bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 3171: IL-25/IL-17E does not induce breast tumor cell apoptosis and both IL-17A and IL-25/IL-17E contribute to breast cancer survival and proliferation associated with generation of pro-oncogenic low molecular forms of cyclin E
Authors: Giustiniani Jérôme , Curé Hervé , Garbar Christian , Merrouche Yacine , Bonnefoy Nathalie , Bastid Jérémy , Alberici Gilles , Eliaou Jean-François , Bensussan Armand
Published: August 2015

Pro-inflammatory IL-17 cytokines were initially described for their pathogenic role in chronic inflammatory diseases and subsequent accumulating evidence indicated their involvement in carcinogenesis. In the present study we focused our work on IL-17A and IL-17E which are found in the breast tumoral microenvironment. Cell proliferation and cytotoxic assays as well as Quantitative PCR and Western Blot analysis of oncogenic pathways were performed using several breast cancer cell lines and primary tumor cells. We report that IL-17A and IL-17E receptor subunits (IL17RA, RB and RC chains) are up-regulated in breast cancers versus normal samples. Moreover, IL-17E, which is undetectable in most normal breast tissues tested, is expressed at higher levels in tumors. We studied the molecular signaling following the stimulation of cell lines with IL-17A and IL-17E. We found that both cytokines induced cell proliferation and activation of pathways involved in cells survival. Accordingly, IL-17A and IL-17E promoted resistance to Docetaxel but failed to induce apoptosis as previously reported for IL-17E. Interestingly, we also revealed that both cytokines induced the generation of tumorigenic low molecular weight forms of cyclin E (LMW-E), high levels of which correlate strongly with a poor survival in breast cancer patients. These results show for the first time some of the molecular pathways activated by IL-17A and IL-17E that may participate to their pro-oncogenic activity in breast cancers.

Citation Format: Jérôme Giustiniani, Hervé Curé, Christian Garbar, Yacine Merrouche, Nathalie Bonnefoy, Jérémy Bastid, Gilles Alberici, Jean-François Eliaou, Armand Bensussan. IL-25/IL-17E does not induce breast tumor cell apoptosis and both IL-17A and IL-25/IL-17E contribute to breast cancer survival and proliferation associated with generation of pro-oncogenic low molecular forms of cyclin E. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3171. doi:10.1158/1538-7445.AM2015-3171
Abstract 3200: Acidic microenvironment activates endoplasmic reticulum stress pathways through GPR4 in human vascular endothelial cells
Authors: Dong Lixue , Krewson Elizabeth A. , Yang Li V.
Published: August 2015

The tumor microenvironment is characterized by acidosis and hypoxia due to tumor heterogeneity, aerobic glycolysis (“Warburg effect”), and defective vasculature that is inefficient to deliver oxygen and nutrients and to remove metabolic acid byproduct. How the acidic microenvironment affects the function of blood vessels, however, is not well defined. GPR4, a member of the proton-sensing G protein-coupled receptors, has high expression in endothelial cells. We have previously reported that acidosis induces a broad inflammatory response in human vascular endothelial cells through the GPR4 receptor. Acidosis also increases the expression of several endoplasmic reticulum (ER) stress genes such as CHOP and ATF3. In the current study, we have thoroughly examined acidosis/GPR4-induced ER stress pathways in human umbilical vein endothelial cells (HUVEC). All three arms of the ER stress/unfolded protein response (UPR) pathways are activated by acidosis in HUVEC, as we observed an increased expression of phosphorylated eIF2α, phosphorylated IRE1α, and cleaved ATF6 upon acidic pH treatment. In addition, the expression of other downstream mediators of the UPR, such as ATF4, ATF3, CHOP and spliced XBP1, were also induced by acidosis at the mRNA and/or protein levels. Through genetic modifications and a small molecule inhibitor to modulate the expression level or activity of GPR4 in HUVEC, we found that GPR4 plays an important role in mediating the ER stress response induced by acidosis stimulation. As ER stress/UPR can cause inflammation and cell apoptosis, acidosis/GPR4-induced ER stress pathways in endothelial cells may regulate angiogenesis and inflammatory response in the acidic tumor microenvironment.

Citation Format: Lixue Dong, Elizabeth A. Krewson, Li V. Yang. Acidic microenvironment activates endoplasmic reticulum stress pathways through GPR4 in human vascular endothelial cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3200. doi:10.1158/1538-7445.AM2015-3200
Abstract 3201: Complement component C3 and complement factor B regulate growth of cutaneous squamous cell carcinoma
Authors: Riihila Pilvi , Farshchian Mehdi , Kallajoki Markku , Kivisaari Atte , Meri Seppo , Grenman Reidar , Heljasvaara Ritva , Pihlajaniemi Taina , Peltonen Juha , Peltonen Sirkku , Kahari Veli-Matti
Published: August 2015

Cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer and its incidence is increasing globally. We have examined the role of complement component C3 and complement factor B (CFB) in the progression of cSCC. Significantly elevated mRNA levels for C3 and CFB were detected din cSCC cell lines (n = 8) compared to normal human epidermal keratinocytes (n = 11) by quantitative real-time reverse transcriptase-PCR. Increased production of C3 and CFB by cSCC cell lines was detected by western blotting. The mRNA levels for C3 and CFB were also markedly higher in cSCC tumors (n = 6) than in normal skin (n = 10). Tumor cell specific staining for C3 and CFB was detected in cSCC tumors in vivo by immunohistochemistry and the staining intensity was stronger in invasive cSCCs (n = 71) than in cSCC in situ (n = 69), premalignant epidermal lesions (actinic keratoses, n = 65) and normal skin (n = 5). Significant upregulation of C3 and CFB mRNA expression was also noted in chemically induced mouse skin cSCCs (n = 27) compared to benign papillomas (n = 17). The expression of C3 and CFB at mRNA and protein level was markedly higher in invasive tumorigenic Ha-ras-transformed HaCaT cell line than in benign tumorigenic ras-transformed HaCaT cells and parental non-tumorigenic HaCaT cells. The expression of both C3 and CFB was significantly upregulated by IFN-γ and TNF-α in cSCC cells. Knockdown of CFB and C3 by specific siRNAs inhibited migration of cSCC cells. Knockdown of CFB inhibited proliferation of cSCC cells and this was associated with potent inhibition of ERK1/2 activation. Knockdown of C3 and CFB also significantly inhibited growth of human cSCC xenograft tumors in vivo in SCID mice. These results provide evidence for the role of C3 and CFB in progression of cSCC and identify them as specific biomarkers and putative therapeutic targets for invasive cSCC.

Citation Format: Pilvi Riihila, Mehdi Farshchian, Markku Kallajoki, Atte Kivisaari, Seppo Meri, Reidar Grenman, Ritva Heljasvaara, Taina Pihlajaniemi, Juha Peltonen, Sirkku Peltonen, Veli-Matti Kahari. Complement component C3 and complement factor B regulate growth of cutaneous squamous cell carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3201. doi:10.1158/1538-7445.AM2015-3201
Abstract 3203: Multiple myeloma microenvironment and obesity
Authors: Bullwinkle Erica
Published: August 2015

Multiple myeloma accounts for roughly 1% of all cancers diagnosed in the United States each year. Risk factors include environmental exposure, age, ancestry, gender, and obesity. Rates of obesity are on the rise in the United States and around the world; in the United States alone, 69% of adults are either overweight (BMI 25-30) or obese (BMI 30-35) and 6.3% of adults are extremely obese (BMI > 35). Although there is a strong epidemiological correlation between obesity and multiple myeloma, the mechanism by which adipocytes contribute to the development and progression of the cancer has yet to be identified. In this study, we isolated stem cells from patients undergoing elective liposuction surgery, differentiated the stem cells into adipocytes, and co-cultured the adipocytes with RPMI 8226 or NCI-H929 multiple myeloma (MM) cell lines. MM cells proliferated faster when co-cultured with adipocytes versus growing alone. MM growth rate was significantly higher in response to adipocytes from obese patients in comparison to adipocytes from normal weight individuals. Further, conditioned media from adipocytes from obese patients significantly increased pro-angiogenic signaling within a tube formation assay, induced an increase in MM cell adhesion, and increased expression of matrix metalloproteinases. In summary, our data suggests that adipocytes in the MM microenvironment contribute to MM progression and should be further evaluated as a possible therapeutic target.

Citation Format: Erica Bullwinkle. Multiple myeloma microenvironment and obesity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3203. doi:10.1158/1538-7445.AM2015-3203
Abstract 3216: Immunogenicity and genomic profiling reveal sub-clonal diversity of a murine acute myeloid leukemia (AML) cell line
Authors: Brinster Carine , DRISS Virginie , Quesnel Bruno , Figeac Martin , Leprêtre Frédéric , Villenet Céline , Briche Isabelle
Published: August 2015

In acute myeloid leukemia (AML), clonal heterogeneity at diagnosis and the presence of minor sub-clones were shown to be responsible for minimal residual disease and relapses in patients. Several studies have proposed that their persistence could be due to their dormant state (i.e. quiescence and/or control of their growth by immune cells). As contribution of immunity to clonal persistence could not be evaluated in xenografts models, we assessed for the clonal diversity of a murine AML cell line. Genomic analyses revealed heterogeneity among the parental cell line and its derived clones. Injected individually into immune-deficient mice, all clones induced AML with different kinetics. However, when administered into immune-competent animals, some clones triggered AML with no mice survival, whereas others elicited reduced lethality rates. The leukemia-surviving mice presented an efficient anti-tumoral CTL activity and reduced lymphopenia. Investigating for residual leukemic cells in the organs of these mice, elimination rather than persistence was observed. Thus, we showed that genetic heterogeneity among the clones led to differential immunogenicity resulting either in their immune escape or elimination. Such findings could have potent implications for new immunotherapeutic strategies in patients.

Citation Format: Carine Brinster, Virginie DRISS, Bruno Quesnel, Martin Figeac, Frédéric Leprêtre, Céline Villenet, Isabelle Briche. Immunogenicity and genomic profiling reveal sub-clonal diversity of a murine acute myeloid leukemia (AML) cell line. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3216. doi:10.1158/1538-7445.AM2015-3216
Abstract 3219: A patient-centric repository of PDX models for translational oncology research
Authors: Khor Tin O. , Ben Zvi Ido , Katz Amanda , Vasquez-Dunddel David , Sloma Ido , Ciznadija Daniel , Sidransky David , Paz Keren
Published: August 2015

Patient-derived xenograft (PDX) models maintain the complex intra-tumoral biology and heterogeneity of an intact malignancy, as well as the interplay with stromal components and other cells fluxing into the tumor environment. This intrinsic cross-talk between different elements of the tumor makes PDX models a superior tool for translational drug discovery research and personalized oncology studies. Champions PDX models were originally developed for personalizing cancer treatments through the different Champions clinical programs. These models accurately reflect the population of patients enrolling in clinical trials. We describe herein our extensive TumorBank of PDX models, a valuable resource for translational oncology research to predetermine target populations for intervention with novel therapeutics in specific cancer subtypes.

