bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1045: Differentiated tumor cells secrete stem cell factor (SCF) to promote maintenance of cancer stem cells and induce EMT in colorectal tumors
Authors: Fatrai Szabolcs , Schelven Susanne J. van , Rinkes Inne H.M. Borel , Kranenburg Onno 
Published: May 2015

Abstract
Colorectal tumors are hierarchically organized in which cancer stem cells (CSCs) are at the top of the hierarchy and give rise to non-tumorigenic differentiated tumor cells (DTC). The maintenance of normal intestinal stem cells requires ‘niche’ signals that are provided, at least in the small intestine, by neighboring differentiated Paneth cells. CSC maintenance may also depend on niche signals although little is known about the nature of such signals and their potential source.
For the present study we tested the hypothesis that DTCs could provide CSC-maintaining signals. We used CSC-enriched colonosphere cultures that were established from human colorectal tumors and CSC-derived stably differentiated offspring that was derived from them. We found that DTCs established from multiple colorectal tumors greatly increased the clone-forming capacity of CSCs. This effect was reproduced by DTC-conditioned medium, suggesting the involvement of a secreted factor. By using a cytokine array we identified stem cell factor (SCF) as a major DTC-secreted factor. While SCF was mainly produced by DTCs, its receptor, c-Kit, was mainly expressed by CSCs. Indeed, recombinant SCF enhanced clone-forming capacity to a similar extent as DTC-conditioned medium. Furthermore, basal and DTC-stimulated clone-forming capacity was strongly reduced in the presence of an SCF-neutralizing antibody or in the presence of the cKit inhibitors Imatinib or ISCK03. qPCR and western blot analysis showed that inhibition of cKit caused a strong reduction in the expression of stem cell genes, including LGR5, CD133, OLMF4 and SOX2. Furthermore, DTCs induce the E-to N-cadherin switch in CSCs and to a strong increase in the expression of EMT markers such as vimentin, ZEB1, ZEB2, SNAIL1 and fibronectin. cKIT inhibitors prevented EMT.
Our results identify a critical role for non-tumorigenic DTCs in the support of colorectal CSCs. DTCs induce EMT and EMT-associated stem cell characteristics at least in part via paracrine SCF-cKit signaling. We conclude that cKit inhibitors that are widely used in the clinic to treat gastrointestinal stromal tumors (GIST) and acute myeloid leukemia (AML), may have therapeutic value in the treatment of (a subgroup of) colorectal tumors.
Citation Format: Szabolcs Fatrai, Susanne J. van Schelven, Inne H.M. Borel Rinkes, Onno Kranenburg. Differentiated tumor cells secrete stem cell factor (SCF) to promote maintenance of cancer stem cells and induce EMT in colorectal tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1045. doi:10.1158/1538-7445.AM2014-1045
Abstract 1046: Molecular link between HER2 and epithelial-to-mesenchymal transition in breast cancer
Authors: Gupta Parul , Srivastava Sanjay K. 
Published: May 2015

Abstract
Breast cancer is a second most lethal form of cancer. Metastasis is responsible for about 90% of cancer- related deaths. Metastasis is a multi-step process and epithelial to mesenchymal transition (EMT) is the initiating step. HER2 is overexpressed in about 25-30% of breast cancer patients and responsible for poor prognosis. Our results show a novel role of HER2 in inducing EMT in breast cancer cells. To delineate the mechanism of EMT and role of HER2, we used MDA-MB-231, MCF-7 breast cancer cells with their syngeneic variants having stable HER2 overexpression (referred to as high HER2 or HH cells) and 4T-1 cells. The Boyden's chamber assay showed that HH cells were more invasive than the parent cells. The higher invasive potential of cells was accompanied with increased expression of mesenchymal markers like N-cadherin, along with suppression of epithelial markers like Cytokeratin-18. HER2 overexpression was also associated with enhanced expression of transcription factors like SNAIL and ZEB-1 that orchestrate the process of EMT. It is known that TGFβ is a master regulator of EMT process in cancer cells. Interestingly, HH cells exhibited higher levels of TGFβ protein and mRNA levels along with increased expression of SMADs relative to the parent cell lines. SMADs are the classical downstream effector molecules for TGFβ. Hence these results indicate that HER2 overexpression modulates TGFβ signaling to promote the process of EMT. In addition, induction of SNAIL, TGFβ and SMAD4 by heregulin treatment further established the role of HER2 in EMT process. To confirm the requirement of HER2 in the maintenance of mesenchymal traits, we silenced HER2 in MDA-MB-231 and MDA-MB-231 (HH) cells. HER2 silencing suppressed the invasion and mesenchymal markers indicating a direct connection of EMT with HER2 in breast cancer cells. Taken together our results for the first time provides a molecular evidence for the regulation of EMT by HER2 through TGFβ signaling. Further mechanistic and pre-clinical in vivo studies are under progress. [Supported in part by R01 grant CA129038 (to S.K.S) awarded by the National Cancer Institute].
