bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2263: Mitochondrial ATAD3A combines with GRP78 to regulate the stability of the WASF3 metastasis-promoting gene
Authors: teng yong , ren xiaoou , Cowell John 
Published: August 2015

Abstract
ATAD3A is an integral mitochondrial membrane protein with unknown function, although we now show that high-level expression is associated with poor survival in breast cancer patients. Using a mass spectrometry approach we have demonstrated that ATAD3A interacts with the WASF3 metastasis promoting protein. Knockdown of ATAD3A leads to decreased WASF3 protein levels in breast and colon cancer cells. Silencing ATAD3A also results in loss of both cell anchorage-independent growth and invasion and suppression of tumor growth and metastasis in vivo using NSG immuno-compromised mice. HSP70 is responsible for stabilizing WASF3 in the cytoplasm, but inactivation of HSP70 does not lead to loss of WASF3 stability at the mitochondrial membrane, where presumably it is protected through its interaction with ATAD3A. In response to endoplasmic reticulum stress, increases in the GRP78 protein level leads to increased WASF3 protein levels. We also show that ATAD3A was present in a WASF3-GRP78 complex and suppression of GRP78 led to destabilization of WASF3 at the mitochondrial membrane, which was ATAD3A dependent. Furthermore, ATAD3A-mediated suppression of CDH1/E-cadherin occurs through its regulation of GRP78-mediated WASF3 stability. It appears, therefore, that stabilization of WASF3 function occurs through its interaction with ATAD3A and GRP78, which may provide a bridge between the endoplasmic reticulum and mitochondria, allowing communication between the two organelles. These findings also suggest that pharmacologic inhibition of ATAD3A could be an effective therapeutic strategy to treat human cancer.
Citation Format: yong teng, xiaoou ren, John Cowell. Mitochondrial ATAD3A combines with GRP78 to regulate the stability of the WASF3 metastasis-promoting 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 2263. doi:10.1158/1538-7445.AM2015-2263
Abstract 2276: Oncostatin M promotes breast cancer metastasis to lung by affecting initial stages of metastasis
Authors: Tawara Ken , Bolin Celeste , Koncinsky Jordan , Jorcyk Cheryl L. 
Published: August 2015

Abstract
Recent studies suggest that cancer cells destined to establish metastatic lesions may shed early during tumor development, potentially even from carcinoma in situ. Furthermore, these cells may disseminate and lay dormant in a metastatic microenvironment (MME) for years before macrometastases are detectable. While inflammatory cytokines are known to be important in promoting breast cancer metastasis, their effect on tumor cell dissemination needs to be clarified. In this study, we investigate the effect of the interleukin-6-related, inflammatory cytokine oncostatin M (OSM) on early stages of breast cancer metastasis. First, we establish the expression pattern of OSM in human breast tissue using tissue microarrays. OSM is expressed in epithelial cells at higher levels in invasive ductal carcinoma (IDC) than in adjacent normal breast tissue, but is expressed at highest levels in ductal carcinoma in situ (DCIS). This suggests that autocrine-produced OSM may be important in breast tumor invasion and in the promotion of initial steps of metastasis. OSM increases early stage metastatic potential in vitro in aggressive 4T1.2 triple negative breast cancer cells (TNBCs) by inducing tumor cell detachment and migration. These findings are corroborated by in vivo studies using an orthotopic 4T1.2 mouse model of breast cancer. Reduced OSM expression in 4T1.2 (4T1.2-shOSM) cells is sufficient to inhibit the progression and the final number and volume of metastases in the lung, as well as circulating tumor cell (CTC) numbers in Balb/c mice. The number of CTCs is further reduced in a Balb/c OSM knockout background, demonstrating the importance of both paracrine- and autocrine-produced OSM in this process. Furthermore, orthotopic injection of 4T1.2-shOSM cells increases animal survival post-primary tumor resection, while bypassing the early stages of metastasis by injecting cells directly into the systemic circulation does not. As expected, in an orthotopic xenograft MDA-MB-231 human breast cancer mouse model, peri-tumoral injection of recombinant OSM increases the number of CTCs as well as spontaneous metastasis to lung. Taken together, these results suggest that suppression of OSM levels in the tumor microenvironment could be a highly effective therapeutic strategy for halting breast cancer metastasis to lung.
Citation Format: Ken Tawara, Celeste Bolin, Jordan Koncinsky, Cheryl L. Jorcyk. Oncostatin M promotes breast cancer metastasis to lung by affecting initial stages of 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 2276. doi:10.1158/1538-7445.AM2015-2276
Abstract 2288: Lipoprotein(a) and vitamin C affect the development of breast cancer tumors in Lp(a)+; Gulo-/- mice
Authors: Cha John , Roomi M. Waheed , Niedzwiecki Aleksandra , Rath Matthias 
Published: August 2015