Tumor tissue from over 950 patients with a variety of primary and metastatic solid malignancies, across all ages and ethnicities and encompassing both treatment-naïve and heavily-pretreated individuals, has been implanted into immunodeficient mice with successful engraftment observed in ∼72% of cases. Comprehensive and translational-relevant clinical annotations have been maintained for these PDX models, including patient demographics, disease stage, anatomic location, tumor grade and histology, and treatment history. Importantly, whole exome and RNA sequencing, tissue histopathology, and protein immunohistochemistry have all been applied to 297 of these models. Finally, 70 of the models were screened against the corresponding patient's treatment used in the clinic, demonstrating a sensitivity of 98%, specificity of 76%, positive predictive value of 89% and negative predictive value of 96%. This wealth of information can be accessed through the Champions TumorGraft Database. The combination of extensive molecular and clinical annotation, together with opportunities for unlimited prospective preclinical testing, makes Champions TumorBank a pioneering resource for pharmaceutical companies seeking to identify target populations for therapeutic intervention.

Citation Format: Tin O. Khor, Ido Ben Zvi, Amanda Katz, David Vasquez-Dunddel, Ido Sloma, Daniel Ciznadija, David Sidransky, Keren Paz. A patient-centric repository of PDX models for translational oncology research. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3219. doi:10.1158/1538-7445.AM2015-3219
Abstract 3224: Molecular Response LLC tumor bank and patient-derived tumor xenograft models: a powerful translational engine for discovery and development of novel oncology therapeutics
Authors: Broudy Thomas , Ricono Jill , Scott Colleen , Nair Praveen , Thatte Jayant , Mirsaidi Cyrus
Published: August 2015

Patient-derived xenograft (PDX) models have been established from the world's largest living tumor bank at Molecular Response and used to mimic clinical trial settings with patients with heterogeneous populations and heterogeneous disease within oncology indications for a faster and less expensive path to test novel compounds in a more predictive preclinical setting. Overall, the collection is comprised of 144 000 tumor samples corresponding to 70 000 unique patients and continues to grow with new patient samples added routinely. For several patients, multiple samples were collected at different times (before and after treatment) or at different locations (primary/ metastatic). This allows evaluation of drug efficiency in pre and post treatment application which mimics a clinical setting as well the ability to monitor the effect of drug on the primary tumor and a matched metastatic tumor. For banked tumors, we have histo-pathological and molecular data as well as FFPE slides, DNA, RNA and chemosensitivity data from the original patient. MRL currently has over 350 PDX models in progress and has established >300 unique PDX models in multiple indications. Many established PDX models have confirmed histology and mutational profiling (Next-Gen sequencing) to demonstrate preservation of the biological characteristics of these models to the original patient sample as well as between passages within the model. MRL's vast collection of patient samples allows clients the ability to focus on unique subsets of patients for a custom model build or the ability to choose from our extensive list of established PDX models to further drug discovery of novel compounds.

Citation Format: Thomas Broudy, Jill Ricono, Colleen Scott, Praveen Nair, Jayant Thatte, Cyrus Mirsaidi. Molecular Response LLC tumor bank and patient-derived tumor xenograft models: a powerful translational engine for discovery and development of novel oncology therapeutics. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3224. doi:10.1158/1538-7445.AM2015-3224
Abstract 3226: Patient-derived xenograft (PDX) models for triple negative breast cancer (TNBC): A pre-clinical platform for drug discovery
Authors: Thatte Jayant , Meza Miguel , Ricono Jill , Mirsaidi Cyrus , Broudy Thomas
Published: August 2015

In the United States, TNBC comprises 15-20% of breast cancers and are characterized by the lack of expression of estrogen receptor, progesterone receptor and receptor tyrosine protein kinase ERBB2 or Her-2/neu oncogene amplification. As a result, this type of breast cancer is difficult to treat as most of the chemotherapies target these 3 receptors. TNBC is highly aggressive and is associated with high morbidity, mortality and shorter disease-free survival. Given its heterogeneous clinical presentation, histology and response to therapy, prognosis and management of TNBC is complicated. In this study, we report development and characterization of the TNBC PDX model. We used patient derived TNBC tissues to generate 5 new TNBC models in NOD-SCID mice. Patient tumors were pre-screened for their ER, PR and Her-2/Neu expression by IHC, prior to inoculation in mice. Efficacy of two standard of care drugs, Cisplatin and Vinorelbine in the TNBC PDX model demonstrates the potential utility of the TNBC model in drug discovery effort in oncology for treatment of TNBC.