Citation Format: Parul Gupta, Sanjay K. Srivastava. Molecular link between HER2 and epithelial-to-mesenchymal transition in breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1046. doi:10.1158/1538-7445.AM2014-1046
Abstract 1052: Dual role of MEK1/2 and MEK5 in the reversal of epithelial-to-mesenchymal transition
Authors: Hoang Van T. , Elliott Steven , Martin Elizabeth C. , Rhodes Lyndsay V. , Segar Henry C. , Burks Hope , Chakrabarty Suravi , Monlish Darlene , Phamduy Theresa B. , Chrisey Doug , Cavanaugh Jane E. , Flaherty Patrick , Collins-Burow Bridgette M. , Burow Matthew E. 
Published: May 2015

Abstract
The mitogen-activated protein kinase (MAPK) pathway has well-established roles in cellular processes including proliferation, differentiation, and regulation of cell fate, namely survival and apoptosis. In breast cancer, constitutive activation of the MAPK/extracellular signal-regulated kinases (ERK) pathways have been linked to chemoresistance and metastatic progression through distinct mechanisms including the activation of epithelial-to-mesenchymal transition (EMT). Our previous studies have shown that overexpression of MEK5 promotes EMT markers and induces the progression to a mesenchymal phenotype. Here, we tested the effects of a novel MEK1/2 and MEK5 inhibitor, SC-1-151, and other known MAPK signaling inhibitors (PD184,352 (MEK1/2), AZD6244 (MEK1/2), BIRB796 (p38)) on a panel of mesenchymal and highly metastatic breast cancer cell lines. While the MEK1/2 and p38 inhibitors decreased cell viability across cell lines, only the dual inhibition of MEK1/2 and MEK5 though the use of SC-1-151 demonstrated a change in cell morphology indicative of mesenchymal-to-epithelial transition (MET). Furthermore, the cells exhibited a significant decrease in migration potential following SC-1-151 treatment.
Further analysis of the effects of SC-1-151 in the triple-negative breast cancer cell lines revealed an alteration of the genes associated with EMT, notably a decrease in expression of Fra-1, a transcription factor downstream of MAPK. Immuno-compromised mice inoculated with the MDA-MD-231 cell line and treated with SC-1-151 demonstrated decreased tumor volumes compared to vehicle-treated animals at day 30 post cell injection, implicating the role of MEK inhibition on tumorigenesis. These data demonstrate the need for a better understanding of the dual role of MEK1/2 and MEK5 signaling in breast cancer, and suggest that inhibition of the MEK1/2 and MEK5 signaling pathways leads to a decrease in EMT and cell migration.
Citation Format: Van T. Hoang, Steven Elliott, Elizabeth C. Martin, Lyndsay V. Rhodes, Henry C. Segar, Hope Burks, Suravi Chakrabarty, Darlene Monlish, Theresa B. Phamduy, Doug Chrisey, Jane E. Cavanaugh, Patrick Flaherty, Bridgette M. Collins-Burow, Matthew E. Burow. Dual role of MEK1/2 and MEK5 in the reversal of epithelial-to-mesenchymal transition. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1052. doi:10.1158/1538-7445.AM2014-1052
Abstract 1057: LPA stimulates EMT of ovarian cancer cells via gip2 and gep oncogenes
Authors: Ha Ji Hee , Ward Jeremy , Dhanasekaran Danny N. 
