpCAM proteolysis by ADAM17 and presenilin 2 proteases. Furthermore, EGFR inhibitor, AG1478, and MEK inhibitor, U0126, both decreased the production of EpICD, which was found to be necessary for nuclear accumulation of β-catenin protein and expression of HIF1α target genes in vitro and in mouse xenograft models. In clinical samples from colorectal carcinoma patients, high levels of nuclear EpICD predicted metastasis and poor prognosis. Importantly, we also showed that EpAb2-6, an anti-EpCAM neutralizing monoclonal antibody, inhibited EpEX-activated EGFR-PI3K-AKT signaling and induced apoptotic signaling through FOXO3a activation of HTRA2 gene expression. This antibody also inhibited the nuclear translocation of EpICD and oncogenic signaling through β-catenin. Finally, in both metastatic and orthotopic animal models of colorectal cancer, EpAb2-6 therapy exhibited an antitumor effect and markedly extended the survival time of mice. Taken together, the results demonstrate that EpEX contributes to malignancy by functioning as a growth factor, which activates EpICD-mediated signaling, thereby enhancing colon cancer cell survival. Furthermore, the data indicate that EpEX can be considered as a promising target for treatment of colon cancer.
Citation Format: Kang-Hao Liang, Hsien-Cheng Tso, Shao-Hsi Hung, Mei-Ying Liao, Han-Chung Wu. The molecular mechanisms of EpCAM in regulating tumor progression in colon cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4670.
Abstract 4677: Inhibition of 15-PGDH causes Kras-driven tumor expansion through prostaglandin E2-ALDH1 signaling in the pancreas
Authors: Ishimoto Takatsugu , Arima Kota , Uchihara Tomoyuki , Miyake Keisuke , Yonemura Atsuko , Yasuda Tadahito , Itoyama Rumi , Iwatsuki Masaaki , Baba Yoshifumi , Yoshida Naoya , Baba Hideo 
Published: August 2019

Abstract
Chronic inflammation has a crucial role in cancer development and the progression of various tumors, including pancreatic ductal adenocarcinoma (PDAC). The arachidonate cascade is a major inflammatory pathway that produces several metabolites, such as prostaglandin E2 (PGE2). 15-hydroxyprostaglandin dehydrogenase (15-PGDH) participates in the degradation of PGE2 and has attracted attention in recent years. Although inhibition of 15-PGDH is reported to lead to PGE2 accumulation and expand tissue stem cell fraction, the role for pancreatic tumor progression is still unknown. The aim of this study is to elucidate the regulatory mechanism and functional role of 15-PGDH for cancer stem-like cell expansion during tumor progression in pancreas. We found that 15-PGDH expression is frequently down-regulated in PDAC cells and significantly correlated with the number of infiltrating macrophages in human PDAC tissues. Moreover, direct co-culture assay revealed that macrophage derived interleukin-1 beta down-regulates 15-PGDH expression in PDAC cells. Furthermore, pharmacological blockade of 15-PGDH led to PGE2 accumulation, and promoted growth and sphere formation through the expansion of ALDH1-positive cells. We also elucidated the molecular mechanism that PGE2 accumulation by 15-PGDH inhibition increases CYP26A1 expression and subsequently depletes all-trans retinoic acid, and results in ALDH1 up-regulation. Finally, genetic ablation of 15-Pgdh promoted tumorigenesis in KrasLSL-G12D; Ptf1aCre/+ mice through the expansion of ALDH1-positive cells. Our findings highlight the role and significance of PGE2 degradation pathway for PDAC tumor progression.
Note: This abstract was not presented at the meeting.
Citation Format: Takatsugu Ishimoto, Kota Arima, Tomoyuki Uchihara, Keisuke Miyake, Atsuko Yonemura, Tadahito Yasuda, Rumi Itoyama, Masaaki Iwatsuki, Yoshifumi Baba, Naoya Yoshida, Hideo Baba. Inhibition of 15-PGDH causes Kras-driven tumor expansion through prostaglandin E2-ALDH1 signaling in the pancreas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4677.
Abstract 4680: KRAS activation in gastric adenocarcinoma stimulates epithelial-to-mesenchymal transition to cancer stem-like cells and promotes metastasis
Authors: Yoon Changhwan , Till Jacob , Cho Soo-Jeong , Chang Kevin , Lin Jian-Xian , Ryeom Sandra , Yoon Sam 
Published: August 2019