Abstract
Lipoprotein(a), composed of LDL and an adhesive protein apo(a), is produced in humans and primates, the species which lost an ability to synthesize vitamin C endogenously. We have shown earlier that Lp(a), due to its strong ECM binding properties, may be considered a biological ‘stability’ molecule for the structurally weakened connective tissue in the vascular wall. The development and progression of cancer is characterized by loss of ECM integrity which facilitates tumor growth and metastasis. We developed a unique mouse model lacking endogenous vitamin C production (Gulo-/-) and synthesizing human Lp(a) (lp(a)+), which has been used in this study to investigate the role of Lp(a) and other lipoproteins in cancer.
The female Gulo-/-:Lp(a)+ and control wild type Balb/c mice were orthotopically inoculated with 4T1 breast cancer cells (500,000) The transgenic and control mice were divided into 4 different dietary groups in respect to dietary vitamin C intake: A) low ascorbate intake for 6 weeks; B) high ascorbate intake for 6 weeks; C) low ascorbate intake for 3 weeks followed by high ascorbate for 3 weeks; D)high ascorbate intake for 3 weeks followed by low ascorbate for 3 weeks. Control groups of Lp(a)+;Gulo(-/-) mice without tumor inoculation were put on the same Vitamin C regimens. Wild type controls included mice without and with 4T1 inoculation kept on regular mouse chow for 6 weeks.
After 6 weeks all (100%) wild type mice developed tumors, while 50% of Lp(a)+;Gulo(-/-) mice kept on high ascorbate diet for 6 weeks did not develop primary tumors and in only a small number of mice some residual tumor cells or inflammatory infiltrates were detected in the lungs by histology. In transgenic mice supplemented with low vitamin C for 6 weeks, the reduction of primary tumors incidence was 33% compared to wild type mice. In addition, primary tumors from wild type mice were on average over 2-fold larger (1.80+/-0.62g) than tumors from Lp(a)+;Gulo(-/-) mice on continual low Vitamin C (0.77+/-0.98g) or continual high Vitamin C (0.63+/-1.09g. Primary tumors from Lp(a)+;Gulo(-/-) mice immunostained positively for Lp(a) and their size was inversely proportional Lp(a) cholesterol serum levels. Lp(a) could not be detected in tumors from wild type mice and the presence of tumors was associated with higher LDL serum levels. The results implicate that Lp(a) may play a role in controlling tumor growth and expansion through its ECM adhesive properties.
Citation Format: John Cha, M. Waheed Roomi, Aleksandra Niedzwiecki, Matthias Rath. Lipoprotein(a) and vitamin C affect the development of breast cancer tumors in Lp(a)+; Gulo-/- mice. [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 2288. doi:10.1158/1538-7445.AM2015-2288
Abstract 2293: Deletion of Tid1 in hepatocyte promotes steatosis, fibrosis, and tumorigenesis
Authors: Chen Yu-Syuan , Lo Jeng-Fan 
Published: August 2015

Abstract
Background: Tid1, DnaJ cochaperone protein, is a mammalian homolog of the Drosophila tumor suppressor Tid56 whose anti-tumor function is through its capacity to regulate cell differentiation in imaginal discs. In our previous studies, we found Tid1 regulates early mouse embryogenesis and T cell development. In addition, it has been identified that Tid1 can act as a tumor suppressor in breast, colon, lung and head and neck cancer. Tid1 protein is highly expressed in mouse and human hepatocyte. However, the physiological role of Tid1 in hepatocyte development and hepatic tumorigenesis remains elusive.
Methods: Mice with loss of Tid1 lead to embryonic lethality as early as E4.5. Therefore; we generated a hepatocyte specific Tid1 knockout mice by crossing the Tid1flx/flx mice generated in our lab with transgenic mice expressing Cre recombinase activity driven by albumin promoter. Both spontaneous or carcinogen (diethylnitrosamine; DEN) mediated hepatocellular carcinoma (HCC) in Tid1 deficiency mice will be monitored. In addition, the physiological function of hepatocytes including albumin, plasma alanine aminotransferase (ALT), triglyceride (TG) and cholesterol collected from the control and mutant mice will be examined.
Results: We have successfully established mice with hepatocyte specific ablation of Tid1 mice. Immunohistochemistry staining and western blot showed that conditional knockout mice were deficient on Tid1 expression in hepatocyte. Deletion of Tid1 in hepatocyte caused the hepatic steatosis and fibrosis. Consequently, spontaneous HCC tumor was found in thirteen-month-old Tid1 knockout mice. In DEN-treated mice model, deletion of Tid1 also enhanced the induction of HCC accompanying with elevatiof of plasma ALT and cholesterol.
Conclusion: The progression of steatosis, fibrosis to HCC was observed in Tid1 deficient mice, which similarly reflects to those observed in tumorigenesis of human HCC. Therefore, we could further characterize the molecular mechanisms to understand how human HCC is developed through our Tid1-deficent HCC mice model. Ultimately, therapeutic regime for HCC could be developed from the Tid1-deficent mice for improving future HCC therapy.
Citation Format: Yu-Syuan Chen, Jeng-Fan Lo. Deletion of Tid1 in hepatocyte promotes steatosis, fibrosis, and 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 2293. doi:10.1158/1538-7445.AM2015-2293
Abstract 2298: Profiling of syngeneic models by anti-PD1, anti-CTLA4 immunotherapeutics and deep sequencing enables better selection of models for immune targeted combination therapy
Authors: Zhang Lan , Zhang Juan , Shi Qian 
Published: August 2015