Published: May 2015

Abstract
Ovarian cancer is currently the most fatal gynecological cancer with a 5-year survival rate of only 45%. Recent studies have identified a critical role for lysophosphatidic acid (LPA) in the genesis and the progression of ovarian cancer. In order to identify transcription factors that are induced by LPA, a commercial pathway reporter array was used. Hypoxia induced factor 1 (HIF-1α) induction was the most prominent response showing more than 150 fold transcriptional activation compared with control. LPA treatment under normoxic and hypoxic (1% O2) conditions increased HIF-1α protein level, which leads to epithelial-to-mesenchymal transition (EMT) in the ovarian cancer cell line OVCA432. We also found that stimulation of the OVCA432 cells with LPA at normoxic and hypoxic conditions led to a significant increase of the mRNA and protein expression of the EMT transcription factor Twist. Immunofluorescent imaging confirmed that Twist levels were significantly up-regulated and that Twist was translocated to the nucleus as early as 4 hours after stimulation with LPA in both a normoxic and hypoxic environment. Additionally, immunofluorescent imaging showed that expression of E-cadherin on the periphery of the cell as well as in the whole cell was greatly reduced when cells were stimulated with LPA in normoxic and hypoxic conditions. Finally, our study demonstrated that LPA-mediated induction of EMT required both gip2 and gep oncogenes. Overall, our study indicated that the downstream components regulated by oncogenic G-proteins could potentially be targeted in the future to prevent EMT in ovarian cancer.
Citation Format: Ji Hee Ha, Jeremy Ward, Danny N. Dhanasekaran. LPA stimulates EMT of ovarian cancer cells via gip2 and gep oncogenes. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1057. doi:10.1158/1538-7445.AM2014-1057
Abstract 106: A requirement for FADD and its phosphorylation for KRAS-driven oncogenesis
Authors: Bowman Brittany M. , Galban Stefanie , Hoff Benjamin A. , Heist Kevin A. , Boes Jennifer L. , Galban Craig J. , Patel Rajiv M. , Zhang Jianke , Ross Brian D. , Rehemtulla Alnawaz 
Published: May 2015

Abstract
Lung cancer accounts for 27% of all cancer deaths worldwide. 80% of these deaths are due to a specific subtype Non-small cell lung cancer (NSCLC). Almost half of all NSCLC patients carry gatekeeper mutations in the EGFR/KRAS pathway. Although KRAS mutations are the most prevalent mutations in human cancers, therapies targeting KRAS have fallen short. Tyrosine kinase inhibitors have been successful in NSCLC patients with mutant or amplified EGFR, however resistance to these inhibitors is common. Thus therapies targeting mutant KRAS or its downstream effectors are desperately needed for the treatment of NSCLC.
FAS Associated Death Domain (FADD) is a well characterized adaptor protein involved in death receptor mediated apoptosis, but more recently has been implicated in the regulation of other cellular functions such as cell cycle and proliferation. Increasing evidence suggests that it is FADD's phosphorylated state which regulates these non-apoptotic signaling pathways. We and others have previously identified phosphorylated FADD as a predictor of aggressiveness and clinical stage in lung and head and neck cancer patients, respectively.
Using non-invasive bioluminescence and µCT imaging in a Kras driven mouse model of NSCLC, we demonstrate the requirement for FADD in tumor progression. Lung-specific activation of KrasG12D and simultaneous FADD deletion resulted in reduced lung tumor burden. Furthermore lung lesions of KrasG12D FADD null mice were significantly smaller with a decrease in proliferative index. Similar findings were obtained in MEFs, where siRNA mediated Kras knockdown or the use of MEK inhibitors resulted in a Kras dependent decrease in FADD phosphorylation, decrease in cell cycle progression and cell proliferation. These data propound the phosphorylation of FADD as a downstream event of Kras signaling and demonstrate its requirement for Kras dependent neoplasia in a mouse model for NSCLC.