Abstract
BACKGROUND:
Our previous work showed that in a mouse model of gastric adenocarcinoma (GA) with loss of p53 and Cdh1 that adding oncogenic Kras (a.k.a triple conditional or Tcon mice) accelerates tumorigenesis and metastasis. The Receptor Tyrosine Kinase (RTK)-RAS signaling pathway is altered in 60% of GAs, and KRAS is amplified or mutated in 17% of GAs. There is some evidence that RTK-RAS signaling and oncogenic KRAS are important in the epithelial-to-mesenchymal transition (EMT) and maintenance of cancer stem-like cells (CSCs). We hypothesized that RTK-RAS activation in GA CSCs increases the metastatic potential of these cells.
METHODS:
The RTK-RAS pathway and KRAS were examined in nontransformed HFE-145 gastric epithelial cells, tumor-derived organoids derived from Tcon mice, human GA cell lines (AGS and KATOIII), AGS xenografts, and a tissue microarray of human GAs from 115 patients undergoing surgical resection. KRAS was inhibited using shRNA, and the RTK-RAS pathway was blocked using a MEK inhibitor PD0325901.
RESULTS:
Kras activity was much higher in GA cell lines grown as spheroids compared to GA cell lines grown monolayers. Metastasis following KRAS activation in GA cells results from stimulation of epithelial-to-mesenchymal transition (EMT) to cancer stem-like cells (CSCs). In organoids derived from our mouse model, Kras knockdown decreased spheroid formation, expression of EMT-related proteins, migration, and invasion; similar effects, as well as reversal of chemoresistance, were observed following KRAS knockdown in patient tumor-derived GA cell lines. KRAS inhibition in GA spheroid cells led to reduced flank xenograft growth, loss of the infiltrative tumor border, fewer lung metastases, and increased survival. Supporting clinical relevance, high tumor levels of CD44 (a marker of CSCs) and KRAS activation were independent predictors of worse overall survival in 115 GA patients.
CONCLUSION:
In this study, we show that the addition of oncogenic KRAS into gastric epithelial cells leads to EMT and acquisition of CSC phenotypes. Inhibition of KRAS in GA cell lines and in tumor derived organoids reverses EMT and inhibit CSC phenotypes. We conclude that metastasis following KRAS activation in GA cells likely results from stimulation of EMT and transition to CSCs.
Citation Format: Changhwan Yoon, Jacob Till, Soo-Jeong Cho, Kevin Chang, Jian-Xian Lin, Sandra Ryeom, Sam Yoon. KRAS activation in gastric adenocarcinoma stimulates epithelial-to-mesenchymal transition to cancer stem-like cells and promotes metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4680.
Abstract 4682: TGFB signaling disruption in the formation of oral pre-neoplasia
Authors: Andl Claudia D. , Means Anna L. , Lewis James S. , Rothaus Alexandra , Andl Thomas 
Published: August 2019

Abstract
In humans, tissue homeostasis has to be maintained for decades without significant loss of functionality. Epithelia such as the oral mucosa achieve this through the self-renewing capabilities of stem cells. These life-long residents of the oral mucosa maintain homeostasis of the epithelium and at the same time have to be able to protect themselves from the main threats to longevity, i.e., stem cell exhaustion and malignant conversion and carcinogenesis. A key pathway in mediating cell cycle arrest in oral keratinocytes is mediated by TGFB superfamily signaling. There is good evidence implicating TGFB signaling as a tumor suppressor pathway in oral cancer. We have previously shown that disruption of TGFB signaling and cell adhesion can lead to oral squamous cell carcinoma. In vitro using oral keratinocytes, we found that TGFB regulates the stem cell compartment, inducing gene expression of quiescent stem cell markers MECP2, XPC, ITGB1 and PDPN. Using multiplex immunofluorescence, we have stained a tissue microarray containing 28 cases of squamous cell carcinoma, 4 adenocarcinoma, 4 metastatic carcinoma, 6 hyperplasia, and 5 adjacent inflammatory as well as normal adjacent and normal tissues. The antibodies selected were MECP2, XPC, ITGB1 and K15 in combination with the proliferation marker ki67 to determine if TGFB signaling regulates markers of stem cell quiescence. This quiescent gene signature highlighted a basal niche for slow-cycling cells, reserve stem cells. During oral disease progression, marker expression was abandoned in favor of increased proliferation. In vivo, a mouse model in which KrasG12D expression was induced and the Smad4 gene deleted specifically in the adult epithelium showed invasive cancers in the oral cavity. These Smad4-negative tumors express Sox9, a marker of human OSCCs and a TGFB target, which we have also observed to be upregulated in human premalignant lesions. Sox9-positive areas in the mouse tumors are associated with a downregulation of quiescent oral stem cell markers Krt15 and Mecp2, same as we observed in immunostainings of human tissues. In conclusion, TGFB and SMAD4 regulate quiescent stem cells and loss of this pathways allows invasive cancers to develop in the setting of oncogene expression. Furthermore, we could show that MECP2 in combination with other markers identifies quiescent basal cells in the human oral mucosa and is lost as TGFB signaling is disrupted in tumorigenesis.
Citation Format: Claudia D. Andl, Anna L. Means, James S. Lewis, Alexandra Rothaus, Thomas Andl. TGFB signaling disruption in the formation of oral pre-neoplasia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4682.
Abstract 4683: Targeting GPCR signaling in HER2+ breast cancer suppresses cancer stem cell tumorigenicity and sensitizes HER2-targeted therapies
Authors: Wang Wei , Bhargava Dharmendra , Ye Yuan Chao , Chen Songhai 
Published: August 2019

