bluuebunny/crossref_metadata_2025 huggingface dataset:
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

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

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

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

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

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<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

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

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 >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 >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

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
Abstract 1193: Establishment of patient tumor-derived orthotopic xenograft models of metastatic pediatric germinoma
Authors: Lindsay Holly B. , Kogiso Mari , Qi Lin , Yee Teo Wan , Huang Yulun , Mao Hua , Lin Frank , Baxter Patricia , Su Jack M. , Terashima Keita , Perlaky Laszlo , Lau Ching C. , Parsons Donald W. , Chintagumpala Murali , Li Xiao-Nan
Published: May 2015

Despite comprising up to 10% of pediatric CNS tumors, an animal model of intracranial germinoma has not been previously established. Standard of case for germinoma is radiation therapy, with recent evidence that neo-adjuvant chemotherapy may allow reduction of radiation dose, but concern for neuro-cognitive toxicity remains despite the reduction of radiation. A clinically relevant animal model of germinoma would facilitate investigation and discovery of novel agents which may obviate the need for radiation in the future. To develop xenograft mouse models, we implanted germinoma tumor cells from two children with metastatic disease, one from a surgical specimen of a cervical metastatic tumor and the second from disseminated tumor cells in the CSF, directly into the right cerebral hemispheres of NOD-SCID mice. Both patient tumor samples have undergone whole exome sequencing; one of the two models has a germinoma-associated mutation in c-kit. The tumors have been serially passaged in xenografts for 3-5 times, with each passaged tumor maintaining the ability to generate tumors, suggestive of the persistence of viable tumorigenic/tumor stem cells. Data from additional tumor models established by our lab have confirmed molecular and genetic fidelity between xenograft-initiating human brain tumors and their corresponding murine models. The orthotopic location in the mouse brain of the xenograft model should also reasonably replicate the human germinoma tumor microenvironment. Cultured cells are currently growing from both tumor models in order to establish germinoma cell lines. In summary, our orthotopic xenograft murine models of two metastatic pediatric germinomas are the first to be established for this tumor type. These models will allow much needed pre-clinical drug testing of chemotherapeutics and combination therapies as well as further biologic characterization of pediatric germinomas.

Citation Format: Holly B. Lindsay, Mari Kogiso, Lin Qi, Teo Wan Yee, Yulun Huang, Hua Mao, Frank Lin, Patricia Baxter, Jack M. Su, Keita Terashima, Laszlo Perlaky, Ching C. Lau, Donald W. Parsons, Murali Chintagumpala, Xiao-Nan Li. Establishment of patient tumor-derived orthotopic xenograft models of metastatic pediatric germinoma. [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 1193. doi:10.1158/1538-7445.AM2014-1193
Abstract 120: Runx3 inhibited epithelial to mesenchymal transition promotes motility and invasiveness of colon cancer cells through reduction of ROS generation
Authors: Kim Bo Ram , Kang Myoung Hee , Kim Jung Lim , Jang Yoo Jin , Lee Sun I. , Kim Jun Suk , Oh Sang Cheul
Published: May 2015

Approximately 90% of all cancer deaths arise from the metastatic spread of primary tumours. Most colon cancer metastasis occurs. Runx3(runt-related transcription factor3) is known as tumor suppressor gene in gastrointestinal epithelium. Recent reports have been shown that loss of Runx3 induce proliferative effect in gastric cancer cells. However, their roles and underlying mechanism in colon cancer cell lines are not yet known. In this study, we investigated the function of Runx3 in human colon cancer cells. The proliferation, migration, and invasion of colon cancer cells in response to using the Runx3 expression vector for various times were investigated using MTT, wound healing, and Matrigel invasion assay, respectively. The morphologic changes of colon cancer cells through the EMT process were monitored by immunofluorescence staining and Western blot assay for EMT markers Twist and Vimentin. We found that Runx3 overexpressing cell inhibited cell motility and invasiveness in colon cancer, and this process was enhanced by Runx3 siRNA. We observed that the mRNA expressions of Runx3 was enhanced by Runx3 overexpressing cell, whereas no increase of these factors was observed when the Runx3 siRNA was transfection. Overexpression of Runx3 decreases protein expression of EMT (Epithelial-Mesenchymal transition) markers. In addition, Runx3 knockdown upregulates MMP2 activity. The ROS production was decreased in Runx3-overexpressing cells. These results indicate that Runx3 signaling pathway can contribute to ROS generation enhancing the metastatic potential of tumor cells. Our findings suggest that Runx3 signaling processes through ROS and MMP2 the inhibition of these pathway blocked the metastatic potential of colon cancer cell lines.