In summary our findings demonstrate that elevated FADD and phosphorylated FADD levels are predictive of poor survival in an animal model of NSCLC agreeing with clinical findings. Furthermore, it implicates phosphorylation of FADD downstream of KRAS activation and thus suggests FADD phosphorylation as a valid target in the treatment of NSCLC patients.
Citation Format: Brittany M. Bowman, Stefanie Galban, Benjamin A. Hoff, Kevin A. Heist, Jennifer L. Boes, Craig J. Galban, Rajiv M. Patel, Jianke Zhang, Brian D. Ross, Alnawaz Rehemtulla. A requirement for FADD and its phosphorylation for KRAS-driven oncogenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 106. doi:10.1158/1538-7445.AM2014-106
Abstract 1066: MicroRNA-125b mediated par2 activation-induced cell migration
Authors: YANG LAN 
Published: May 2015

Abstract
Backgrounds: Tumor microenvironment plays a promoting role in cancer metastasis. As important component of the microenvironment, some proteinases regulate tumorigenesis through selective activation of proteinase activated receptor 2 (PAR2). Our previous study demonstrated that overexpression of PAR2 was significantly correlated with lymphatic metastasis in colorectal cancers.
Aims: To identify whether and by what mechanisms PAR2 promotes cell migration.
Methods and Results: Activation of PAR2 with activating peptide (PAR2-AP, 100μM) dramatically increased cell migration in different cell lines which was measured by transwell assay. In addition, miR-125b was reduced at 6 and 12 hours, while the migration was observed at 12 hours after PAR2-AP treatment. Consistent with previous report, inhibitor of miR-125b dramatically prompted cell migration in A549 cells. To test whether the downregulation of miR-125b mediates PAR2-induced migration, miR-125b mimic was transfected into A549 cells to recover the reduction of miR-125b induced by PAR2 activation. It was showed that miR-125b mimic also successfully blocked PAR2-induced cell migration. Furthermore, pretreatment with 5-aza-CdR (5umol/L) for 24h dramatically prevented PAR2-induced downregulation of miR-125b in A549 cells. It suggests that methylation of miR125b promoter may be the mechanism by which PAR2 repressed the expression of miR-125b. On the other hand, the data showed that Lin28B was increased dramatically by miR-125b inhibitor, which indicated that Lin28B may be the downstream target gene of miR-125b in A549 cells. Most importantly, we found that upregulation of PAR2 and downregulation of miR-125b were significantly correlated with lymphatic metastasis in human colorectal cancer specimens.
Conclusion: Our study demonstrated that activation of PAR2 promotes cell migration through miR-125b, which may contribute to PAR2-related lymphatic metastasis in CRC.
Citation Format: LAN YANG. MicroRNA-125b mediated par2 activation-induced cell migration. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1066. doi:10.1158/1538-7445.AM2014-1066
Abstract 1069: M1 macrophages suppress tumorigenesis via accumulated p53 and upregulated STAT1 in lung cancer
Authors: Hsiao Yi-Jing , Su Kang-Yi , Chen Jian-Wei , Yu Sung-Liang 
Published: May 2015

Abstract
Purpose
Macrophages involved in innate immunity and possess cytotoxicity via NO, ROS and pro-inflammatory cytokines, such as TNF-α and IFN-γ. But long-term effects of M1 macrophages on cancer cells, especially their tumoricidal activity, remain unclear. In our previous study, conditioned medium (CM) from M1 macrophages can induce A549 apoptosis and senescence, but detail mechanism is unexplored.
Materials & Methods
Lung cancer cell lines, A549 and H460, are cells with wild-type p53, but H1299 is p53-null. Cytokine and cDNA microarray were used to evaluate the content of M1 macrophages and their effects on A549 cell. Flow cytometry was assessed cell apoptosis; real-time PCR and Western blot were assessed the expression of identified genes and proteins. Clinical statistical analysis for predicting survival of lung cancer patients was applied by a published clinical microarray dataset.
