bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1153: Stromal FoxM1 and p53 in lung cancer as mediators of tumor progression, metastatic spread and chemo-resistance
Authors: Kamer Iris , Daniel Inbal , Perry Gili , Onn Amir , Bar Jair 
Published: May 2015

Abstract
Introduction:
Insight into the processes of tumor initiation and progression as well as metastatic spread and response to therapies requires studies that take into consideration the stromal and epithelial components of tumors. Both FoxM1 and p53 have a major role in the progression, metastasis and chemo-resistance of non-small cell lung cancer (NSCLC). p53 is a well-recognized tumor-suppressor gene, commonly mutated in NSCLC and correlated with tumor aggressiveness. An anti-tumor role of p53 in the stroma has been demonstrated by us and others. p53 is reported to suppress FoxM1 transcription. FoxM1 is an oncogene, contributing to lung cancer progression and metastatic spread. Little is known about the role of FoxM1 in cancer's micro-environment. We hypothesized that tumor-induced-downregulation of p53 and upregulation of FoxM1 in the stromal compartments promotes lung cancer progression, metastatic spread and chemo-resistance.
Materials and Methods:
Cancer associated fibroblasts (CAFs) and normal fibroblasts (NFs) were produced from fresh lung tumor specimens. Cell lines and primary cells were grown in standard tissue culture conditions. Co-cultures were performed using transwell culture systems. DNA damage was induced by cisplatin treatment. Expression levels of mRNA and proteins were tested by real-time RT-PCR and western blots.
Results:
We have found FoxM1 levels to be higher in primary lung CAFs compared to NFs. In addition, CAFs that were treated with conditioned media of transformed epithelial cells showed down-regulation of stromal-p53 and up-regulation of FoxM1, in DNA damage conditions. mRNA levels of FoxM1 remain stable. While cancer-cells-CM up-regulate FoxM1 in CAFs, it was found to down-regulates it in NFs, suggesting both cancer and CAFs have evolved a unique mechanism of FoxM1 induction in stroma.
In order to examine a possible paracrine effect between p53 levels in the stroma, and FoxM1 levels in tumor cells, we co-cultivated fibroblasts knocked-down for p53 with lung cancer cells and found up-regulation of FoxM1 the tumor cells.
Summary:
We demonstrate up-regulation of stromal FoxM1 by cancer-secreted-factors as well as by stable CAFs modifications, concomitantly to stromal p53 down-regulation. High stromal FoxM1 may promote tumor cells aggressiveness, similarly to low stromal p53, possibly being downstream to p53. Elaboration of these pathways will deepen our understanding of lung cancer and suggest novel therapeutic targets.
Citation Format: Iris Kamer, Inbal Daniel, Gili Perry, Amir Onn, Jair Bar. Stromal FoxM1 and p53 in lung cancer as mediators of tumor progression, metastatic spread and chemo-resistance. [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 1153. doi:10.1158/1538-7445.AM2014-1153
Abstract 1155: Chemoresistance acquisition by ovarian adenocarcinoma cells due to microenvironment
Authors: Thibault Benoit , Castells Magali , Mihas Delphine , Genre Ludivine , Gandy Cecile , Mery Eliane , Delord Jean Pierre , Couderc Bettina C. 
Published: May 2015

