bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4101: Stromal cell-induced alterations in the response of colorectal cancer cell to demethylating agents
Authors: Das Viswanath , Skolekova Svetlana , Agrawal Khushboo , Gursky Jan , Kučerová Lucia , Hajdúch Marián 
Published: July 2016

Abstract
Epigenetic mechanisms such as DNA hypermethylation, that results in gene silencing, is closely associated with resistance to platinum-based chemotherapy for colorectal cancer (CRC). DNA methyltransferase inhibitors (DNMTi) that reactivate and induce reexpression of silenced gene have the potential to improve the outcome of platinum-based and other therapies in CRC. In fact, non-cytotoxic concentrations of azacitidine, a clinically used DNMTi, has been reported to resensitize platinum-resistant ovarian cells to carboplatin. Hypomethylating agents, such as azacitidine and decitabine have shown significant promise in hematologic malignancies; however, studies on their application to CRC and other solid tumors have yielded ambivalent results potentially due to the complexities of the tumor microenvironment that result from the numerous cell type interactions.
In this study, we analyzed the impact of different tumor-stroma ratios on cancer cell response to azacitidine, decitabine, and two lead compounds identified by in vitro screens in two-dimensional (2D) and three-dimensional (3D) co-cultures of colorectal HCT116 carcinoma demethylation reporter cells and adipose-derived mesenchymal stromal cells (MSCs) isolated from healthy individuals undergoing elective lipoaspiration. Each subject provided informed consent. Activity of hypomethylating drugs was examined in 2D and 3D cultures of different tumor-stroma ratios using confocal microscopy, flow cytometry, and MTT analyses.
Our preliminary flow cytometry results show an altered response of hypomethylating agents in cocultures of HCT116 and MSCs compared to monocultures of HCT116 cells alone. There was an increase in demethylation of HCT116 cells in 3D cultures containing a higher ratio of stromal cells following treatment with low concentration of decitabine. Furthermore, confocal analysis 3D co-cultures at various z-plane heights revealed increased demethylation at low concentrations of all drugs in cultures with high stromal cell numbers. These results indicate that intratumoral stroma may alter the sensitivity of cancer cells to demethylating agents and warrant further studies.
Citation Format: Viswanath Das, Svetlana Skolekova, Khushboo Agrawal, Jan Gursky, Lucia Kučerová, Marián Hajdúch. Stromal cell-induced alterations in the response of colorectal cancer cell to demethylating agents. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4101.
Abstract 4103: Cancer cell-stromal cell crosstalk drives fibroblast senescence and tumor progression in large cell carcinoma of the lung in culture and in vivo
Authors: Lugo Roberto , Gabasa Marta , Andriani Francesca , Puig Marta , Facchinetti Federica , Ramírez Josep , Gómez-Caro Abel , Pastorino Ugo , Gascón Pere , Davalos Albert , Reguart Noemí , Roz Luca , Alcaraz Jordi 
Published: July 2016

Abstract
Permanent cell cycle arrest through senescence has been previously regarded as a protective mechanism against tumor progression. In contrast, there is evidence that senescence in tumor-associated fibroblasts (TAFs) enhances tumor growth. Senescence has been reported in tumor associated fibroblasts (TAFs) from a growing list of selected cancer types. However, the presence of senescent TAFs in lung cancer remains undefined. To address this gap of knowledge, we examined common markers of senescence in primary TAFs from the 3 major non-small cell lung cancer (NSCLC) subtypes: adenocarcinoma (ADC), squamous cell carcinoma (SCC) and large cell carcinoma (LCC). Given the difficulties in gathering LCC-TAFs owing to the lower prevalence of LCC compared to the other subtypes, primary fibroblasts from 2 independent cell collections were used. We found an enrichment of the myofibroblast-like phenotype in TAFs regardless their histologic subtype, yet senescence was observed in LCC-TAFs only. Likewise, co-culturing normal lung fibroblasts with LCC (but not ADC or SCC) cancer cells was sufficient to induce senescence, and this induction was prevented in the presence of an antioxidant, indicating that it is mediated through oxidative stress. Of note, senescent fibroblasts provided growth and invasive advantages to LCC cells in culture and in vivo beyond those provided by control (non-senescent) fibroblasts. These results expand recent evidence that challenges the common assumption that lung TAFs are a heterogeneous myofibroblast-like cell population regardless their histologic subtype. Of note, because LCC often distinguishes itself in the clinic by its aggressive nature, our findings support that senescent or senescent-like TAFs may contribute to the selective aggressive behavior of LCC tumors.
Citation Format: Roberto Lugo, Marta Gabasa, Francesca Andriani, Marta Puig, Federica Facchinetti, Josep Ramírez, Abel Gómez-Caro, Ugo Pastorino, Pere Gascón, Albert Davalos, Noemí Reguart, Luca Roz, Jordi Alcaraz. Cancer cell-stromal cell crosstalk drives fibroblast senescence and tumor progression in large cell carcinoma of the lung in culture and in vivo. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4103.
Abstract 4104: Characterization and validation of an implantable chronic lung imaging window
Authors: Entenberg David , Harney Allison , Voiculescu Sonia E. , Wang Yarong , Oktay Maja , Condeelis John 
Published: July 2016