Citation Format: Bo Ram Kim, Myoung Hee Kang, Jung Lim Kim, Yoo Jin Jang, Sun Il Lee, Jun Suk Kim, Sang Cheul Oh. Runx3 inhibited epithelial to mesenchymal transition promotes motility and invasiveness of colon cancer cells through reduction of ROS generation. [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 120. doi:10.1158/1538-7445.AM2014-120
Abstract 1200: Characterization of a novel radiation-induced sarcoma cell line
Authors: Lang Julie E. , Nokes Brandon , Sheth Grishma , Novak Petr , Fuchs Laura , Watts George S. , Futscher Bernard W. , Mineyev Neal , Zhu Weizhu , LeBeau Lauren , Nagle Ray , Cranmer Lee
Published: May 2015

Background: Radiation-induced sarcoma (RIS) is a potential complication of cancer treatment. No widely available cell line models currently exist to facilitate studies of RIS. Methods: We derived a primary human cell line, UACC-SARC1, from a RIS. Short tandem repeat (STR) genotyping was used to confirm that this cell line was propagated from the tumor. Further characterization of this cell line involved comparing 24 markers using immunocytochemistry (ICC) to immunohistochemistry (IHC) of the tumor, a Matrigel invasion assay, karyotyping of the cell line, comparative genomic hybridization (CGH), DNA sequencing using the Ion AmpliSeq Cancer panel and in vivo mouse xenografts after subcutaneous injection of UACC-SARC1 in immunodeficient mice. Results: STR profiling of UACC-SARC1 was virtually identical to its parental tumor. IHC analysis of the tumor and ICC analysis of UACC-SARC1 revealed shared expression of vimentin, osteonectin, CD68, Ki67 and PTEN but tumor-restricted expression of the histiocyte markers α1-antitrypsin and α1-antichymotrypsin. Karyotyping of the tumor demonstrated aneuploidy. CGH provided direct genetic comparison between the tumor and UACC-SARC1. Sequencing of 740 mutation hotspots revealed no mutations in UACC-SARC1 nor in the tumor. SCID mice xenografts exhibited tumor formation but resulting tumors failed to metastasize. Further xenografts with NOD SCID gamma (NSG) mice are planned. The doubling time of UACC-SARC1 was 28.3 hours. Conclusion: Our novel RIS strain constitutes a useful tool for pre-clinical studies of this rare, aggressive disease.

Citation Format: Julie E. Lang, Brandon Nokes, Grishma Sheth, Petr Novak, Laura Fuchs, George S. Watts, Bernard W. Futscher, Neal Mineyev, Weizhu Zhu, Lauren LeBeau, Ray Nagle, Lee Cranmer. Characterization of a novel radiation-induced sarcoma cell line. [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 1200. doi:10.1158/1538-7445.AM2014-1200
Abstract 1201: Establishment and characterization of cell lines derived from a murine model of PTEN-deficient prostate cancer
Authors: Yoshikawa Kazuhiro , Velasco Marco A. De , Kura Yurie , Ando Naomi , Fukushima Emiko , Hatanaka Yuji , Yamamoto Yutaka , Shimizu Nobutaka , Yoshimura Kazuhiro , Nozawa Masahiro , Nishio Kazuto , Uemura Hirotsugu
Published: May 2015