Abstract
Epithelial Ovarian Carcinoma is characterized by high frequency of recurrence (70% of patients) and carboplatin resistance acquisition. We recently showed that Carcinoma-Associated-Mesenchymal Stem Cells (CA-MSC) are involved in ovarian tumor growth via the facilitation of angiogenesis in the tumor site as well as in ovarian cancer chemoresistance acquisition. Our aim is to identify the mechanisms by which CA-MSC activate tumor cells signaling pathway for both effects. First we showed that factors released by CA-MSC are able to induce angiogenic cytokines (IL-6, IL-8 and VEGF) synthesis by tumor cells in a cell line specific way. Second, CA-MSC are able to attract and activate macrophages into a M2 TAM like phenotype and allow them to secrete a huge quantity of pro-angiogenic cytokines, favorable to tumor progression of all the associated ovarian adenocarcinoma cells tested. Third, factors released by CA-MSC protect adenocarcinoma cells from carboplatin-induced apoptosis by inhibiting the activation of effector caspases 3 and 7, inducing the activation of PI3K/Akt pathway signalling and the phosphorylation of the downstream target XIAP (caspase inhibitor from IAP family). XIAP depletion by siRNA strategy or inhibitors permitted to restore carboplatin-induced apoptosis in ovarian cancer cells stimulated by CA-MSC conditioned medium . Our results suggested targeting factors released by CA-MSC could be of interest in ovarian cancer therapy.
Note: This abstract was not presented at the meeting.
Citation Format: Benoit Thibault, Magali Castells, Delphine Mihas, Ludivine Genre, Cecile Gandy, Eliane Mery, Jean Pierre Delord, Bettina C. Couderc. Chemoresistance acquisition by ovarian adenocarcinoma cells due to microenvironment. [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 1155. doi:10.1158/1538-7445.AM2014-1155
Abstract 116: ATF3 suppresses the invasion and metastasis of esophageal squamous cell carcinoma cells by inducing the MDM2-mediated degradation of MMP-2
Authors: Xie Jianjun , Xu Liyan , Li Enmin 
Published: May 2015

Abstract
Objective: Activating transcription factor 3 (ATF3) was a transcription factor involved in cell cycle progression, invasion and metastasis of cancer cells. This study explored the clinical significance and biological function of ATF3 in esophageal squamous cell carcinomas (ESCC). Methods: Tissue microarray analysis, immunohistochemistry and Western blotting were utilized to examine the expression status of ATF3 in 150 ESCC samples and 21 paired adjacent normal epithelial tissues. Impact of ATF3 altered expression on cell growth, invasion, metastasis and the underlying mechanisms were also assessed by using in vitro and animal models of ESCC. Results: ATF3 expression was significantly lower in ESCC tissue than in the adjacent normal squamous mucosa (P=0.001). ATF3 expression was associated with both overall survival (OS, P=0.006) and disease-free survival (DFS, P=0.001) of ESCC patients. Multivariate analysis showed that ATF3 was an independent prognostic factor in ESCC. Experimentally, forced expression of ATF3 led to decreased cell growth and invasion properties in vitro, whereas knockdown of ATF3 did the opposite. ATF3 expression inhibited the tumourigenesis and lung metastasis of ESCC cells in nude mice. Further analysis revealed that the expression and activity of MMP-2 was decreased upon ATF3 expression. ATF3 upregulated MDM2 and formed an ATF3/MDM2/MMP-2 complex that facilitated MDM2-mediated MMP-2 degradation and subsequently inhibited the invasion and metastasis of ESCC cells. Finally, we showed that Cisplatin could suppress the invasion of ESCC cells by targeting the ATF3/MDM2/MMP-2 signaling. Conclusions: Decreased ATF3 expression in ESCC resulted in increased invasion and metastasis and contributed to ESCC poor prognosis. ATF3 expression is an ESCC candidate clinical prognostic marker and a potential treatment target.
Citation Format: Jianjun Xie, Liyan Xu, Enmin Li. ATF3 suppresses the invasion and metastasis of esophageal squamous cell carcinoma cells by inducing the MDM2-mediated degradation of MMP-2. [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 116. doi:10.1158/1538-7445.AM2014-116
Abstract 1168: Cathelicidin is a novel mediator of cancer immune surveillance
Authors: Gross Emilie T. , Peinado Carlos D. , Perez Isis G. , Keshavarz Samaneh , Bui Jack D. 
Published: May 2015

Abstract
Cathelicidins are evolutionarily conserved anti-microbial peptides that have been identified in several epithelial tissues and a wide variety of immune cells. These peptides display multiple host-defense activities, as well as documented but underexplored antitumor activity. Using the regressor MCA sarcoma system as a model of immune mediated tumor rejection, we observed that deficiency in cathelicidin in cnlp-/- mice impaired the rejection of multiple regressor cell lines. Cnlp-/- mice also developed spontaneous lymphoma with age, thus confirming in a separate model system the requirement for cathelicidin in tumor immune surveillance. To decipher the immune defect that may engender impaired tumor surveillance, macrophages from cnlp-/- versus wild type (wt) mice were examined. Interestingly, cnlp-/- macrophages were defective in polarizing towards an antitumor M1 phenotype and less potent at phagocytosing target tumor cells.
Altogether, these preliminary data suggest a crucial role of cathelicidin in limiting tumor formation and progression. Future experiments will define the role of cathelicidin in tumor surveillance mediated by macrophages and potentially other innate cells that also express cathelicidin, such as neutrophils and natural killer cells.
Citation Format: Emilie T. Gross, Carlos D. Peinado, Isis G. Perez, Samaneh Keshavarz, Jack D. Bui. Cathelicidin is a novel mediator of cancer immune surveillance. [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 1168. doi:10.1158/1538-7445.AM2014-1168
Abstract 1173: HIF-1 promotes the infiltration of regulatory T cells into the tumor via TGF-β
Authors: Teramoto Koji , Ohshio Yasuhiko , Hanaoka Jun , Takano Atsushi , Daigo Yataro 
Published: May 2015