Abstract
Syngeneic tumor models have long been used in cancer research. Recently, the clinical success of anti-CTLA4 and anti-PD1 antibodies resulted in increased interests in using syngeneic models to evaluate cancer immunotherapeutics. Furthermore, as researchers discovered many of the existing or developing inhibitors of the canonical signaling pathways may interact with immune-environment, thus may synergize with cancer immunotherapies, they are looking for suitable models that may evaluate the combination of those therapies. To meet this demand, Crown has established a large collection of syngeneic models that covers most of the tumor types. Those models have been extensively profiled in vivo using anti-PD1, anti-CTLA4 antibodies, providing information necessary for selecting models and doses for combination therapy. Mostly recently, we have generated detailed maps of the expressional and mutational profiles of those models, as well as identified the alternative gene spliced transcripts, post-transcriptional modifications, gene fusion using RNA-seq. These data will enable selection of models based on researchers’ specific targets. Combining with the in vivo immunotherapy profiles of the models, our comprehensive syngeneic models with profiling data are useful tools in developing combinatory cancer immunotherapies that may one day benefit the patients.
Citation Format: Lan Zhang, Juan Zhang, Qian Shi. Profiling of syngeneic models by anti-PD1, anti-CTLA4 immunotherapeutics and deep sequencing enables better selection of models for immune targeted combination therapy. [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 2298. doi:10.1158/1538-7445.AM2015-2298
Abstract 2300: LIN28 cooperates with Wnt signaling to drive invasive intestinal and colorectal adenocarcinoma in mouse and human
Authors: Tu Ho-Chou , Schwitalla Sarah , Qian Zhirong , LaPier Grace , Yermalovich Alena , Ku Yuan-Chieh , Chen Shann-Ching , Viswanathan Srinivas R. , Zhu Hao , Nishihara Reiko , Inamura Kentaro , Kim Sun A. , Morikawa Reppi , Mima Kosuke , sukawa Yasutaka , Yang Juhong , Meredith Gavin , Fuchs Charles S. , Ogino Shuji , Daley George Q. 
Published: August 2015

Abstract
Despite extensive investigation into the molecular basis of tumor development, colorectal cancer (CRC) remains a major contributor to cancer-related mortality. LIN28A and LIN28B are highly related RNA-binding proteins that influence development, tissue regeneration and oncogenesis. Here we demonstrate that overexpression of LIN28 drives invasive intestinal adenocarcinoma and cooperates with the Wnt pathway to promote tumor initiation and progression in murine models. Importantly, conditional withdrawal of LIN28 reduced tumor volume and increased tumor differentiation, indicating that LIN28 contributes to tumor maintenance. Furthermore, co-expression of a LIN28-resistant form of the let-7 microRNA reduced tumor burden. We detected aberrant expression of LIN28 in 38% of a large series of tumor samples from human CRC, and LIN28 expression levels were associated with invasive tumor growth pattern. Our robust late-stage CRC murine model demonstrates strong roles for LIN28 in promoting CRC initiation, growth and progression, and suggests the therapeutic potential in targeting the LIN28/let-7 pathway.
Citation Format: Ho-Chou Tu, Sarah Schwitalla, Zhirong Qian, Grace LaPier, Alena Yermalovich, Yuan-Chieh Ku, Shann-Ching Chen, Srinivas R. Viswanathan, Hao Zhu, Reiko Nishihara, Kentaro Inamura, Sun A. Kim, Reppi Morikawa, Kosuke Mima, Yasutaka sukawa, Juhong Yang, Gavin Meredith, Charles S. Fuchs, Shuji Ogino, George Q. Daley. LIN28 cooperates with Wnt signaling to drive invasive intestinal and colorectal adenocarcinoma in mouse and human. [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 2300. doi:10.1158/1538-7445.AM2015-2300
Abstract 2334: Disruption of TGF-β-regulated CTCF suppression of telomerase links a human stem cell disorder to tumorigenesis
Authors: Chen Jian , Chen Jiun-Sheng , Yao Zhixing , Jogunoori Wilma , Mishra Bibhuti , Herlong Franklin H. , Jeong Yun Seong , Mistry Nipun A. , Zhang Jianping , Su Xiaoping , Rashid Asif , Davila Marta , Stroehlein John R. , Shay Jerry W. , Mishra Lopa 
Published: August 2015