Inactivation of the tumor suppressor PTEN is a common event in human prostate cancer that leads to increased activation of the PI3K pathway. Crosstalk between the PI3K signaling cascade and other cancer regulatory pathways contributes to the growth and survival of cancer cells. To better understand the mechanisms involved in the transformation process and to establish an in vivo screening system for novel treatment strategies, we previously developed a genetically engineered mouse model of prostate cancer that is based on the conditional inactivation of PTEN. In this model, inactivation of PTEN results in the stage-specific development of prostate cancer that recapitulates most features of the human disease including the development of castration-resistant prostate cancer (CRPC). The purpose of our study was to establish and characterize a panel of cell lines derived from this model in order to study the disease mechanisms at the cellular level and to establish a cell-based assay system to complement our in vivo program for pre-clinical screening of novel anticancer drugs. A panel of 7 cell lines derived from castration-naïve prostate tumors and 6 cell lines derived from CRPC were established. Cells lines were characterized for morphological, growth, differentiation, and molecular profiles in vitro as well as for their tumorigenic potential in vivo. The cell lines were also tested against a panel of cytotoxic and molecular targeting drugs and compared to the sensitivity of human prostate cell lines. Overall, our comprehensive analysis summarizes the functionality and potential application as cell-based system for developing treatment strategies against prostate cancer.

Citation Format: Kazuhiro Yoshikawa, Marco A. De Velasco, Yurie Kura, Naomi Ando, Emiko Fukushima, Yuji Hatanaka, Yutaka Yamamoto, Nobutaka Shimizu, Kazuhiro Yoshimura, Masahiro Nozawa, Kazuto Nishio, Hirotsugu Uemura. Establishment and characterization of cell lines derived from a murine model of PTEN-deficient prostate 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 1201. doi:10.1158/1538-7445.AM2014-1201
Abstract 1204: Establishment of a patient-derived orthotopic xenograft (PDOX) model of patient cervical cancer
Authors: Hiroshima Yukihiko , Zhang Yong , Maawy Ali , Sato Sho , Murakami Takashi , Yamamoto Mako , Uehara Fuminari , Miwa Shinji , Yano Shuya , Momiyama Masashi , Chishima Takashi , Tanaka Kuniya , Maawy Ali , Endo Itaru , Hoffman Robert M.
Published: May 2015

We implanted a tumor resected from a patient with metastatic HER-2-positive cervical cancer from 8 NOD/SCID mice (F1; NOD/SCID-sc) and 10 nude mice (F1; Nude-sc) subcutaneously, and 8 nude mice (F1; Nude-soi) orthotopically. Five out of 8 NOD/SCID mice died within 7 days after implantation. Infections around the surgical wound, loss of weight and of lethargy were observed in post-operatively in other mice. We examined the tumor-take rate of each model 8 weeks after implantation. Tumors grew in 3 out of 3 mice in F1; NOD/SCID-sc (100 %); 7 out of 10 mice in F1; nude-sc (70 %) and 6 out of 8 mice in F1; nude-soi group (75 %), respectively. The metastatic tumors (peritoneal dissemination, liver metastasis, lung metastasis or lymph node metastasis) were detected in 4 mice in F1; nude-soi mice (50 %). We found all xenografts including the metastatic tumors had histological structures similar to the original tumor and were stained by anti-human HER-2 antibody. Next, we implanted the small fragments of subcutaneous tumors from F1; Nude-sc mice (F2; sc-sc) or the primary tumors of F1; nude-soi mice (F2; soi-sc) to another set of nude mice (20 mice each) subcutaneously, and examined the tumor-take rate of each group 4 weeks and 8 weeks after implantation. Eight mice in the F2; sc-sc group (40 %) and 16 mice in the F2; soi-sc group (80 %) had tumors at week 4, and 15 mice in the F2; sc-sc group (75 %) and 19 mice in the F2; soi-sc group (95 %) had tumors at week 8. These results suggest that PDOX in nude mouse model recapitulates the biological behaviors of the original tumor and has the sufficient tumor-take rate.

Citation Format: Yukihiko Hiroshima, Yong Zhang, Ali Maawy, Sho Sato, Takashi Murakami, Mako Yamamoto, Fuminari Uehara, Shinji Miwa, Shuya Yano, Masashi Momiyama, Takashi Chishima, Kuniya Tanaka, Ali Maawy, Itaru Endo, Robert M. Hoffman. Establishment of a patient-derived orthotopic xenograft (PDOX) model of patient cervical 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 1204. doi:10.1158/1538-7445.AM2014-1204
Abstract 1207: Pharmacodynamic evaluation of ADCC mediated effects in humanized IL2 or IL15 NOG mice models
Authors: Mignard Caroline , Mirjolet Jean-Francois , Duchamp Olivier , Ohnishi Yasuyuki , Katano Ikumi , Ito Mamoru
Published: May 2015

Humanized mice (i.e. immunodeficient NOG mice engrafted with human hematopoietic stem cells (HSC)) have demonstrated their usefulness for studying the human immune system. These models should help recapitulating some pathology such as viral infection and then are suitable system to evaluate new human specific therapies. Nevertheless, one issue of these models is the incomplete maturation of natural killer (NK) cell subpopulation.