Abstract
In the growing tumor under hypoxia, a transcription factor, hypoxia-inducible factor-1 (HIF-1) plays a critical role in regulating expressions of various genes associated with tumor growth. In order to elucidate the immunosuppression promoted by the hypoxic tumor microenvironment, we focused on a relationship between HIF-1 and an immunosuppressive cytokine, transforming growth factor-beta (TGF-β). TGF-β which is released from either tumor cells or tumor stromal cells and suppresses anti-tumor immune responses in tumor-bearing hosts may be regulated by HIF-1 in the hypoxic tumor microenvironment. In this report, we hypothesized that inhibition of HIF-1 in tumor cells would improve an immunosuppression to augment anti-tumor immune responses, and examined the possibilities in the tumor-bearing mice model. The transfected mouse lymphoma cells E.G7 with HIF-1 shRNA was administered to C57BL/6 mice subcutaneously at the flank. Three weeks later, anti-tumor immune responses elicited in the mice were examined. As results, in mice bearing the transfected E.G7 with HIF-1 shRNA, the protein level of TGF-β in the tumor tissue was decreased as compared with that in mice bearing the transfected E.G7 with control shRNA or the non-transfected E.G7. The infiltration of Foxp3+ cells in the tumor tissue was decreased in mice bearing the transfected E.G7 with HIF-1 shRNA. When spleen cells from those tumor-bearing mice were stimulated with E.G7-derived antigen, cytotoxic activity against target E.G7 cells were enhanced in mice bearing the transfected E.G7 with HIF-1 shRNA. While there were no significant differences in the cell proliferation between the transfected E.G7 cells with HIF-1 shRNA and those with control shRNA or non-transfected E.G7 cells in vitro, tumor growth was effectively suppressed in mice bearing the transfected E.G7 with HIF-1 shRNA. Inhibition of HIF-1 in tumor cells decreased the level of TGF-β in the hypoxic tumor microenvironment, leading to suppression of infiltrating Foxp3+ cells and improvement of anti-tumor immune responses. These results demonstrate that hypoxia in the tumor microenvironment is responsible for the induction of immunosuppression through the infiltration of regulatory T cells by TGF-β.
Citation Format: Koji Teramoto, Yasuhiko Ohshio, Jun Hanaoka, Atsushi Takano, Yataro Daigo. HIF-1 promotes the infiltration of regulatory T cells into the tumor via TGF-β. [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 1173. doi:10.1158/1538-7445.AM2014-1173
Abstract 1180: CCL-4 affects prostate cancer cell migration and tumorigenesis
Authors: Rohena-Rivera Krizia , Sánchez-Vázquez María M. , Merly-Torres Némesis , Casillas-González Joseph A. , Padín-López Yarimar , Forestier-Román Ingrid , Martínez-Ferrer Magaly 
Published: May 2015

