bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3126: Renca RCC syngeneic model to evaluate efficacy of novel antisense oligonucleotides targeting TGF-β isoforms
Authors: Korhonen Hanna , Redon Julie-Orlane , France Damien , Serin Guillaume , Bichat Francis , Jaschinski Frank , Wosikowski Katja , Janicot Michel 
Published: May 2015

Abstract
Transforming growth factor beta (TGF-β represents a family of cytokines, which function as the primary mediators for TGF-β signaling via TGF-β receptor type II (TβIIR) and both non-canonical and canonical downstream signaling pathways. TGF-β is associated with a wide range of biological processes in oncology, including tumor cell invasion, migration, angiogenesis, immunosuppression, as well as regulation of tumor stem cell properties. Hence, optimal preclinical evaluation of efficacy of TGF-β antagonists is challenging. Isarna Therapeutics has designed and developed selective and potent LNA-modified antisense oligonucleotides targeting the various TGF-β isoforms. In order to adequately evaluate selected preclinical development candidates, Oncodesign has developed customized experimental Renca tumor models in syngeneic and/or immunodeficient mice. The Renca cell line was established from a murine transplantable renal adenocarcinoma of spontaneous origin, and has been used under various experimental conditions: (1) subcutaneous tumor model by inoculating cells into the flanks of the animals; (2) the pulmonary metastatic tumor model by an intravenous injection of cells into the tail vein; and (3) the orthotopic tumor model by injecting cells into the renal subcapsule (and subsequent pulmonary metastasis). Outcome of this development program and preliminary results for selected TGF-β antisense oligonucleotides will be presented and discussed.
Citation Format: Hanna Korhonen, Julie-Orlane Redon, Damien France, Guillaume Serin, Francis Bichat, Frank Jaschinski, Katja Wosikowski, Michel Janicot. Renca RCC syngeneic model to evaluate efficacy of novel antisense oligonucleotides targeting TGF-β isoforms. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3126. doi:10.1158/1538-7445.AM2014-3126
Abstract 3127: The effect of Guizhi Fuling Wan (GFW) on bladder tumor growth in a mouse model
Authors: Lu Chi-Chen , Tseng Ling-Huei , Chen Syue-Yi , Wu Jiann-Der , Wu Shu-Fen , Chan Michael W.Y. , Leu Yu-Wei , Hsu Cheng-Da 
Published: May 2015

Abstract
Bladder cancer is the second most common malignancy of the genitourinary tumors in the world and tenth most common cancer in Taiwan. The most common type of bladder cancer is urothelial carcinoma (UC, formerly known as transitional cell carcinoma, TCC). The incidence rate is particularly high in southwestern coast of Taiwan. Treatment for superficial non-invasive bladder carcinoma is currently using intravesical chemotherapy with mitomycin C and BCG after transurethral resection of bladder tumor (TUR-BT). However, this therapy usually causes adverse effects including urinary frequency, urinary urgency, hematuria and tuberculosis infection. Therefore, we intend to find a complementary and alternative medicine for bladder cancer treatment which can bring a good result with less side effects. In our previous study, we found that a traditional Chinese Medicine (TCM), Guizhi Fuling Wan (GFW) had an effect on growth inhibition of human bladder cancer cell lines as same as mitomycin-C, doxorubicin and cisplatin, but had mild toxicicity on normal human bladder epithelial cells. In this study we investigated whether GFW could be used as an intravesical chemotherapy agent in our orthotopic bladder cancer mouse model and compared its adverse effect with mitomycin-C and BCG. A mouse bladder cancer cell line, MB49, was selected and evaluated its response to GFW treatment. Cell Counting Kit-8 (CCK-8) assay was employed to analyze cell viability and flow cytometry was used to determine cell cycle and apoptosis. MB49 cells were implanted into female C57BL/6 mice to generate our orthotopic bladder tumor model which was confirmed under a microscope in histology by hematoxylin and eosin staining. Our data showed that GFW was a potent inhibitor of the proliferation of mouse bladder cancer cells in vitro as well as inhibited the tumor growth on MB49 bladder cancer orthotopic model. In addition, bladder hemorrhage which was observed in bladder cancer mice had completely disappeared 17 days after the intravesical GFW-treatment. These results support GFW as a strong candidate for intravesicle chemotherapy against bladder cancer.
Citation Format: Chi-Chen Lu, Ling-Huei Tseng, Syue-Yi Chen, Jiann-Der Wu, Shu-Fen Wu, Michael W.Y. Chan, Yu-Wei Leu, Cheng-Da Hsu. The effect of Guizhi Fuling Wan (GFW) on bladder tumor growth in a mouse model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3127. doi:10.1158/1538-7445.AM2014-3127
Abstract 3130: Zoledronic acid inhibits proliferation and metastasis of human pancreatic cancer in the patient-derived orthotopic xenograft (PDOX) model by targeting tumor-educated macrophages
Authors: Hiroshima Yukihiko , Hassenein Mohamed K. , Menen Rhiana , Katz Matthew H.g. , Fleming Jason B. , Sato Sho , Murakami Takashi , Yamamoto Mako , Uehara Fuminari , Miwa Shinji , Yano Shuya , Momiyama Masashi , Maawy Ali , Chishima Takashi , Tanaka Kuniya , Bouvet Michael , Endo Itaru , Hoffman Robert M. 
Published: May 2015