This lake of NK cell functionality was solved by the Central Institute for Experimental Animals (CIEA) with the second generation of transgenic NOG mice expressing human IL2 or IL15 (NK-NOG). The serum levels of hIL-2 and hIL-15 in mice were 1-2 and 0.1-0.2 ng/mL, respectively. In these mice, human NK cells differentiated from HSC are well distributed in the mouse body (peripheral blood, bone marrow, spleen…). They expressed various NK receptors such as NKp30, NKp44, NKp46, etc., granzyme A and perforin, indicating their maturity in the mice. They are also fully functional as evidenced using an ex vivo 51Cr release assay demonstrating lysis properties of human NK cells from collected spleen of HSC-humanized mice.In vivo proof of concept studies were successfully performed with humanized NK-NOG mice xenografted with either human Burkitt's disseminated lymphoma cells or with human solid tumors treated with humanized therapeutic antibodies. Prediction of ADCC-mediated antitumor activity of humanized antibodies is now routinely feasible for preclinical evaluation using these new in vivo NK-NOG models.

Citation Format: Caroline Mignard, Jean-Francois Mirjolet, Olivier Duchamp, Yasuyuki Ohnishi, Ikumi Katano, Mamoru Ito. Pharmacodynamic evaluation of ADCC mediated effects in humanized IL2 or IL15 NOG mice 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 1207. doi:10.1158/1538-7445.AM2014-1207
Abstract 1209: Comparison of lung adenocarcinoma development in genetically engineered mouse and in humans - similarities and differences
Authors: Popper Helmut H. , Grabner Beatrice , Casanova Emilio , Eferl Robert , Shuan Rao , Penninger Josef
Published: May 2015

Lung adenocarcinoma (AC) induced by carcinogen inhalation never came close to the human counterpart. This has changed with the creation of genetically engineered models.

Different types of mouse AC were studied, some of them with a KRAS codon12 mutation background, others with HRAS mutants inserted; in most additional hits were introduced (ATG5, PTEN, PI3K, p53). Development of AC was followed for 28 weeks. Human lung AC subtypes and precursor lesions served for comparison.

AC in mice starts with papillary growth at the bronchoalveolar junction (baJ). Tumor spreads into the alveolar periphery. Due to different cell to alveolar size alveoli are filled almost completely, simulating solid growth. At a certain size hypoxic necrosis is seen in centers, followed by neoangiogenesis and desmoplastic stroma formation. Finally invasion of tumor cells into stroma occur. Metastasis is rare, due to high tumor load, causing early death. Vascular invasion is seen, if second carcinogenic hits are applied.

Dissimilarities with human precursor and AC types are: AC in mice are all non-mucinous, they are predominant papillary or solid, often with a high degree of signet ring cell formation; in addition there seems to be a requirement of large tumor size before invasion and metastasis occur. To understand AC development knowledge of the anatomy and histology of mouse and human lung is necessary, but these models open a new way of investigating lung AC.

Citation Format: Helmut H. Popper, Beatrice Grabner, Emilio Casanova, Robert Eferl, Rao Shuan, Josef Penninger. Comparison of lung adenocarcinoma development in genetically engineered mouse and in humans - similarities and differences. [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 1209. doi:10.1158/1538-7445.AM2014-1209
Abstract 121: Sulforaphene inhibited migration through down-regulating the Hedgehog signaling in SUM159 human breast cancer cells
Authors: Bao Cheng , Lee Jaehoo , Ko Jiwon , Park Hyun-Chang , Lee Hong jin
Published: May 2015