Abstract
G protein coupled receptors (GPCRs) are the largest family of cell surface receptors with over 800 members. Aberrant activation of GPCRs has been implicated in cancer initiation and development. However, many of GPCRs are overexpressed in cancer cells, making it difficult to target individual GPCRs for cancer treatment. In this study, we have tested a new approach of targeting GPCRs in HER2+ breast cancer by blocking their common pathways downstream of G proteins. By mammary gland-specific expression of the pertussis toxin (PTx) catalytic subunit, a selective inhibitor that uncouples a subgroup of GPCRs from activating Gi/o proteins, we demonstrated that blocking GPCR downstream signaling delayed the onset of HER2-driven spontaneous mammary tumor formation and suppressed lung metastasis. Moreover, we showed that aberrant HER2 signaling upregulated Gi/o-GPCR expression in breast cancer cells, which in turn activated the ErbB/HER family of protein-tyrosine kinases via Src and PI3K pathways to maintain cancer stem cell tumorigenicity. Targeting Gi/o-GPCR signaling by PTx, Src or PI3K inhibitors sensitizes HER2+ breast cancer to HER2-targeted therapies. Together, our data demonstrate that targeting GPCR downstream signal pathways may represent a new approach to ablate CSCs to block tumor progression and augment HER2-targeted therapeutics.
Citation Format: Wei Wang, Dharmendra Bhargava, Yuan Chao Ye, Songhai Chen. Targeting GPCR signaling in HER2+ breast cancer suppresses cancer stem cell tumorigenicity and sensitizes HER2-targeted therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4683.
Abstract 4686: Stem-like cells and bulk cells in breast cell lines express distinct combinations of Eph receptors and ephrin ligands
Authors: Lucero Mariana , Thind Jaspreet , Senaati Shayan , Jimenez Belinda , Zadeh Tanin , Kandpal Raj P. 
Published: August 2019

Abstract
Purpose: The maintenance of the breast cancer stem cell niche in mammary tumors has been attributed to aberrant expression of Eph receptors and ephrin ligands. The current study aims to identify Eph receptors and ephrin ligands that may contribute to the tumorigenic and invasive breast cancer phenotypes, and can potentially be used to classify tumor specific stem cells and target them for therapeutic intervention.
Methods: The bulk cells and stem-like cells from MCF10A, MCF7 and MDA-MB-231 cell lines were separated based on CD44+/CD24+ and CD44+/CD24- combinations of cell surface markers, respectively. These cell lines represent non-tumorigenic breast epithelium (MCF10A), non-invasive breast carcinoma (MCF7), and invasive triple negative breast carcinoma (MDA-MB-231). The profiles of Eph receptors and ephrin ligands were determined by qPCR. The changes in selected transcripts were confirmed by immunocytochemistry and western blot analysis.
Results: Our study revealed that Eph receptors and ephrin ligands have distinct expression signatures in CD44+/CD24- tumor-initiating cells relative to the bulk tumor cell population. Such combinatorial expression of these molecules in stem cells and bulk cells may modulate and maintain breast tumor phenotypes. The differential patterns of expression are evidenced by changes in qualitative as well as quantitative combinations of Eph receptors and ephrin ligands. The levels of EphA8 transcript were notably lower in CD44+/CD24- cells as compared to bulk MCF7 cells. However, EphA8 was significantly upregulated in stem cells as compared to bulk cells isolated from MDA-MB-231 cell line.
Conclusion: The relative abundance of Eph receptors and ephrin ligands in stem and bulk cells provides molecular signatures of stem cells specific to tumor phenotypes. The combinatorial expression of these molecules corresponds to invasiveness of breast cancer cells, which can be potentially exploited for diagnostics and therapeutics.
Citation Format: Mariana Lucero, Jaspreet Thind, Shayan Senaati, Belinda Jimenez, Tanin Zadeh, Raj P. Kandpal. Stem-like cells and bulk cells in breast cell lines express distinct combinations of Eph receptors and ephrin ligands [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4686.
Abstract 47: Analyzing immune cell infiltration of cancer spheroids in a 3D cell culture platform
Authors: Lim Sei Hien , Kuan Chee Mun , Campisi Marco , Chiono Valeria , Pavesi Andrea 
Published: August 2019