Citation Format: Jayant Thatte, Miguel Meza, Jill Ricono, Cyrus Mirsaidi, Thomas Broudy. Patient-derived xenograft (PDX) models for triple negative breast cancer (TNBC): A pre-clinical platform for drug discovery. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3226. doi:10.1158/1538-7445.AM2015-3226
Abstract 3232: CEP-37440, a highly selective and potent dual inhibitor of ALK and FAK1 inhibits the proliferation of inflammatory breast cancer cells
Authors: Salem Israa , Aburto Lucy , Addya Sankar , Chervoneva Inna , Mu Zhaomei , Ruggeri Bruce , Cristofanilli Massimo , Fernandez Sandra V.
Published: August 2015

Inflammatory breast cancer (IBC) is a very aggressive type of advanced breast cancer with a poor prognosis. Due to its propensity to rapidly metastasize, IBC is responsible for a disproportionate number of breast cancer-related deaths; 15% of all breast cancer deaths result from this disease. Approximately 30% of IBC patients have distant metastases at time of diagnosis, in contrast to 5% of patients with non-IBC breast cancers. Currently, there is no adequate adjuvant therapy to reduce the risk of recurrence and mortality in IBC patients. We recently found that FAK1, also known as PTK2, is amplified, up-regulated and phosphorylated (active) in some inflammatory breast cancer cells [1]. The focal adhesion kinase FAK1 is a cytoplasmic tyrosine kinase that localizes to focal adhesions, and controls a number of cell pathways including proliferation, viability and survival. Activated FAK1 is absent or low in normal tissue and benign neoplasms and up-regulated in invasive and metastatic tumors. In this study, we investigated a new dual FAK1/ALK inhibitor, CEP-37440, in vitro and in vivo using preclinical models of IBC. We found that 300 nM CEP-37440 was able to decrease the proliferation of the triple negative FC-IBC02 cell line and, 1000 nM CEP-37440 was able to complete inhibit the proliferation of these cells. SUM190 showed a 50% decreased in proliferation when these cells were treated with 1000 nM CEP-37440. Genes involved in functions such as cellular growth and proliferation, cell cycle, cell death and survival and cellular movement and cell-to cell signaling and interaction were differentially regulated by CEP-37440 in sensitive IBC cell lines. Among them, TGFβ1 and MMP3 were down-regulated and DKK3, CAV1 and TFPI2 were up-regulated by CEP-37440. In FC-IBC02 orthotopic breast cancer xenograft models, CEP-37440 was able to reduce the growth of the primary tumor and inhibit the development of spontaneous metastases in brain. In conclusion, CEP-37440 was highly effective in reducing the proliferation in vitro and in vivo of IBC cells that expressed high levels of phospho-FAK (Tyr397).

References

1. Fernandez S, Robertson F, Pei J, Aburto-Chumpitaz L, Mu Z, Chu K, Alpaugh K, Huang Y, Cao Y, Ye Z et al: Inflammatory breast cancer (IBC): clues for targeted therapies. Breast Cancer Res Treat 2013, 140:23-33.

Citation Format: Israa Salem, Lucy Aburto, Sankar Addya, Inna Chervoneva, Zhaomei Mu, Bruce Ruggeri, Massimo Cristofanilli, Sandra V. Fernandez. CEP-37440, a highly selective and potent dual inhibitor of ALK and FAK1 inhibits the proliferation of inflammatory breast cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3232. doi:10.1158/1538-7445.AM2015-3232
Abstract 3233: Contribution of cell types and genetic alterations in breast cancer progression
Authors: Bhagirath Divya , Zhao Xiangshan , West William W. , Band Hamid , Band Vimla
Published: August 2015

Breast cancer is classified in to different subtypes based on gene expression profiling. Significantly distinct subtypes present different outcome for patient survival, thus underscoring importance of understanding the role of precursor cell and genetic alterations in breast cancer subtypes. In the present study we are evaluating the role of defined combination of oncogenes in two distinct cell types in regulating the oncogenesis and metastatic behavior. We have earlier developed two hTERT-immortalized human stem/progenitor cell lines that are designated as K5+/K19- or K5+/K19+. We introduced different oncogenes in these cell lines and then examined their oncogenic potential, tumor formation and metastasis, using both in vitro and in vivo assays. We found that combinations of mutant H-Ras(mRas) and mutant p53(mp53), together with either wild type ErbB2(wtErbB2) or wild type EGFR(wtEGFR) efficiently transformed both cell types. Tumors formed by these cells were histologically heterogeneous, with variable proportions of luminal, basal-like and claudin-low type components dependent on cell types and oncogene combinations. Notably, K5+/K19- cells transformed with mRas/mp53/wtEGFR combination had significantly longer latency for primary tumor development than those expressing mRas/mp53/wtErbB2. Despite the longer latency, overall oncogene combination mRas/mp53/wtEGFR give early lung metastasis onset in both K5+/K19- and K5+/K19+ cells as compared to mRas/mp53/wtErbB2 indicating higher metastatic potential of this combination. Besides the effect of different oncogene combinations, we also found that K5+/K19+ cells overall had shorter primary tumor latency, and high metastatic potential than K5+/K19- cells. Histological and biochemical characterization of metastatic tumors is underway and will be discussed at the time of presentation. Our results suggest that both the genetic alteration and cell type contribute to oncogenicity of breast tumors.