Accumulating evidences have demonstrated the antineoplastic properties of sulforaphane, a major isothiocyanates present in cruciferous vegetables. However, the natural analogue of sulforaphane, sulforaphene, rich in radish, has yet not been extensively studied for its potential in preventing cancer. In this study, sulforaphene exerted inhibiting effect on migration of SUM159 human breast cancer cells, the migrated cells were reduced from 72.3% in control group to 17.5% in sulforaphene(10uM) treated group. The Hedgehog signaling, known to be involved in cancer invasiveness, was found to be regulated by sulforaphene. The mRNA and protein expression of Gli1 and Smoothened(Smo) which were Hedgehog signaling activating mediators were significantly suppressed by sulforaphene, but the expression of Patched1(Ptch1) an inhibiting mediator, was induced. In addition, the Hedgehog signaling inhibitors, cyclopamine and vismodegib, strongly inhibited the migration of SUM159 breast cancer cells, suggesting the association of Hedgehog signaling with the migration of breast cancer cells. Taken together, sulforaphene significantly inhibited the migration via down-regulating the Hedgehog signaling pathway and suggest that sulforaphene may be considered as a potent phytochemical in suppressing the mammary carcinogenesis.

Citation Format: Cheng Bao, Jaehoo Lee, Jiwon Ko, Hyun-Chang Park, Hong jin Lee. Sulforaphene inhibited migration through down-regulating the Hedgehog signaling in SUM159 human breast cancer cells. [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 121. doi:10.1158/1538-7445.AM2014-121
Abstract 1210: A patient derived xenograft tumor model platform for “mouse trials”
Authors: Yan Ying , Yu Tengfei , Du Wei , Tong Guosheng , Yang Yuefei , Tan Tingting , Yang Xuqin , Liu Zhenhua , Gu Jiali , Hua Liang , Zhang Wei , Ye Xin K. , Gu Zhenyu
Published: May 2015

From Chinese cancer patients, close to 600 patient derived xenograft (PDX) tumor models have been established (> P3, three passages in mice) at GenenDesign through serial passages in the immune-compromised nude mice. The major collection of GenenDesign PDX tumor model platform represents cancer types that are prevalent in Asian patients, including gastric cancer (> 200 models), esophageal cancer (>100 models), liver cancer (∼50 models), pancreatic cancer (>60 models) and lung cancer (> 80 models). Establishment of variant PDX models from the same patient tumor is on-going to support translational studies of tumor heterogeneity.

Initial characterization indicates that the mouse PDX models have captured the major histopathological characteristics of the original human tumors. Reproducible growth curves for PDX models (>P3) support their usage in efficacy analysis of anti-cancer therapeutic agents. Response curves to SoC (standard of care) chemotherapies such as Paclitaxel for lung cancer, FOLFOX for gastric cancer and Sorafenib for liver cancer have been established in the PDX tumor models, providing a baseline for further investigation of novel therapies in a combination setting.

On-going molecular characterization including oncogene mutational analysis and target specific IHC and FISH analysis has identified panels of PDX tumor models with aberrations in key oncogenic signaling pathways, including lung panels with EGFR overexpression or KRAS mutations, gastric panels with FGFR2 amplification or being HER2 positive, lung and gastric panels with cMET overexpression. Testing of Herceptin in the gastric HER2 positive tumor panel resulted in observations similar to that from the ToGA trial. At the same time, Herceptin resistant PDX tumor variants (de novo or acquired) were identified or established. The PDX tumor model panels facilitate translational studies in a “mouse trial” format in a setting similar to clinical trials to test patient stratification strategies and drug response predictive biomarkers for emerging therapeutic modalities.

Citation Format: Ying Yan, Tengfei Yu, Wei Du, Guosheng Tong, Yuefei Yang, Tingting Tan, Xuqin Yang, Zhenhua Liu, Jiali Gu, Liang Hua, Wei Zhang, Xin K. Ye, Zhenyu Gu. A patient derived xenograft tumor model platform for “mouse trials”. [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 1210. doi:10.1158/1538-7445.AM2014-1210
Abstract 1212: Studying cancer drug resistance in patient derived xenograft tumor models
Authors: Yu Tengfei , Yan Ying , Du Wei , Yang Yuefei , Tan Tingting , Yang Xuqin , Gu Jiali , Hua Liang , Ye Xin K. , Gu Zhenyu
Published: May 2015

Anti-cancer drugs, either targeted therapies or cytotoxic chemotherapies, have proven to be effective in treating certain cancer patients. However, in most cases, tumors recur and become resistant to the treatment after a period of time. There are urgent needs to understand the underlying drug resistance mechanisms, to discover drug resistance targets and drug resistance biomarkers and to develop new therapies or combination therapies to tackle this widely occurring clinical problem. Currently the main approaches to study cancer drug resistance include analyzing clinical samples and developing drug resistance models in vitro. Numerous potential resistance mechanisms have been revealed. However, validation of these findings in a clinical-like setting and to test therapies in preclinical studies requires in vivo tumor models of drug resistance.