Abstract
Background: Beckwith-Wiedemann syndrome (BWS) is a human stem cell disorder with a prevalence of 1 in 14,000. Its clinical manifestations include an 800-fold increased risk of tumorigenesis; yet the precise mechanism of BWS-associated tumorigenesis remains elusive. In a previous study, we showed that epigenetic silencing of β2-spectrin (β2SP, gene SPTBN1), a cytoskeletal protein and a Smad adaptor for Transforming Growth Factor-beta (TGF-β) signaling, was a causal factor in BWS. To determine the mechanism for the oncogenic switch, and whether it is related to the role of β2SP in TGF-β signaling transduction or secondary to its cytoskeletal functions, we analyzed disruption of two elements of the TGF-β pathway by generating double heterozygous Sptbn1+/−/Smad3+/− mice.
Materials & Methods: Tumorigenesis analysis in Sptbn1+/− /Smad3+/− mice. Whole-transcriptome sequencing and IPA analyses were performed in the BWS cells and Sptbn1+/−; Sptbn1−/−; Smad3+/−; and Sptbn1+/−/Smad3+/− MEFs. Immunohistochemical analyses were performed for determining the expression of TERT in BWS tumors and mice liver, pancreas and stomach tissue specimens. ChIP assays were performed for examining the recruitment of β2SP/Smad3/CTCF complex at the promoter of TERT.
Results: (1) 80% of Sptbn1+/−/Smad3+/− mice developed multiple tumors that were phenotypically similar to those of patients with BWS. (2) Somatic mutations in SPTBN1 and SMAD3 occur in multiple human sporadic cancers. (3) Disruption of the TGF-β pathway in Sptbn1+/−/Smad3+/− mice and BWS cells. (4) β2SP Interacts with SMAD3 in a TGF-β-dependent manner. (5) β2SP and SMAD3 interact with CTCF in the cell nucleus. (6) Dysfunction of the β2SP/SMAD3/CTCF complex increases hTERT levels in BWS and in β2SP+/-/Smad3+/- mice.
Conclusions: We present a novel model of the molecular pathogenesis of BWS by demonstrating a potential shift arising from disruption of TGF-β signaling leading to BWS-associated tumorigenesis and human sporadic cancer development.
Citation Format: Jian Chen, Jiun-Sheng Chen, Zhixing Yao, Wilma Jogunoori, Bibhuti Mishra, Franklin H. Herlong, Yun Seong Jeong, Nipun A. Mistry, Jianping Zhang, Xiaoping Su, Asif Rashid, Marta Davila, John R. Stroehlein, Jerry W. Shay, Lopa Mishra. Disruption of TGF-β-regulated CTCF suppression of telomerase links a human stem cell disorder to 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 2334. doi:10.1158/1538-7445.AM2015-2334
Abstract 2343: Tumor microenvironment regulates the fate of myeloid cells by controlling STAT3 activity
Authors: Kumar Vinit , Cheng Pingyan , Condamine Thomas , Gabrilovich Dmitry 
Published: August 2015