Citation Format: Divya Bhagirath, Xiangshan Zhao, William W. West, Hamid Band, Vimla Band. Contribution of cell types and genetic alterations in breast cancer progression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3233. doi:10.1158/1538-7445.AM2015-3233
Abstract 3238: Taiwanin A targets against nonsteroidal anti-inflammatory drug-activated gene-1 in human lung carcinoma
Authors: Chuang Hong-Meng , Harn Horng-Jyh
Published: August 2015

Taiwanin A (α,β-bis(piperonylidene)-γ-butyrolactone) is isolated from Taiwania cryptomerioides. Similar to paclitaxel, Taiwanin A also extracted from tree barks and have anti-tumor activity in breast, liver, and lung cancer cell lines. The objective of this study is to demonstrate the cytotoxicity of Taiwanin A against tumor cells by increasing the expression of Non-steroidal anti-inflammatory drug-activated gene (NAG-1). NAG-1 has been reported to have antitumor and pro-apoptotic activity, suggesting potential target for cancer therapy. Silencing NAG-1 mRNA expression in A549 reduces the cytotoxicity caused by Taiwanin A. Furthermore, the c-Jun-N-terminal kinase/Ste20-related protein proline/alanine-rich kinase (JNK/SPAK) pathway played a key role in the action of NAG-1 on cell viability, whereas the addition of the JNK pathway inhibitor, SP600125, resulted in the inhibitory effect of NAG-1 and recovery of Taiwanin A treated cells. Xenograft tumor model showed that Taiwanin A dose-dependently significantly decreases tumor mediated growth in nude mice by increasing NAG-1 expression accompanied tumor apoptosis. These data support the conclusion that Taiwanin A inhibits lung carcinoma growth by increasing NAG-1 expression via the JNK pathway both in vivo and in vitro. This result might be contributed to compound design for increasing cytotoxicity activity in the future.

Citation Format: Hong-Meng Chuang, Horng-Jyh Harn. Taiwanin A targets against nonsteroidal anti-inflammatory drug-activated gene-1 in human lung carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3238. doi:10.1158/1538-7445.AM2015-3238
Abstract 3247: Primary tumor cell lines generated from patient-derived-xenograft models are useful tools for study tumor biology, drug efficacy
Authors: Hu Gang , Huang Yong , Xie Fubo , Tang Xuzhen , Yang Xueyan , Liu Kunyan , Zhang Yixin , Tao Weikang , Zhou He
Published: August 2015

Patient-derived-xenograft (PDX) models have been widely used in the biomedical research. They recapitulate the genomic diversity/heterogeneity of patient tumors, maintain a lot of the characteristics of the original tumors and showed much better correlation with clinical outcome comparing to traditional cell line derived xenograft models. However, the relatively low throughput and time-consuming nature of PDX studies prevent them from being used in large scale screening or mechanistic studies. To address this, different cancer cell lines have been developed in our laboratory from the PDX tumors. We performed STR analyses to validate their identity. Whole exome sequencing, RNA-seq, SNP array 6.0 were performed on selected cell lines. When we compared 5 of these cell lines with their parental PDX tumors, over 93% of the CNVs identified in the cell lines were also found in the corresponding PDX models. Copy number analyses also revealed similar focal amplifications both on the cell lines and the original PDX models. More importantly, efficacy studies using different compounds showed similar drug responses using in vitro cell culture, xenografts using these cell lines and original PDX models. Our data demonstrated the high fidelity of these cell lines to their parental PDX models. In addition, we generated cell lines from progressed tumors upon exposure to long term drug treatment. The pair of treatment sensitive and resistant tumor cell lines facilitated the research on development of drug resistance. Overall, while maintaining the genetic background and phenotypic characteristics of the PDX models, these primary tumor cell lines serve as a bridge between the high-throughput drug screening and highly clinical relevant PDX models. They represent useful tools in biomedical research.

Citation Format: Gang Hu, Yong Huang, Fubo Xie, Xuzhen Tang, Xueyan Yang, Kunyan Liu, Yixin Zhang, Weikang Tao, He Zhou. Primary tumor cell lines generated from patient-derived-xenograft models are useful tools for study tumor biology, drug efficacy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3247. doi:10.1158/1538-7445.AM2015-3247
Abstract 3249: Recurrent 3p21 deletion in head and neck squamous cell carcinoma identifies SEMA3F as an anti-lymphangiogenic metastasis suppressor gene
Authors: Doçi Colleen L. , Mikelis Constantinos M. , Lionakis Michail S. , Molinolo Alfredo A. , Gutkind J Silvio
Published: August 2015

Head and neck squamous cell carcinomas (HNSCC) often metastasize to locoregional lymph nodes, and lymph node involvement represents one of the most important prognostic factors of poor clinical outcome. HNSCC are remarkably lymphangiogenic and represent a clear example of a cancer that utilizes the lymphatic vasculature for malignant dissemination; however, the molecular mechanisms underlying lymphangiogenesis in HNSCC is still poorly understood. Of interest, we found that an axon guidance molecule, Semaphorin 3F (SEMA3F), is among the top 1% underexpressed genes in HNSCC, and that genomic loss of SEMA3F correlates with increased metastasis and decreased survival. SEMA3F acts on its co-receptors, plexins and neuropilins, among which neuropilin-2 (NRP2) is highly expressed in lymphatic endothelial cells (LECs) but not in oral epithelium and most HNSCCs. We show that recombinant SEMA3F promotes LEC collapse and potently inhibits lymphangiogenesis in vivo. By reconstituting all possible plexin and neuropilin combinations, we found that SEMA3F acts through multiple receptors, but predominantly requires NRP2 to signal in LECs. Using orthotopic HNSCC metastasis mouse models, we provide direct evidence that SEMA3F re-expression diminishes lymphangiogenesis and lymph node metastasis. Furthermore, analysis of a large tissue collection revealed that SEMA3F is progressively lost during HNSCC progression, concomitant with increased tumor lymphangiogenesis. SEMA3F is localized to 3p21, an early and frequently deleted locus in HNSCC and many other prevalent human malignancies. Thus, SEMA3F may represent an antilymphangiogenic metastasis suppressor gene widely lost during cancer progression, hence serving as a prognostic biomarker and an attractive target for therapeutic intervention to halt metastasis.