Abstract
Prostate cancer (PCa) is the most frequently diagnosed and the second leading cause of cancer-related deaths in the United States. Inflammatory processes have been related to cancer progression and metastasis. Macrophage inflammatory protein 1β or CCL-4 has been reported as a differentially expressed chemokine among patients that showed PCa recurrence after radical prostastectomy. The aim of this study is to determine the role and mechanism of CCL-4 in the progression of PCa using in vitro and in vivo models. PC3 (androgen-independent) and 22RV1 (androgen-dependent) cell lines were treated in vitro with CCL-4 at concentrations of 0.001ng/mL and 0.1ng/mL and subjected to migration (Wound Healing) and invasion (Boyden Chamber) assays. The role of CCL-4 in PCa tumor progression was evaluated using a xenograft model in which the anterior prostate lobes of SCID mice were ortothopically injected with 250,000 22RV1 cells or 500,000 PC3 cells. CCL-4 was administered bi-weekly at concentrations of 0.001ng/mL and 0.1ng/mL with intraperitoneal injections during 4 weeks (22RV1) or 8 weeks (PC3). Tumor volumes were calculated using a caliper and tissue was collected, fixed and processed for gross examination, immunohistochemical, and gene expression analysis. In vitro studies indicated that PC3 cells treated with CCL4 had significantly increased migration when compared to control (P&lt;0.05). Additionaly, in vivo, CCL-4 increased tumor volume when compared with tumors generated in mice treated with vehicle. Tumors developed with CCL-4 showed an increased expression of desmin, alpha-smooth muscle actin (α-sma), and phospho histone 3 (pH3). Gene expression analysis showed that CCL-4 modulates the expression of several genes involved in PCa progression including PTEN, β-Catenin, and matrix metalloproteinases. Real-Time PCR confirmed increased expression of MMP-11. This study shows that CCL4 alters migration of PC3 cells and 22RV1 cells in vitro. Additionally, CCL4 treatment induces tumor growth in vivo using a SCID mouse orthotopic model. Interestingly tumors treated with CCL4 were associated with increased levels of alpha smooth muscle actin, proliferation as well as increased levels of matrix metalloproteinases. Our results indicate that CCL4 may promote tumor growth and metastasis in vivo by increasing proliferation and altering migration.
Citation Format: Krizia Rohena-Rivera, María M. Sánchez-Vázquez, Némesis Merly-Torres, Joseph A. Casillas-González, Yarimar Padín-López, Ingrid Forestier-Román, Magaly Martínez-Ferrer. CCL-4 affects prostate cancer cell migration and tumorigenesis. [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 1180. doi:10.1158/1538-7445.AM2014-1180
Abstract 1187: The Champions TumorGraft Bank: A demographically-rich repository of preclinical TumorGraft models
Authors: Khor Tin , Vasquez David , Katz Amanda , Baia Gilson , Ciznadija Daniel , Sidransky David , Paz Keren 
Published: May 2015

Abstract
Many oncology pharmaceuticals fail during phased clinical trials, having been advanced based on research using flawed preclinical models that do not accurately replicate human tumor biology. For example, numerous models are based on genetically-engineered mice, which are often generated from limited numbers of genetic aberrations. As such, they may not accurately represent either the chaotic heterogeneity that exists within intact human tumors or throughout the clinical population. TumorGrafts, in which patient-derived tumor tissue is directly engrafted into immunodeficient mice, offer a step forward in this unresolved issue. These models maintain the complex intra-tumoral heterogeneity and biology of an intact malignancy, as well its 3-dimensional interplay with stromal components and other cells fluxing into the immediate environment. The intrinsic cross-talk between the different compartments of the tumor is also retained.
We wanted to generate a repository of these tumor models and make them available to the research community for use in pharmaceutical development and basic research processes. Here we describe our extensive bank of live TumorGrafts comprising a range of different tumor types, from more common cancers, including lung, colon, and breast, to a number of rare subtypes such as adenoid cystic carcinoma. These models were originally developed for personalizing cancer treatments and are derived from patient populations across all ages and ethnicities, encompassing both treatment-naïve and heavily-treated individuals. Furthermore, because of our distinct patient-focus, we maintain detailed clinical histories, as well as molecular data where available. Hence, the bank is a reasonable surrogate of the population from which treatment groups are typically drawn for clinical trials and could potentially be of value for predetermining target populations for therapeutic intervention. The Champions TumorGraft Bank provides superior pre-clinical models that faithfully capture all the biological and molecular features of cancer and can serve basic and clinical research groups as an increasingly valuable source for drug development and biomarker discovery.
Citation Format: Tin Khor, David Vasquez, Amanda Katz, Gilson Baia, Daniel Ciznadija, David Sidransky, Keren Paz. The Champions TumorGraft Bank: A demographically-rich repository of preclinical TumorGraft models. [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 1187. doi:10.1158/1538-7445.AM2014-1187
Abstract 1189: Establishment of patient-derived xenograft (PDX) models for small cell lung cancer (SCLC) as a preclinical platform for drug development
Authors: Carlson Patrick , Ricono Jill , Mullins Chelsea , Broudy Thomas , Mirsaidi Cyrus , Nair Praveen 
Published: May 2015