Abstract
Metastatic disease is the major cause of cancer mortality and is responsible for over 1/2 million deaths each year in the U.S. alone. Of the three most common sites of metastasis observed clinically (bone, lung and liver), the most difficult to study using intravital microscopy is the lung; a delicate organ in perpetual motion. Recent advances in intravital microscopy have enabled visualization of the live intact lung, but are limited in the duration over which they can be utilized (hours) and require major invasive surgeries. Both of these limitations reduce their usefulness in the study of single cell events in the lung and are susceptible to introducing artefacts. We report the development of a novel, minimally invasive surgical protocol for the implantation of a long-lasting lung imaging window. Once implanted, this window allows for the repeated, non-invasive visualization of living, breathing lung tissue over a period of two weeks without the need for ventilation, vacuum plates, or gated imaging equipment. Here we characterize and validate the use of this window in living mice. The window is well tolerated, does not cause infection or inflammation, and offers a 4mm view of the left lung. We utilize it to visualize, with single cell resolution, the progression of experimental metastasis from the arrival of a single cell to the formation of micro-metastases. The development of this novel optical window will allow visualization of, with single cell resolution, tumor microenvironments and metastatic progression within the lung over extended periods of time. This approach to imaging live lung tissue has the potential to reveal the mechanisms underlying many diseases affecting the lung as well as the means to directly evaluate responses to therapeutics in in real time and within a single animal.
Citation Format: David Entenberg, Allison Harney, Sonia E. Voiculescu, Yarong Wang, Maja Oktay, John Condeelis. Characterization and validation of an implantable chronic lung imaging window. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4104.
Abstract 4110: Color-coded imaging of the tumor microenvironment of malignant lymphoma in a syngeneic mouse model
Authors: Matsumoto Takuro , Suetsugu Atsushi , Hasegawa Kosuke , Nakamura Miki , Aoki Hitomi , Kunisada Takahiro , Tsurumi Hisashi , Shimizu Masahito , Hoffman Robert M. 
Published: July 2016

Abstract
EL4-RFP lymphoma cells were injected in the spleen of C57/BL6 GFP transgenic mice. EL4-RFP metastasis was observed in the lymph nodes of the supra mediastinum and abdomen and in the liver 28 days later. The EL4-RFP tumors in the spleen (primary injection site), liver, supra mediastinum lymph nodes, abdominal lymph nodes, bone marrow, and lung were visualized with the Olympus FV1000 scanning laser confocal microscope. EL4-RFP tumors in the liver, lymph nodes, and bone marrow in C57/BL6 GFP mice were rich in GFP stromal cells such as macrophages, fibroblasts, dendritic cells, and normal lymphocytes derived from the host animal. Phagocytosis of EL4-RFP lymphoma cells by macrophages, as well as dendritic cells and fibroblasts, were observed in culture. Small tumors were observed in the spleen (primary injection site), but the stroma cells in the spleen tumors were abundant. We could observe that in the lung, no mass formation of lymphoma cells occurred, but lymphoma cells circulated in lung peripheral blood vessels.
Citation Format: Takuro Matsumoto, Atsushi Suetsugu, Kosuke Hasegawa, Miki Nakamura, Hitomi Aoki, Takahiro Kunisada, Hisashi Tsurumi, Masahito Shimizu, Robert M. Hoffman. Color-coded imaging of the tumor microenvironment of malignant lymphoma in a syngeneic mouse model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4110.
Abstract 4112: Geminin overexpression-dependent recruitment and crosstalk with mesenchymal stem cells enhances aggressiveness in triple-negative breast cancers
Authors: Bonner Theresa , Ananthula Suryatheja , Nordan Janene , Batth Simran , Marshall Gailen D. , Gardner Lauren H. , Shimizu Yoshiko , ElShamy Wael M. 
Published: July 2016