Abstract
The adoption of in vitro 3D cell culture models as a bridge between conventional 2D cell culture models and the complex in vivo animal models has been increasing. A carefully designed 3D model can run biological assays with animal model-like complexities but with the simplicity and affordability of traditional cell culture. For example, traditional 2D and transwell assays of immune cell infiltration efficiency are unrealistic, as cell migration is gravity-driven. AIM 3D cell culture chips offer a more realistic immune cell infiltration model by compartmentalizing immune cells and cancer spheroids in parallel channels. The chips consist of a 3D hydrogel channel and two flanking media channels. Cancer spheroids are cultured within the hydrogel channel while immune cells are seeded in one of the media channels. The seeded immune cells are required to actively invade and seek out target cancer cells in 3D hydrogel in AIM chips before they can infiltrate the cancer spheroids. This is a process similar to immune cell infiltration in vivo. By utilizing high content confocal imaging, fluorescent-labeled immune cells that migrate into the 3D hydrogel can be visualized and quantified. This assay, in combination with adoptive T cell therapy or immune checkpoint blockade, can determine the roles of tumor infiltrated lymphocytes in immunotherapy through quantifying the live: dead ratio of cancer spheroids in the chips. This is particularly useful as a quality control tool for cellular adoptive immunotherapy where the infiltration efficiency and tumoricidal activity of engineered immune cells can be accessed in vitro. In summary, AIM 3D cell culture chips create a more physiologically relevant 3D microenvironment for visualizing immune cell infiltration of cancer spheroids.
Citation Format: Sei Hien Lim, Chee Mun Kuan, Marco Campisi, Valeria Chiono, Andrea Pavesi. Analyzing immune cell infiltration of cancer spheroids in a 3D cell culture platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 47.
Abstract 471: Tumor clonal status predicts clinical outcomes of non-small-cell lung cancer
Authors: Kim Eun Young , Lee Sanghoon , Kim Arum , Kim Tae Hee , Chang Yoon Soo 
Published: August 2019

Abstract
Background: Intratumoral heterogeneity is a major cause of resistance to therapeutic agents and treatment failure. In this study, we evaluated clonal status, which reflects intratumoral heterogeneity, in non-small-cell lung cancer (NSCLC) and we discussed its clinical implications.
Materials and Methods: Targeted sequencing was performed using a customized panel comprising 70 solid tumor-associated genes on samples obtained from 99 lung adenocarcinoma cases. In parallel, TCGA-LUAD cases with clinical information were extracted from the GDC data portal for validation. Clonal status was identified from the allele frequency of the mutated gene using the Maftools package.
Results: We found no significant relationships with stage between the total number of mutations or the number of variants when classified according to the variant effect predictor. There was a positive correlation between the maximum primary tumor diameter and the number of clones (σ=0.2318, P-value = 0.0339). Additionally, the number of clones increased with stage (p-value= 0.0220, Kruskal-Wallis chi-squared test). Disease-free survival (DFS) was significantly shorter among cases wherein tumors comprised two or more clones than among cases in which tumors were comprised of only one clone (P-value = 0.008, Log-rank test). A multivariate model that controlled for total number of mutations, tumor stage, sex, age, and smoking indicated that the number of clones was an independent determinant of DFS.
Conclusions: Number of clones comprising the primary lesion was positively correlated with tumor size and stage, and was an independent factor affecting clinical outcome, indicating that a description of tumor clonality may be required for next-generation sequencing.
Citation Format: Eun Young Kim, Sanghoon Lee, Arum Kim, Tae Hee Kim, Yoon Soo Chang. Tumor clonal status predicts clinical outcomes of non-small-cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 471.