Citation Format: Colleen L. Doçi, Constantinos M. Mikelis, Michail S. Lionakis, Alfredo A. Molinolo, J Silvio Gutkind. Recurrent 3p21 deletion in head and neck squamous cell carcinoma identifies SEMA3F as an anti-lymphangiogenic metastasis suppressor gene. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3249. doi:10.1158/1538-7445.AM2015-3249
Abstract 3262: Mitochondrial haplotype effects on tumor formation and metastasis are both cell autonomous and non-cell autonomous
Authors: Brinker Amanda E. , Vivian Carolyn J. , Feeley Kyle P. , Ballinger Scott W. , Welch Danny R.
Published: August 2015

Increasing data support roles for mitochondrial genomes in complex diseases, including cancer. We hypothesize that primary tumor formation and metastasis can arise from inherited mitochondrial differences. To test directly the role of mitochondrial DNA (mtDNA) in mammary cancer tumorigenicity and metastasis, we generated Mitochondrial Nuclear Exchange (MNX) mice. This unique animal model is created by moving the nucleus from an oocyte of one strain into an enucleated oocyte of a different strain. By exchanging the nucleus of mouse strains promoting or inhibiting metastatic efficiency, mtDNA effects can be distinguished from phenotypes which would occur due to nuclear admixing. To determine if a change in the mtDNA background impacts metastasis in a cell autonomous manner, two FVB transgenic mouse strains encoding either Her2 or PyMT oncogenes were crossed with MNX mice with FVB nuclear DNA and mtDNA from either BALB/cJ or C57BL6J strains. The mtDNA were chosen because of higher or lower metastatic efficiency, respectively (PMID9679770, PMID16491073). Latency of mammary tumor formation in MNX mice with C57BL/6 mtDNA is longer for both Her2 and PyMT. Lung metastases are smaller in C57BL6 but larger in BALB/c MNX crosses with the PyMT. Studies measuring metastasis efficiency in the MNX crosses with Her2 are still in progress. To determine whether the mitochondrial haplotype alters tumorigenicity or metastasis in a non-cell autonomous manner, syngeneic tumor cells were injected orthotopically and ectopically (i.v.). Tumor formation and metastasis differ in a tumor and mtDNA-dependent manner. For example, E0771 forms significantly more lung metastases in C57BL/6n:C3H/HeNmt mice compared to controls. To explore underlying mechanisms, metabolic differences were observed in MNX and matched wild type mouse embryonic fibroblasts using the Seahorse bioanalyzer. Conclusion: mtDNA affects mammary cancer development and progression via both genetic and non-cell autonomous mechanisms in the tumor microenvironment. Support: Susan G. Komen for the Cure (SAC11037), Natl Fndn Cancer Res, Steiner Family Fund for Metastasis Research, Kansas Bioscience Authority, CA134981, P30-CA168524

Citation Format: Amanda E. Brinker, Carolyn J. Vivian, Kyle P. Feeley, Scott W. Ballinger, Danny R. Welch. Mitochondrial haplotype effects on tumor formation and metastasis are both cell autonomous and non-cell autonomous. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3262. doi:10.1158/1538-7445.AM2015-3262
Abstract 3263: Investigating TIP60's role in regulating cancer metastasis
Authors: Zhang Yanzhou
Published: August 2015

HIV-Tat-interacting protein 60 KDa (TIP60) is a lysine acetyltransferase implicated in multiple cellular pathways such as transcription, DNA damage-induced checkpoint activation, and apoptosis. TIP60 is a haploinsufficient tumor suppressor and known to be down-regulated in cancers, including virus induced cancers. Cell migration or epithelial-mesenchymal transition (EMT) is a highly conserved cellular program that allows polarized, immotile epithelial cells to convert to motile mesenchymal cells. Recent studies show that down-regulation of TIP60 correlate with cancer metastasis with higher tumor node metastasis (TNM) and poor survival rates. Yet the mechanism of how TIP60 regulate EMT remains unknown. In this study we found TIP60 acts as an inhibitor of cell migration and negatively regulates metastasis capability of breast cancer cells. By using in vitro and in vivo models we show that overexpression of TIP60 inhibit breast cancer metastasis. Furthermore, analyses of our expression data reveal that the levels of cell adhesion genes are significantly changed in the absence of TIP60. Mechanistically, we show TIP60 to interact with Snail2 and regulate its ability to bind to its target promoters. Interestingly, we also found that TIP60 is significantly down-regulated in the breast cancer patient, and levels of TIP60 were significantly decreased as the disease progressed and its expression negatively correlates with metastasis. In summary, our data suggests that patients with lower TIP60 expression have a poor prognosis of overall and disease free survival.