Abstract
Introduction: Tumor resident mesenchymal stem cells (MSCs) promote cancer progression. Pathways involved in recruitment of MSCs to breast tumor cells remain largely undefined. We aimed at defining the mechanism whereby geminin overexpressing breast tumor cells recruit and interact with MSCs to increase their own aggressiveness.
Experimental Procedures: We used co-culturing assay, immunohistochemistry, in vitro invasion assay with or without cytokines neutralization, western blot analysis, immunoprecipitation, immunofluorescence, ELISA, exposure to hypoxic conditions, cytokines receptor inactivation, in vivo orthotopic tumor formation assay in the presence or absence of inhibitors to the proposed signaling pathways, analysis of publically available data sets for the association of selected factors with overall survival, distant metastasis free survival and recurrent free survival to define the mechanism geminin overexpressing cells employ in vivo to recruit and initiate bi-directional interactions with MSCs in order to enhance their own aggressiveness.
Results: Here we show that geminin-dependent acetylation of chromatin HMGB1 (Ac-HMGB1) leads to its release to the extracellular space. Extracellular Ac-HMGB1 promotes geminin overexpressing (GemOE) cells survival by binding to RAGE receptors. Extracellular Ac-HMGB1 also triggers expression and activation of RAGE in the non-expressing MSCs leading to induction of CXCR4 expression and migration of MSCs towards SDF1/CXCL12-expressing GemOE cells. Inhibiting c-Abl, RAGE or CXCR4 prevented MSCs recruitment to GemOE cells in vitro and in vivo. Reciprocal interactions between GemOE cells and MSCs elevate the TIC, basal and EMT traits in GemOE cells leading to enhanced aggressiveness. Indeed, faster, larger and more aggressive tumors develop when GemOE cells are co-injected with MSCs in orthotropic tumor model. Concurrently, inhibiting c-Abl and thus geminin function or RAGE or CXCR4 activity in the in vivo model not only suppressed MSCs recruitment to the orthotopic breast tumors, but also led to decrease in TIC, basal and EMT phenotypes in these tumors.
Conclusion: We suggest that GemOE generates metastatic tumors in part through recruiting and interacting with MSCs.
Citation Format: Theresa Bonner, Suryatheja Ananthula, Janene Nordan, Simran Batth, Gailen D. Marshall, Lauren H. Gardner, Yoshiko Shimizu, Wael M. ElShamy. Geminin overexpression-dependent recruitment and crosstalk with mesenchymal stem cells enhances aggressiveness in triple-negative breast cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4112.
Abstract 4116: Anti-tumor and anti-metastasis efficacy of a novel Notch inhibitor (PF-03084014) in hepatocellular carcinoma
Authors: Chuanxing Wu , Xiaoqi Wang 
Published: July 2016

