bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5748: Roles of miR29c-ID2 axis in tumor initiating cells of breast ductal carcinoma in situ
Authors: Liu Yin , Pandey Puspa R. , Sharma Sambad , Wu Kerui , Xing Fei , Watabe Kounosuke 
Published: July 2017

Abstract
Ductal carcinoma in situ (DCIS) is an early-stage form of breast cancer that accounts for over 20% of all breast cancers in the US. Therefore, prevention of DCIS is a major goal for reducing breast cancer incidence. However, the underlying molecular and pathological mechanisms of DCIS remain poorly understood. It is believed that tumor-initiating cells are formed at a very early stage of tumorigenesis, which then leads to the progression of DCIS. Our recent work that focused on tumor-initiating cells of DCIS revealed that the expression of miR29c in tumor-initiating cells was significantly down-regulated in DCIS cells compared to that in normal cells. Furthermore, we found that the ID2 gene is one of the targets of miR29c in tumor-initiating cells and that miR29c suppresses the ID2 gene by directly binding to the 3’-UTR sequence. ID2 is a well-known dedifferentiation factor in embryonic development, and the ID family is involved in progression of cancer by affecting cell differentiation and proliferation. We also found that ectopic expression of ID2 in premalignant cells accelerated tumor growth and promoted self-renewal of tumor-initiating cells in DCIS, suggesting that ID2 also controls cancer cell dedifferentiation and promotes tumor-initiating cells formation. These results indicate that the miR29c-ID2 axis plays a critical role in self-renewal of DICS in vivo and that ID2 is a potential biomarker for tumor-initiating cells in DCIS. ID2 is thought to sequester E-protein transcription factors and thus regulates a wide range of gene expression. Our data suggest that ID2 upregulates expression of several cancers stem cell genes including SOX2, which is a well- known self-renewal regulator of stem cells. ID2 also upregulates the fatty acid synthase gene (FASN), which promotes cancer cell proliferation and survival. We also found that FASN expression was significantly suppressed by pterostilbene, indicating potential utility of this natural compound for preventing DCIS formation. Taken together, these results suggest that miR29c-ID2 functions as master regulators in forming DCIS. ID2 promotes self-renewal of tumor-initiating cells by regulating expression of the SOX2 and FASN genes.
Note: This abstract was not presented at the meeting.
Citation Format: Yin Liu, Puspa R. Pandey, Sambad Sharma, Kerui Wu, Fei Xing, Kounosuke Watabe. Roles of miR29c-ID2 axis in tumor initiating cells of breast ductal carcinoma in situ [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5748. doi:10.1158/1538-7445.AM2017-5748
Abstract 5755: In vitro reconstitution of high-grade serous ovarian carcinoma from primary fallopian tube secretory epithelial cells
Authors: Nakamura Kohei , Nakayama Kentaro , Kiyono Tohru , Ishikawa Noriyoshi , Minamoto Toshiko , Ishibashi Tomoka , Sanuki Kaori , Yamashita Hitomi , Ono Ruriko , Iida Kouji , Sasamori Hiroki , Sultana Razia , Hossain Mohammad Mahmud , Ishikawa Masako , Kyo Satoru 
Published: July 2017

Abstract
Purpose: Recent studies suggest that fallopian tube secretory epithelial cells (FTSECs) are potential cells-of-origin for high-grade serous ovarian carcinoma (HGSOC). Several genetic alterations are involved in HGSOC carcinogenesis, but the minimal requirement for tumor initiation remains unclear. Therefore, we sought to identify oncogenic mutations indispensable for HGSOC carcinogenesis in a stepwise model using immortalized FTSECs.
Experimental Design: We established an in vitro stepwise carcinogenesis model using immortalized FTSECs overexpressing cyclin D1, CDK4R24C, and hTERT, and mimicked select genetic abnormalities identified as gene alterations essential for carcinogenesis, including p53, c-Myc, or RAS/PI3K pathway mutations.
Results: Our analyses revealed two distinct patterns of gene alterations essential for HGSOC carcinogenesis: p53/KRAS/AKT and p53/KRAS/c-Myc. Dominant-negative p53 expression alone or in combination with oncogenic KRAS (KRASV12), constitutively active AKT (CA-AKT), or c-Myc in immortalized cells failed to induce a tumorigenic phenotype; however, overexpression of either CA-AKT or c-Myc in combination with dominant-negative p53 and KRASV12 was sufficient to confer tumorigenic potential. Importantly, all transformed FTSECs formed tumors in xenograft mice, which were grossly, histologically, and immunohistochemically similar to human HGSOC. Interestingly, mice harboring tumors with c-Myc amplifications displayed extensive metastases, consistent with the increased dissemination observed in their human counterparts. C-Myc is associated with cell proliferation in vitro; therefore, this genetic abnormality may promote HGSOC progression.
Conclusions: Collectively, our data showed that aberrant p53/KRASV12/c-Myc or p53/KRASV12/PI3K-AKT signaling is the minimal requirement for FTSEC carcinogenesis. Moreover, the model generated with this evidence will likely facilitate analysis of early events in HGSOC carcinogenesis.
Citation Format: Kohei Nakamura, Kentaro Nakayama, Tohru Kiyono, Noriyoshi Ishikawa, Toshiko Minamoto, Tomoka Ishibashi, Kaori Sanuki, Hitomi Yamashita, Ruriko Ono, Kouji Iida, Hiroki Sasamori, Razia Sultana, Mohammad Mahmud Hossain, Masako Ishikawa, Satoru Kyo. In vitro reconstitution of high-grade serous ovarian carcinoma from primary fallopian tube secretory epithelial cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5755. doi:10.1158/1538-7445.AM2017-5755
Abstract 5758: Elevated level of estrogen enhances chemotherapeutic efficacy potentially through epigenetic mechanism in human breast cancer cells
Authors: Chang Yu-Wei , Singh Kamaleshwar 
Published: July 2017