Abstract
The abnormal differentiation of myeloid cells is one of the key features of altered immune response in cancer. Myeloid derived suppressor cells (MDSC) are a major component of immune suppressive network. MDSC accumulate in large numbers in peripheral lymphoid organs and inside tumors. Previous data indicated that the fate of MDSC depends on the localization of these cells. In contrast to peripheral lymphoid organs such as spleen, inside tumors, MDSC rapidly differentiate to tumor associated macrophages with potent immune suppressive activity. We have demonstrated that this phenomenon is mediated by dramatic down-regulation of STAT3 activity in MDSC at tumor site. In cancer patients, MDSC at tumor site also had substantially lower level of pSTAT3 than MDSC in peripheral blood. These results were unexpected, since high level of STAT3 activity is a hallmark of MDSC present in blood and lymphoid organs. The mice with constitutively active STAT3 had shown the dramatic expansion of MDSC and down-regulation of macrophage population in tumor microenvironment, emphasizing the crucial role of STAT3 in myeloid cell differentiation. Hypoxia is an intricate part of tumor microenvironment. We have found that hypoxia caused the down-regulation of STAT3 activity in MDSC. However, the effect of hypoxia on STAT3 activity was not observed in tumor cells. We further demonstrate that the up-regulation of CD45 tyrosine phosphatase activity in MDSC exposed to hypoxia in tumor site was responsible for down-regulation of STAT3 activity. Using KO model we have shown that MDSC devoid of CD45 failed to experience the effect of hypoxia on pSTAT3 down-regulation as well as their differentiation to macrophage at tumor site. Furthermore, the positive regulation of CD45 activity in hypoxia was mediated by the disruption of CD45 protein dimerization via sialylation. The treatment of sialidase abrogated the effect of hypoxia on STAT3 activity in MDSC and differentiation of MDSC to macrophages. This novel mechanism of regulation of myeloid cell differentiation by STAT3 may provide rationale for re-evaluation of therapeutic strategies in cancer.
Citation Format: Vinit Kumar, Pingyan Cheng, Thomas Condamine, Dmitry Gabrilovich. Tumor microenvironment regulates the fate of myeloid cells by controlling STAT3 activity. [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 2343. doi:10.1158/1538-7445.AM2015-2343
Abstract 2368: Differentiated gastric cancer cells have a potential to induce cancer-associated fibroblasts
Authors: Li Yuncheng , Tazawa Hiroshi , Masahiko Nishizaki , Hashimoto Yuuri , Hori Naoto , Katsube Ryoichi , Kuroda Shinji , Noma Kazuhiro , Kagawa Shunsuke , Fujiwara Toshiyoshi 
Published: August 2015

Abstract
Gastric cancer is one of the most common causes of cancer death. Stromal fibroblasts in the tumor microenvironment have recently been implicated in tumor growth, invasion and metastasis. Cancer-associated fibroblasts (CAFs) have been suggested to be responsible for progression of undifferentiated scirrhous gastric cancers with vast fibrous stroma. However, the relationship between differentiated gastric cancer cells and CAFs in tumor progression remains unclear. In this study, we investigated whether differentiated and/or undifferentiated human gastric cancer cells induce CAFs. We used two differentiated human gastric cancer cells (MKN-7, MKN-74) and two undifferentiated human scirrhous gastric cancer cells (KATO-III, NUGC-4). Two types of human normal fibroblasts (WI-38, FEF-3) were used for induction of CAFs. The conditioned media (CM) from all cancer cells were obtained 48 hours after serum starvation. The morphological change and expression of CAF-specific markers (α-smooth muscle actin (α-SMA), fibroblast activation protein-α (FAP)) were analyzed by microscopy and Western blot analysis, respectively, in fibroblasts treated with CM for 120 hours. Moreover, the effect of CM from CAFs in the migration ability of cancer cells was evaluated using in vitro Migration assay. The CM from differentiated MKN-7 and MKN-74 cells induced the morphological change like CAFs in normal human fibroblasts, whereas CM from undifferentiated KATO-III and NUGU-4 cells did not induce. In fact, morphologically changed fibroblasts like CAFs showed increased α-SMA expression, whereas FAP expression was not increased. The CM from morphologically changed fibroblasts, but not normal fibroblasts, significantly enhanced the migration ability of MKN-7 cells. These results suggest that differentiated gastric cancer cells have a potential to induce CAFs in the invasion process of gastric cancers. CAF-targeting therapy may be a promising antitumor strategy in differentiated gastric cancers as well as undifferentiated scirrhous gastric cancers with vast fibrous stroma.
Citation Format: Yuncheng Li, Hiroshi Tazawa, Nishizaki Masahiko, Yuuri Hashimoto, Naoto Hori, Ryoichi Katsube, Shinji Kuroda, Kazuhiro Noma, Shunsuke Kagawa, Toshiyoshi Fujiwara. Differentiated gastric cancer cells have a potential to induce cancer-associated fibroblasts. [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 2368. doi:10.1158/1538-7445.AM2015-2368