Abstract
Hepatocellular Carcinoma (HCC) is well-known for its aggressive growth and highly metastatic potential. Efficacy of current therapy is limited by fast tumor growth and rapid metastasis. Cancer stem cells (CSCs) represent a distinct population that can be prospectively isolated from tumor tissues and have long-term clonal repopulation and self-renewal capacity. They are highly tumorigenic, metastatic, and resistance to conventional radiation and chemotherapy. Therefore, it is essential to identify effective therapy to target CSCs. In our prior study, Notch deregulation was correlated with poor outcome in HCC. In this study, we investigated anti-tumor and anti-metastatic efficacy of a novel Notch inhibitor (PF-03084014) in liver cancer spherical cells in vitro and sphere cell-derived orthotropic model in vivo. PF-03084014 significantly suppressed liver CSCs spheroid formation (derived from 97H HCC cells), with survival rate less than 20% by higher dose of PF-03084014. In accordance, CD90+, EpCAM+ and Oct4+ liver CSC populations significantly decreased, so as down-regulation the stem cell genes expression such as Sox2 and Nanog. These results suggest a suppressive effect of PF-03084014 on liver CSC self-renewal ability. Low dose PF-03084014 induced cancer spheroid cell differentiation leading to chemosensitization. Moreover, Notch inhibitor (PF-03084014) altered liver CSCs stemness properties and blocked spherogenesis of CSCs in vitro, leading to decrease tumorigenicity in vivo. In HCC spherical cell- and non-spherical cell-derived orthotropic model, PF-03084014 effectively inhibited tumor growth, with tumor size was 2570±690 mm3 in vehicle group vs. 800±500 mm3 in Notch inhibitor group (p &lt; 0.001). More importantly, under PF-03084014 treatment, HCC tumor metastasis to lung was significantly reduced (87.5% metastasis rate in vehicle group vs. 18.75% in PF-03084014 group). To explore the potential mechanism, we found PF-03084014 was able to suppress phosphorylation of STAT3 and AKT, the kinases involving in self-renewal of stem cells. PF-03084014 also reversed endothelial mesenchymal transition (EMT) shown by down-regulation of Snail-1 and up-regulation of E-cadherin. Together, PF-03084014 shows a strong anti-cancer and anti-metastasis effect on HCC spherical cell derived in vitro and in vivo model, which provides a preclinical rational of the PF-03084014 to serve as a new novel drug in liver cancer therapy.
Citation Format: Wu Chuanxing, Wang Xiaoqi. Anti-tumor and anti-metastasis efficacy of a novel Notch inhibitor (PF-03084014) in hepatocellular carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4116.
Abstract 4118: Honokiol inhibits lung cancer brain metastasis through inhibition of STAT3 signaling pathway
Authors: Lee Yongik , Pan Jing , Zhang Qi , Wang Yian , You Ming 
Published: July 2016

Abstract
Lung cancer is the leading cause of cancer death in the United States, and metastasis to lymph-node (LN) and distal organs especially brain leads to sever complications and are the major cause of death. Preventing lung cancer development and metastases is important strategy to reduce lung cancer mortality. Honokiol (HNK), a natural compound present in magnolia bark extracts, has a good bioavailability profile and recently has also been shown to readily cross both the blood-brain barrier (BBB). We previously demonstrated that HNK can prevent and inhibit squamous lung cancer cell carcinoma both in-vitro and in-vivo. In the current study, we evaluated the anti-metastatic effects of HNK in both LN and brain murine models of lung tumor metastasis. The H2030-BrM3 (BR-brain seeking) lung tumor cells stably transfected with luciferase and GFP were orthotopically injected into lung for LN metastases, or directly to the left ventricle of mouse heart for brain metastases, LN or brain metastasis was monitored using a non-invasive IVIS bio-luminescent imaging system. To test the efficacy of HNK in preventing tumor cells migrating to LN or brain, mice were given 10 mg/kg per body weight HNK by aerosol (for lung to LN metastasis model) or oral gavage starting the day after tumor cell injection, our results reveal that HNK significantly prevented the metastasis of lung cancer cells to LN and brain. Our results demonstrate that HNK decreased LN metastases incidence to 30% compare to 100% in control mice, and inhibited brain metastasis near 70% compare to control. Furthermore, analysis of HNK's mechanism of action by utilizing both RNA sequencing and receptor tyrosine kinase assay suggests that its effect is primarily mediated by inhibiting STAT3 pathway. HNK specifically inhibits STAT3 phosphorylation, and knock-down STAT3 totally abrogated the anti-metastasis effects of HNK in brain metastatic lung cancer cell lines, PC9-BrM3 and H2030-BrM3. These finding suggest that HNK could provide novel chemopreventive or therapeutic options for preventing both lung tumor progression and lung cancer brain metastasis.
Citation Format: Yongik Lee, Jing Pan, Qi Zhang, Yian Wang, Ming You. Honokiol inhibits lung cancer brain metastasis through inhibition of STAT3 signaling pathway. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4118.
Abstract 4127: Blockade of TGFβ signaling enhances anticancer effect of chemotherapeutics in gynecologic cancers
Authors: Zhu Haiyan , Yang Junhua , Gu Xiang , Sun Luzhe 
Published: July 2016