Abstract
Effectiveness of chemotherapy depends on the age of breast cancer patients. Breast tissues are estrogen sensitive and the levels of ovarian estrogen are age-dependent variable among the breast cancer patients. Whether this variation in estrogen levels influences the chemotherapeutic efficacy in breast cancer patients is unclear. Therefore, the objective of this study was to determine the effects of natural estrogen 17 beta-estradiol on the efficacy of chemotherapy in breast cancer cells. Estrogen responsive MCF-7 breast cancer cells were long-term exposed to 100 pg/ml estrogen for three months. Using these estrogen exposed MCF-7 cells, the efficacy of chemotherapeutic drugs doxorubicin and cisplatin were determined. The result of cell viability and cell cycle analysis revealed increased efficacy of doxorubicin and cisplatin in estrogen-exposed MCF-7 cells as compared to control MCF-7 cells. Gene expression analysis of marker genes for cell cycle, anti-apoptosis, DNA repair, and drug transporter genes further confirmed the increased efficacy of chemotherapeutic drugs in estrogen-exposed cells at molecular level. To further understand the role of epigenetic mechanism in enhanced chemotherapeutic efficacy by estrogen, cells were pre-treated with epigenetic drugs, 5-Aza-2-deoxycytidine and Trichostatin A before doxorubicin and cisplatin treatments. The enhanced efficacy of doxorubicin and cisplatin in estrogen-treated cells was significantly decreased by 5-aza-2 deoxycytidine pre-treatment, suggesting the role of estrogen-induced hypermethylation in enhanced sensitivity of these drugs in estrogen-exposed cells. In conclusion, results of this study demonstrate that sensitivity to chemotherapy depends on the levels of estrogen in breast cancer cells. Findings of this study will have clinical implications in selecting the type and dose of chemotherapy in breast cancer patients depending on the serum estrogen levels that varies in between pre- and post-menopausal age of the patients.
Citation Format: Yu-Wei Chang, Kamaleshwar Singh. Elevated level of estrogen enhances chemotherapeutic efficacy potentially through epigenetic mechanism in human breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5758. doi:10.1158/1538-7445.AM2017-5758
Abstract 5762: PR55-alpha associated PP2A promotes pancreatic tumorigenesis
Authors: Yan Ying , Hein Ashley L. , Seshacharyulu Parthasarathy , Rachagani Satyanarayana , Sheinin Yuri M. , Ouellette Michel M. , Ponnusamy Moorthy P. , Batra Surinder K. 
Published: July 2017