Citation Format: Yanzhou Zhang. Investigating TIP60's role in regulating cancer metastasis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3263. doi:10.1158/1538-7445.AM2015-3263
Abstract 3264: Genome-wide shRNA screen identifies ITIH5 gene as a metastasis suppressor of pancreatic ductal adenocarcinoma (PDAC)
Authors: Sasaki Ken , Kurahara Hiroshi , Natsugoe S , Iwakuma Tomoo , Welch Danny R.
Published: August 2015

Background: PDAC is a leading cause of cancer-related death worldwide, and most patients have incurable disease at diagnosis. Life expectancy is only 3-6 months post-diagnosis, ostensibly due to early dissemination to liver and other vital organs. Results: By transfecting a shRNA library into non-metastatic PDAC line S2-028 followed by experimental metastasis assay, ITIH5 was identified. Metastatic PDAC cell lines (e.g., S2-007, MIAPaCa-2, Panc-1) had significantly lower ITIH5 protein expression compared to immortalized pancreatic ductal epithelial cells and non-/poorly-metastatic PDAC cell lines (e.g., S2-028 and BxPC3). By manipulating expression in different PDAC cell lines (over-expression in S2-007 and MIAPaCa-2, knockdown in non-metastatic S2-028 with two different shRNA) functional and selective regulation of metastasis was observed. Orthotopic tumor growth of PDAC cells was not blocked. Thus ITIH5 qualifies as a metastasis suppressor. Overexpression of ITIH5 significantly inhibited invasion and migration, while down-regulation increased these cellular properties. Immunohistochemistry of a human PDAC tissue microarray (n = 81) revealed that negative expression of ITIH5 showed significantly higher incidence of liver metastasis (P = 0.0482) corresponding with worse prognosis after surgery (P = 0.0299). Conclusions: ITIH5 is a potent metastasis suppressor with suggestive prognostic value in PDAC. Future studies will continue to characterize biochemical properties of ITIH5, identify interaction partners, and investigate the molecular mechanism(s) of action. Support: National Foundation for Cancer Research, Steiner Family Fund and CA168524.

Citation Format: Ken Sasaki, Hiroshi Kurahara, S Natsugoe, Tomoo Iwakuma, Danny R. Welch. Genome-wide shRNA screen identifies ITIH5 gene as a metastasis suppressor of pancreatic ductal adenocarcinoma (PDAC). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3264. doi:10.1158/1538-7445.AM2015-3264
Abstract 3283: The role of formyl peptide receptor 1 (FPR1) in neuroblastoma tumorigenesis
Authors: Snapkov Igor , Öqvist Carl Otto , Figenschau Yngve Anton , Kogner Per , Johnsen John Inge , Sveinbjørnsson Baldur
Published: August 2015

The formyl peptide receptor 1 (FPR1) is a G protein-coupled receptor with pattern recognition properties and is mainly expressed by myeloid cells. It is involved in a broad range of host defense mechanisms and a variety of host-derived agonists of FPR1 have been identified, including formyl peptides released from disrupted mitochondria of necrotic cells.

In the present study, we demonstrate the expression of FPR1 in 7 different neuroblastoma cell lines and in primary tumors. Furthermore, FPR1 is expressed at increased levels in high stage tumors. Addition of the FPR1 agonist N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP) to neuroblastoma cells in vitro caused enhanced proliferative activity, increase of intracellular calcium response and activation of STAT3 and MAPK/ERK signal transduction pathways. All these signal transduction events were abrogated by the use of Cyclosporin H, a specific FPR1 antagonist.

To assess the significance of this receptor in vivo, we developed a set of neuroblastoma cell clones with different expression levels of FPR1. Xenograft models showed that cells with overexpression of the receptor developed tumors significantly faster compared to control group.

Our findings so far suggest that FPR1 may play a significant role in neuroblastoma tumorigenesis and that therapeutic intervention of the FPR1 pathway may be an important clinical strategy in neuroblastoma therapy.

Citation Format: Igor Snapkov, Carl Otto Öqvist, Yngve Anton Figenschau, Per Kogner, John Inge Johnsen, Baldur Sveinbjørnsson. The role of formyl peptide receptor 1 (FPR1) in neuroblastoma tumorigenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3283. doi:10.1158/1538-7445.AM2015-3283
Abstract 3297: Cell phone use and cytokines expression in saliva of the parotid glands
Authors: de Souza Fabrício TA , Gomes Carolina C. , De Marco Luiz Armando , Siqueira Elisa C. , Costa Samuel M. , Correia-Silva Jeane F. , Gomez Ricardo S.
Published: August 2015

The association between cell phone use and the development of parotid tumors is controversial. Because there is unequivocal evidence that the microenvironment is important for tumor formation, we investigated in the parotid glands whether cell phone use alters the expression of cytokines. We used the saliva produced by the parotid glands to assess cytokines levels, comparing the saliva from the gland exposed to cell phone radiation (ipsilateral) to the saliva from the opposite, unexposed parotid (contralateral) of each individual. We compared salivary flow, total protein, IL-1 β, IL-6, IFN-γ and TNF-α between the ipsilateral and contralateral parotids of forty-three individuals. No difference was found for any of these parameters. Our study provides evidence that the exposure of parotid glands to cell phone use does not alter cytokines levels in the parotid. Supported by CAPES, FAPEMIG and CNPq, Brazil.