Abstract
Chemoresistance is a significant clinical challenge in the management of gynecologic malignancies. Previous studies have showed that TGF-β signaling pathway can mediate chemotherapy resistance. However, the underlying mechanisms of how TGF-β pathway is activated and causes chemoresistance are not well understood. Here, we found that ovarian cancer patients displayed an increased RNA transcripts of genes associated with TGF-β signaling after chemotherapy. In vitro, treatment with four commonly used drugs for gynecologic malignancies, including cisplatin, doxorubicin, paclitaxel and camptothecin, activated TGFβ signaling by stimulating phosphorylation of Smad2 and Smad3, two intracellular mediators of TGFβ signaling pathway in ovarian and cervical cancer cell lines. Furthermore, cisplatin and doxorubicin can induced epithelial-mesenchymal transition (EMT) and promote migration. Blockade of TGFβ signaling abrogated chemotherapeutics-stimulated Smad phosphorylation, epithelial-mesenchymal transition, and migration. These observations suggest that chemotherapy-mediated activation of TGFβ signaling may be a mechanism of chemoresistance, and that TGFβ pathway inhibitor may prevent the development of chemoresistant. We are currently testing the anti-tumor efficacy of the combination therapy with a novel pan-TGFβ inhibitor and cisplatin in a mouse xenograft model of ovarian cancer and whether the treatment with TGFβ inhibitor can alleviate symptoms of nephrotoxicity, which is known to be caused by cisplatin. Our studies may reveal new strategies for the treatment of gynecologic malignancies.
Citation Format: Haiyan Zhu, Junhua Yang, Xiang Gu, Luzhe Sun. Blockade of TGFβ signaling enhances anticancer effect of chemotherapeutics in gynecologic cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4127.
Abstract 4131: Blocking endogenous TBX2 abrogates prostate cancer bone metastasis through WNT signaling
Authors: Nandana Srinivas , Tripathi Manisha , Duan Peng , Chu Gina , Zhau Haiyen E. , Matusik Robert J. , Chung Leland W.K. 
Published: July 2016

Abstract
Bone metastasis is a crucial turning point in the progression of PCa and is seen in &gt; 90% of the lethal cases. Identifying factors that mediate the metastatic spread and subsequent remodeling of the bone is highly relevant to successful therapeutic intervention in advanced human prostate cancer (PCa). TBX2, a transcription factor that belongs to the T-box family negatively regulates p21 cell cycle inhibitor and is known to play critical roles during embryonic development and cancer progression. Interestingly, a recent report found TBX2 over-expression in the bone metastases from patients with castrate resistant prostate cancer. We found TBX2 over-expression in human prostate cancer specimens and in aggressive androgen independent human PCa cell lines. Further, we found TBX2 over-expression in bone metastases in multiple xenograft mouse models of human PCa progression. Blocking endogenous TBX2 in PC3 and ARCaPM PCa cells through the use of a dominant negative construct resulted in decreased proliferation, colony formation and invasion in vitro. Utilizing various pre-clinical xenograft mouse models, we found that blocking endogenous TBX2 in PCa cells leads to decreased invasion and abrogation of bone and soft tissue metastasis in vivo. Further, utilizing the intra-tibial mouse model of growth in the bone microenvironment, we found that blocking endogenous TBX2 in PCa cells dramatically reduces bone remodeling. Additionally we found that TBX2 acts upstream of the canonical WNT (WNT3A) signaling in PCa and positively regulates its transcription by binding to its promoter. Further, rescue of WNT3A levels in PCa cells in the context of blocking endogenous TBX2 rescues the metastatic ability of the cells in vivo. Taken together, our findings highlight a novel and critical role of TBX2 in PCa progression, metastasis and the subsequent bone remodeling, and that TBX2 function in PCa is mediated through the canonical WNT signaling.
Citation Format: Srinivas Nandana, Manisha Tripathi, Peng Duan, Gina Chu, Haiyen E. Zhau, Robert J. Matusik, Leland W.K. Chung. Blocking endogenous TBX2 abrogates prostate cancer bone metastasis through WNT signaling. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4131.