Abstract
PP2A holoenzyme consists of a catalytic subunit, a scaffold subunit, and a regulatory subunit. Loss of function analysis using PP2A catalytic inhibitors or inhibition via tumor viral proteins suggest PP2A as a putative tumor suppressor. However, PP2A has also been shown to facilitate the activation of oncogenic signaling pathways when associated with specific regulatory subunits. In this study, we investigated the possible oncogenic role of PP2A in pancreatic cancer. We found a striking increase in the expression of PR55α, a PP2A regulatory subunit, in pancreatic cancer cells compared to normal pancreatic epithelial cells. Consistently, PR55α expression was markedly elevated in pancreatic ductal adenocarcinoma tissues compared to adjacent normal pancreatic tissues (P&lt;0.0001) and correlated with poor survival of pancreatic cancer patients (P&lt;0.0003). RNAi-mediated depletion of PR55α in pancreatic cancer cells resulted in diminished phosphorylation of both AKT and ERK1/2 and decreased protein levels of β-catenin. Accordingly, pancreatic cancer cells with reduced PR55α expression exhibited significantly impaired properties of transformation, including attenuated cell growth, clonogenicity, mobility, and anchorage-independent growth. Moreover, orthotopic implantation of PR55α-depleted pancreatic cancer cells into nude mice showed a marked reduction in tumorigenicity (P&lt;0.001) and distant metastases. These results suggest that PR55α promotes pancreatic cancer development by sustaining hyperactivity of multiple oncogenic signaling pathways, including AKT, ERK and Wnt.
Citation Format: Ying Yan, Ashley L. Hein, Parthasarathy Seshacharyulu, Satyanarayana Rachagani, Yuri M. Sheinin, Michel M. Ouellette, Moorthy P. Ponnusamy, Surinder K. Batra. PR55-alpha associated PP2A promotes pancreatic tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5762. doi:10.1158/1538-7445.AM2017-5762
Abstract 5767: Ex vivo three-dimensional tumor growth assay: 3DX-TGA
Authors: Nair Praveen , Nair Dileep , Hinata Kaede , Mirsaidi Cyrus , Wu Junjie , Hu Yong , Hall Brett M. 
Published: July 2017

Abstract
With a 7% likelihood of regulatory approval, oncology drug registration failure rates lead all therapeutic areas. Further complicating the drug development process, preclinical oncology models poorly reflect tumor tissue biology and produce a high level of false positive data. Yet, monocellular two-dimensional (2D) tissue culture remains the preferred platform for most laboratory preclinical studies. The popularity of 2D tissue culture was driven predominantly by fast and dependable proliferation of human tumor cells rather than alignment to the pathophysiology of human cancer. As a consequence of this artificial selection bias, many registered oncology drugs today are highly toxic with a propensity to attack any dividing cell (i.e., non-targeted). Fortunately, recent advances in genomics, metabolomics and immunology have aided in development of new targeted agents, many of which have achieved regulatory approval.
Nevertheless, rational drug combinations and identification of clinically meaningful drug targets persist as major challenges in oncology, and each can be meaningfully addressed using more diverse and biologically relevant preclinical models. Ex vivo tumor tissue transplant models, such as patient-derived xenografts (PDX) offer greater model diversity and more faithfully reflect patient tumor genetics. However, cost and scalability barriers tend to limit widespread and practical model utility. In addition, there remains a strong selection bias for autocrine human tumors that can quickly adapt to a cross-species mouse host.
As a practical alternative to PDX models, we established, serially propagated and molecularly characterized 300 ex vivo 3D (3DX) models spanning 15 tumor indications. Given patient tumor seeding success rates of over 95%, the 3DX-TGA model enabled diverse pharmacologic evaluation for the vast majority of cancer patient models attempted. After achieving sufficient tumor biomass, typically within 7 to 8 weeks, thirty-one drugs were screened for proliferation and viability endpoints over a three-log dose range. Resistance and sensitivity profiles mirrored population-based response rates for indication-aligned FDA-registered drugs. Taken together, the 3DX-TGA model represents a powerful preclinical ex vivo model that: (1.) more faithfully recapitulates human tumor biology, (2.) can be scaled at a fraction of time and cost compared to PDX models, and (3.) provide a superior screening platform for novel drugs and drug-drug combinations.
Citation Format: Praveen Nair, Dileep Nair, Kaede Hinata, Cyrus Mirsaidi, Junjie Wu, Yong Hu, Brett M. Hall. Ex vivo three-dimensional tumor growth assay: 3DX-TGA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5767. doi:10.1158/1538-7445.AM2017-5767
Abstract 5769: Modeling the tumor invasion front using 3D fluidic tumoroid culture of cancer cells
Authors: Yong Koh Meng Aw , Oliver Christopher , Altemus Megan , Wu Zhi Fen , Merajver Sofia 
Published: July 2017

Abstract
To realize the promise of precision medicine, it is important to integrate phenotypic assessment of cell populations to genomic data. The analysis of invading leader cells at the tumor invasion front is of interest as they may be guided by a targetable molecular phenotype. However, there is a lack of suitable platforms on which to analyze the tumor invasion front. In this study, we have designed and constructed a fluidic device for long-term (several days to weeks) 3-dimensional tumoroid culture of diverse cancer cells. Using this device, we can recapitulate the tumor invasion front and at the same time quantify the invasive potential of different breast cancer cell line models. Analyses of the tumor invasion front indicated a region of higher proliferation and suggest that the leader cells possess a different molecular phenotype from the tumoroid mass. Interestingly, significant heterogeneity among invading cells was still observed, suggesting that there could be: 1) the presence of multiple subpopulations of invasive cells, each with a different clonal genetic signature; and/or 2) reversible phenotypic switching occurring among invading cells due to phenotypic plasticity. These results obtained using this innovative device highlight and present a promising solution to the challenges developing adequate therapeutics accounting for tumor phenotypic heterogeneity. There is potential for the device for use in personalized medicine at diagnosis, allowing for both the quantification of disease progression risk as well as the molecular characterization of the invasive subpopulations from patient samples and their response to tailored therapies.
Citation Format: Koh Meng Aw Yong, Christopher Oliver, Megan Altemus, Zhi Fen Wu, Sofia Merajver. Modeling the tumor invasion front using 3D fluidic tumoroid culture of cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5769. doi:10.1158/1538-7445.AM2017-5769
Abstract 5774: Effect of extrinsic and intrinsic solid stress on tumor spheroid growth
Authors: Guillaume Ludivine , Desmaison Annaick , Ducommun Bernard , Lobjois Valérie 
Published: July 2017