At GenenDesign, we have developed cancer drug resistance PDX tumor models through short term drug testing or long term treatment of xenograft tumor mice. Cancer drugs investigated in our studies include major classes of targeted therapeutic modalities such as Her2 inhibitors, EGFR inhibitors, FGFR inhibitors and cMet/ALK inhibitors, as well as several standard of care (SoC) chemotherapies. From these studies, we have identified de novo resistance models, acquired resistance models and reversible resistance models in multiple cancer types including lung cancer and gastric cancer.

In analyzing more than a dozen of Her2 positive but Herceptin resistance PDX models, we have uncovered molecular abnormalities such as Pten deletion, PI3K mutation, amplification of EGFR, cMet and cyclin E, which have been reported previously to be associated with Herceptin resistance in early studies. Studies are on-going to test whether combination therapies will be effective in overcoming Herceptin resistance.

In drug response profiling of our PDX models, we also found wide spread phenotypical and functional heterogeneity in individual tumors. The heterogeneity within each tumor, in some cases, contributed to evolving of drug resistance from initially responsive tumors.

Citation Format: Tengfei Yu, Ying Yan, Wei Du, Yuefei Yang, Tingting Tan, Xuqin Yang, Jiali Gu, Liang Hua, Xin K. Ye, Zhenyu Gu. Studying cancer drug resistance in patient derived xenograft tumor 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 1212. doi:10.1158/1538-7445.AM2014-1212
Abstract 1214: Preclinical models of prostate cancer: New patient-derived xenografts for preclinical studies and evaluation of prostate cancer biology
Authors: Nguyen Holly M. , Morrissey Colm , Nelson Peter S. , Zhang Xiaotun , Lange Paul H. , Vessella Robert L. , Corey Eva
Published: May 2015

Prostate cancer (PCa) is a heterogeneous disease and in order to increase our understanding of PCa biology and evaluate efficacy of novel pipeline agents, clinically relevant models are needed. It is well known that PCa xenografts are difficult to establish and propagate with approximate take rates of only 20%. During past the 20 years we have established and characterized a large series of LuCaP prostate cancer patient-derived xenografts (PDXs). Herein, we present a summary of the biological and molecular characterization of these PDX LuCaP models.

LuCaP PCa PDX models were derived from primary PCa and various sites of metastases. The histology of the LuCaP PDXs is similar to the originating clinical specimen, and the unsupervised gene expression array clustering analyses revealed an association between the xenograft and the originating specimen. Twenty four of the lines are adenocarcinoma and four exhibit a neuroendocrine phenotype. Characterization of the LuCaP PDX tumors includes expression arrays, RNASeq, exome sequencing, and IHC for multiple markers. Some of the models show Rb deletion, TMPRSS2/ERG translocation, PTEN deletion, PI3K activation and other critical characteristics detected in clinical specimens and associated with PCa progression. In vivo characterizations show responses to androgen suppression spanning the range of responses to this therapy seen in patients; differential levels of serum PSA, tumor-doubling time, and responses to docetaxel. Furthermore, seven of our models elicit an osteoblastic reaction when implanted in the bone.

In summary the diversity of phenotypes and responses of the LuCaP PDXs to therapy are representative of responses seen in the clinical setting. Therefore, the LuCaP PCa PDXs are highly clinically relevant models to study PCa biology and evaluate new treatment modalities. These models are available to researchers worldwide for studies aiming to improve survival of PCa patients and quality of life of men suffering from this disease.

Citation Format: Holly M. Nguyen, Colm Morrissey, Peter S. Nelson, Xiaotun Zhang, Paul H. Lange, Robert L. Vessella, Eva Corey. Preclinical models of prostate cancer: New patient-derived xenografts for preclinical studies and evaluation of prostate cancer biology. [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 1214. doi:10.1158/1538-7445.AM2014-1214