Citation Format: Fabrício TA de Souza, Carolina C. Gomes, Luiz Armando De Marco, Elisa C. Siqueira, Samuel M. Costa, Jeane F. Correia-Silva, Ricardo S. Gomez. Cell phone use and cytokines expression in saliva of the parotid glands. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3297. doi:10.1158/1538-7445.AM2015-3297
Abstract 3302: Subtype-specific radiation response in a mouse model of human breast cancer
Authors: Lee Chen-Ting , Zhou Yingchun , Siamakpour-Reihani Sharareh , Choudhury Kingshuk R. , Dewhirst Mark W. , Horton Janet K.
Published: August 2015

Radiation therapy is an important component of multimodal treatment for women with breast cancer. However, breast radiotherapy is currently delivered uniformly, regardless of breast cancer subtype. Recent clinical data have suggested that different subtypes of breast cancer may respond differently to radiation. Understanding the intrinsic variation of radiation response in breast cancer subtypes would lay the foundation for individualized radiotherapy designed to limit toxicity in those with radiation responsive cancers. Furthermore, identification of molecular targets can be used to modulate treatment outcomes in patients with radiation resistant tumors.

Our previous in vitro studies have identified an association between breast cancer subtype and gene expression profiles in response to radiation in breast tumor cell lines. Cell lines with the greatest response to radiation were luminal subtype and exhibited preferential induction of genes involved in programmed cell death, such as FAS. In this study, we investigated tumor growth and FAS induction in response to radiation in a mouse model of breast cancer. MCF7 (luminal) or SUM159 (basal) cells were implanted orthotopically into the dorsal mammary fat pad of athymic nude mice. These mice were then treated with different doses of radiation. Our results showed that radiation treatment inhibited MCF7 tumor growth in a dose-dependent manner, while radiation treatment had little effect on SUM159 tumor growth. In addition, FAS was induced in MCF7 tumors 24 hour after radiation, but there was no change in FAS expression in SUM159 tumors. However, injection of FAS-stimulating antibody intratumorally led to downstream caspase 8 and PARP activation, suggesting that the FAS signaling pathway remains intact and can be used to modulate radiation response in the resistant SUM159 cells.

In conclusion, these results suggest that there is intrinsic variation in radiation response among breast cancer subtypes and that stimulation of FAS may have the potential to modulate radiation response.

Citation Format: Chen-Ting Lee, Yingchun Zhou, Sharareh Siamakpour-Reihani, Kingshuk R. Choudhury, Mark W. Dewhirst, Janet K. Horton. Subtype-specific radiation response in a mouse model of human breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3302. doi:10.1158/1538-7445.AM2015-3302
Abstract 3305: The role of mTOR in mediating nicotine induced alpha-7 nicotinic acetylcholine receptor activation and the regulation of radiotherapeutic response
Authors: Sobus Samantha L. , Balasubramanian Sundaravadivel , Romano Michelle A. , Warren Graham W.
Published: August 2015

Tobacco use is the single largest preventable risk factor for developing cancer. Furthermore, tobacco is associated with poor therapeutic outcomes in part because its continued use has been shown to decrease the efficacy of conventional chemotherapy and/or radiotherapy (RT). Preclinical data suggests that nicotine administration decreases RT efficacy by activating the alpha-7-nicotinic acetylcholine receptor (a7-nAChR). Our study evaluated the effects of nicotine and selective a7-nAChR agonists (LY 2087101, PHA 543613, PNU 282987, and TC 1698) administration on radiotherapeutic efficacy. H460 and A549 human lung cancer cell lines were dose escalated with nicotine and the a7-nAChR agonists alone or in combination with single fraction X-ray radiation (2, 6 Gy) and cell survival was assessed by clonogenic assay. Nicotine administration and activation of a7-nAChR by LY 2087101 or PHA 543613 was found to have a radioprotective effect in both cell lines by increasing cell survival following RT. Conversely, activation of a7-nAChR by PNU 282987 or TC 1698 did not modulate radiotherapeutic response. Western blot analysis demonstrated that although all four tested a7-nAChR agonists increased phosphorylation of AKT (S473), only PHA 543613 and LY 2087101 were found to also activate mTOR (S2448). Additional clonogenic studies were performed to further examine the role of mTORC1 in governing response to RT. Inhibition of mTORC1 by rapamycin alone sensitized both A549 and H460 cells to the effect of RT. Interestingly, rapamycin treatment was sufficient to block the radioprotective effects of nicotine, PHA 543613, and LY 2087101 in A549 cells, however, in H460 cells rapamycin did not restore radiotherapeutic efficacy. Moreover, examination of Deptor, a key component of mTOR complexes shown to be associated with RT response, demonstrated that a7-nAChR activation by nicotine, PHA 543613, or LY 2087101 increased Deptor degradation in A549 cells, while a7-nAChR activation decreased Deptor degradation in H460 cells. These observations suggest that differences in the regulation of Deptor level may contribute to the variation in both rapamycin sensitivity and restoration of therapeutic efficacy to RT between H460 and A549 cell lines. Additional studies will be necessary to further elucidate the role of the mTOR complexes in mediating a7-nAChR induced modulation of response to RT.

Citation Format: Samantha L. Sobus, Sundaravadivel Balasubramanian, Michelle A. Romano, Graham W. Warren. The role of mTOR in mediating nicotine induced alpha-7 nicotinic acetylcholine receptor activation and the regulation of radiotherapeutic response. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3305. doi:10.1158/1538-7445.AM2015-3305