Abstract
Growth-induced intrinsic solid stress and adaptive response to extrinsic mechanical cues have been recognized as major hurdles to overcome in cancer treatment and any approach that could significantly modulate these parameters would have an impact in improving therapies. An attracting in vitro model to explore this issue is the Multicellular Tumor Spheroid, a 3D culture model reproducing the non-vascularized microtumor environment, proliferation gradient and cellular interactions. To explore and assess spheroid growth-induced solid stress, we couple biological approach to the application of mechanics and modeling. We adapted a method, which consist in partial sectioning of the microtumor and measuring tissue relaxation parameters. Using this strategy, we showed that cell proliferation induced the accumulation of intrinsic mechanical constraint. To investigate the consequence of the accumulation of solid stress at the cell scale, we analyzed 3D cellular organization within spheroids. Using 3D light sheet microscopy (LSM) visualization on optically cleared spheroids combined with 3D reconstruction and automatic algorithms, we were able to determine cell density, nuclear orientation and nuclear shape in whole 3D spheroids. We found that stress accumulation is associated with an increase in cell density and a regionalization of nuclei organization. We also explored the impact of extrinsic stress in 3D culture condition under constraint. We found that mechanical constraint and cytoskeleton control nuclei orientation and using live 3D LSM microscopy we show that mechanical constraint induces an actin cytoskeleton-dependent prometaphase delay. We anticipate that this work will provide key information and parameters to improve our knowledge of the crosstalk between mechanical parameters and tumor growth.
Citation Format: Ludivine Guillaume, Annaick Desmaison, Bernard Ducommun, Valérie Lobjois. Effect of extrinsic and intrinsic solid stress on tumor spheroid growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5774. doi:10.1158/1538-7445.AM2017-5774
Abstract 5790: Assessing the effects of TIMP2 knockout on lung cancer cell lines cultured in 3D
Authors: Peeney David 
Published: July 2017

Abstract
Tissue inhibitor of matrix metalloproteinases (TIMPs) are a small family of endogenous proteins that classically function to inhibit metalloproteinase activity. Since the original description of this protein family in the 80s and 90s, various MMP-independent biological functions of TIMPs have been described. This built the impression that MMP/TIMP ratios may play an important role in tissue homeostasis, an idea which is supported by the observation that altered MMP/TIMP expression ratios are often associated with a number of human conditions such as cancer, cardiovascular and CNS disease. TIMP2 is the most abundantly expressed protein in this family and has previously been shown to interact with several membrane proteins including MT1-MMP, insulin-like growth factor-1 receptor (IGF-I-R) and alpha3 beta1 integrin (α3β1) to mediate downstream intracellular signaling. In addition, TIMP2 has been shown to inhibit growth factor stimulated proliferation, angiogenesis and tumor cell invasion and metastasis, highlighting the potential for TIMP2-based cancer bio-therapies that can be used in conjunction with conventional treatments. Recent studies in our lab highlight that syngeneic lung tumors (LL2 cells; Lewis lung carcinoma) developed in C57BL mice harboring a loss-of-function mutation in TIMP2 are significantly larger than tumors grown in their WT counterparts. To gain a deeper understanding of the role of TIMP2 in tumor initiation and progression we have used CRISPR-Cas9 to develop stable TIMP2 knockout (T2KO) human lung cancer cell lines. Although indistinguishable in 2D culture, T2KO tumor cells display a morphologically distinct phenotype when grown in spheroids. Preliminary data show that, when grown in spheroids, T2KO cells exhibit enhanced EGFR activation in comparison to WT cells. By assessing the functional characteristics and gene expression of T2KO cells grown in 3D culture conditions we hope to gain further insight into the biological functions of TIMP2 and to provide a mechanistic link between the loss of TIMP2 activity and enhanced tumor formation that is observed in our mouse model.
Citation Format: David Peeney. Assessing the effects of TIMP2 knockout on lung cancer cell lines cultured in 3D [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5790. doi:10.1158/1538-7445.AM2017-5790