Abstract
Small cell lung cancer comprises 15-20% of all lung cancer cases, and is more invasive and has a higher rate of proliferation with respect to non-small cell lung cancer, leading to a higher mortality rate. Most cases are responsive to chemotherapy, however there is a high rate of recurrence with treated patients and those in advanced stage of the disease often have a refractory response to treatment. As such, the need for new treatment modalities is critical.
Use of patient-derived tumor xenograft (PDX) models as clinically-relevant preclinical model for novel drug development has gained widespread adoption in recent years. In previous work, we have reported using the Molecular Response tumor bank, comprising &gt;144,000 viable tumor specimens, to establish more than 100 PDX models of various cancer types.
In this work, we describe the development of 8 new SCLC PDX models established from a collection of &gt;300 small cell lung cancer specimens, many of which come from prior-treated and metastatic patients. We report a comprehensive characterization of these models, including: histopathology, immunohistochemistry, and mutation analysis by next-generation sequencing. Additionally, we have evaluated functional response of these models with in vivo pharmacology studies. Current studies are underway to derive correlations between in vivo drug response and mutational status of these models. Our data strongly suggests the potential to use these unique PDX models to aid in efforts in drug development efforts in oncology.
Citation Format: Patrick Carlson, Jill Ricono, Chelsea Mullins, Thomas Broudy, Cyrus Mirsaidi, Praveen Nair. Establishment of patient-derived xenograft (PDX) models for small cell lung cancer (SCLC) as a preclinical platform for drug development. [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 1189. doi:10.1158/1538-7445.AM2014-1189
Abstract 1190: Multifactorial biological processes govern engraftment of patient-derived tumor tissue in immunodeficient mice
Authors: Vasquez-Dunddel David M. , Baia Gilson , Katz Amanda , Ciznadija Daniel , Sidransky David , Paz Keren 
Published: May 2015

Abstract
TumorGrafts (also known as patient-derived xenografts) are a valuable tool for the personalization of oncology treatment, as well as development of new cancer therapeutics. Tumor explants are engrafted into immunodeficient mice and allowed to develop prior to screening against a panel of drugs or drug combinations to assess which best inhibit tumor growth. These models capture the chaotic heterogeneity, histopathology, and biology of the original tumor, as well its 3-dimensional interaction with the surrounding stroma and other cells migrating into the tumor environment. TumorGrafts will serve basic and clinical research groups as an increasingly valuable preclinical model of cancer. One important variable governing the generation of these models is the take rate, or the percentage of patient tumors that successfully engraft and grow in the mice. This is a potentially critical limitation to applying these preclinical models for improving patient treatment and advancing novel drug regimens to the clinic. Hence, there is a need to understand and exploit the mechanisms that influence take rate in order to ensure that the majority of tumor explants readily engraft and expand. We describe here our experience in optimizing the engraftment of patient tumor tissue in immunodeficient mice. We found a number of factors contribute to take rate including tumor type, tissue quantity and quality, engraftment site, oxygenation state, neovascularization and the presence of extracellular stromal components and cells. We have also uncovered a correlation between the growth rate of tumors in the mice and the clinical aggressiveness of the original malignancy, information that may be useful in guiding clinical management. Moreover, we describe how we are now able to consistently use biopsy material rather than surgical explants to establish TumorGrafts, a crucial step forward that allows this technology to benefit patients diagnosed with early-stage cancers or where surgery is not indicated. Although engraftment of patient tumor tissue in immunodeficient mice is a complex process, with multiple factors impacting success, we have effectively optimized this process, improving our take rate and at the same time, reducing the time to obtaining drug screening results, all without compromising tumor integrity.
Citation Format: David M. Vasquez-Dunddel, Gilson Baia, Amanda Katz, Daniel Ciznadija, David Sidransky, Keren Paz. Multifactorial biological processes govern engraftment of patient-derived tumor tissue in immunodeficient mice. [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 1190. doi:10.1158/1538-7445.AM2014-1190