Results
According to our previous results of cDNA microarray, several significantly differential genes were the down-stream of p53, the important initiator for apoptosis. After M1 CM treatment, A549 and H460 cells went apoptosis and p53 was abundantly accumulated. But cell death was not observed in H1299 cells, unless exogenous wt-p53 was expressed and M1 CM treated. Another transcription factor STAT1 was also up-expressed at translational and transcriptional levels after M1 CM stimulation. STAT1 may interact and assist with p53 to cause cell death. IFN-γ which is a well known cytokine for STAT1 activation highly expresses in M1 macrophages, but antibody neutralization can not reverse cell apoptosis. M1 macrophages from human PBMCs also had tumoricidal activity for A549. Moreover, the M1/M2 gene signature from A549 cDNA microarray can predict the patients' survival.
Conclusion Accumulated data show that p53 and STAT1 are the main tumoricidal regulators induced by M1 macrophages in long-term culture and that is IFNs independent signaling pathway. Those data imply that M1 macrophage plays an important role in the immune surveillance for cancer progression. That may be a potential immunol target therapy.
Citation Format: Yi-Jing Hsiao, Kang-Yi Su, Jian-Wei Chen, Sung-Liang Yu. M1 macrophages suppress tumorigenesis via accumulated p53 and upregulated STAT1 in lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1069. doi:10.1158/1538-7445.AM2014-1069
Abstract 1074: Tumor-associated microglia secrete paracrine factors that promote Nf1-deficient optic glial cell growth
Authors: Solga Anne C. , Pong Winnie W. , Cimino Patrick J. , Kim Keun Y. , Walker Jason , Wylie Todd , Magrini Vincent , Rubin Joshua B. , Piwnica-Worms David , Ellisman Mark H. , Mardis Elaine R. , Gutmann David H. 
Published: May 2015

Abstract
Previous studies have demonstrated that brain tumors are composed of heterogeneous mixtures of neoplastic and non-neoplastic (stromal) brain cells. However, current brain tumor therapies are primarily focused on inhibiting the growth of the cancerous cells, largely ignoring the contribution of the surrounding stromal elements. One of these stromal cell types is an immune system-like cell (microglia), which constitutes as many as half of the cells present in human brain tumors (gliomas). The tumor microenvironment is considered to play an important role in tumor formation and maintenance by providing signals that both negatively and positively influence tumor cell growth.
Since children with the neurofibromatosis type 1 (NF1) inherited cancer syndrome are prone to the development of gliomas involving the optic nerve (optic gliomas), we have employed Nf1 genetically-engineered mice as an experimental model system to examine the role of microglia in optic glioma formation and maintenance. We leveraged RNA-sequencing data from FACS-isolated, mouse optic glioma-associated microglia to identify specific paracrine factors that are expressed in tumor-associated, but not normal, microglia. These factors were validated using RNA fluorescent in situ hybridization and investigated for their ability to increase the growth of Nf1-deficient optic nerve astroglial cells in vitro. Current studies are ongoing to determine whether (1) inhibition of microglia function in Nf1 genetically engineered mice reduces the expression of these paracrine factors and (2) inhibiting these factors attenuates optic glioma growth in vivo. Together, these studies identify a novel set of paracrine factors secreted by a key glioma-associated stromal cell type (microglia) relevant to the pathogenesis of NF1-associated tumors, raising the possibility that future therapies might be directed against tumor microenvironment paracrine factors.
Citation Format: Anne C. Solga, Winnie W. Pong, Patrick J. Cimino, Keun Y. Kim, Jason Walker, Todd Wylie, Vincent Magrini, Joshua B. Rubin, David Piwnica-Worms, Mark H. Ellisman, Elaine R. Mardis, David H. Gutmann. Tumor-associated microglia secrete paracrine factors that promote Nf1-deficient optic glial cell growth. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1074. doi:10.1158/1538-7445.AM2014-1074