Abstract
Macrophages harvested from the peritoneal cavity of nude mice with subcutaneous human pancreatic tumors were defined as “tumor-educated macrophages” (EMϕ) and macrophages harvested from mice without tumors were defined as “naïve macrophages” (NMϕ). EMϕ promote tumor growth and metastasis. The aim of the present study was to determine the efficacy of Zoledronic acid (ZA) on EMϕ in a pancreatic cancer patient derived orthotopic xenograft (PDOX) nude mouse model. In this study, EMϕ and NMϕ were compared for their ability to enhance tumor progression. We initially demonstrated that the cancer cells exposed to the conditioned medium harvested from EMϕ culture significantly increased proliferation (p = 0.016) and had more migration stimulation capability (p &lt; 0.001) compared to cultured cancer cells treated with the conditioned medium from NMϕ. Next, we examined the efficacy of ZA on EMϕ, and NMϕ and found that ZA had the ability to kill both EMϕ and NMϕ in vitro. We then demonstrated that EMϕ promoted tumor growth and metastasis in an orthotopic mouse model of a human pancreatic cancer cell line, ZA reduced the tumor growth (p = 0.006) and metastasis (p = 0.025) promoted by EMϕ. Finally, we examined the efficacy of ZA for pancreatic cancer in the PDOX model, and found that the combination of gemcitabine (GEM) and ZA reduced tumor weight (p = 0.016) and tumor growth (p = 0.005) compared to GEM alone. ZA alone reduced metastasis (p = 0.009). These results suggest that ZA inhibits the proliferation and the metastasis of human pancreatic cancer by targeting EMϕ.
Citation Format: Yukihiko Hiroshima, Mohamed K. Hassenein, Rhiana Menen, Matthew H.g. Katz, Jason B. Fleming, Sho Sato, Takashi Murakami, Mako Yamamoto, Fuminari Uehara, Shinji Miwa, Shuya Yano, Masashi Momiyama, Ali Maawy, Takashi Chishima, Kuniya Tanaka, Michael Bouvet, Itaru Endo, Robert M. Hoffman. Zoledronic acid inhibits proliferation and metastasis of human pancreatic cancer in the patient-derived orthotopic xenograft (PDOX) model by targeting tumor-educated macrophages. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3130. doi:10.1158/1538-7445.AM2014-3130
Abstract 3131: Recurrence of cervical cancer following PR agonist withdrawal in mice
Authors: Mehta Fabiola , Ojha Salil , Chung Sang-Hyuk 
Published: May 2015

Abstract
The majority of human cervical cancers are associated with the high-risk human papillomaviruses (HPVs). Their tumorigenic potential stems mainly from viral oncogenes E6 and E7, which are best known to inactivate p53 and pRb tumor suppressor, respectively. Epidemiological studies, however, have suggested that persistent HPV infections are not sufficient and other cofactors are necessary for the progression of the disease. Prior studies using HPV transgenic mice expressing E6 and E7 under the control of K14 promoter (K14E6/K14E7) have demonstrated the requirement of estrogen and estrogen receptor alpha (ERα) for the development of HPV-induced cervical cancer. It was also shown that inhibition of ERα is effective in both treating and preventing cervical cancer in the HPV transgenic mouse model. Another female sex hormone, progesterone, functions through the progesterone receptor (PR), which is a direct transcriptional target of ERα. PR and ERα are transcription factors, members of the nuclear receptor superfamily. We recently demonstrated that a PR agonist, medroxyprogesterone acetate (MPA), is efficient in regressing cervical cancer and cervical intraepithelial neoplasia (CIN) in vivo. This result suggests that PR has an anti-tumorigenic activity in the context of ERα-dependent cervical cancer. In the present study, we investigated whether cervical cancer recurs after stopping MPA treatment using the same mouse model. Consistent with our previous publication, all K14E6/K14E7 double transgenic mice treated with estrogen for 6 months had cervical cancer, which regressed when treated with MPA for 2 months. When the mice were re-treated for 2 months with estrogen after MPA treatment, cervical cancer was observed in all mice. Interestingly, the cancer was also present in all mice that were left untreated for 2 months after MPA treatment. These results suggest that cervical cancer recurs if MPA treatment is ceased. The mice bearing recurring cancer were treated with MPA again for 2 months. It was interesting that the cancer remained in 6 of 7 mice, although cancers deemed smaller than those recurred. Further analyses of these cancers are warranted. Taken together, we conclude that cervical cancer recurred once MPA was withdrawn and recurring cancers partially responded to MPA. It implies that MPA treatment regimen used in the study did not eliminate all cancerous cells. Our results suggest that, if translatable to women, continuation of MPA treatment will be warranted to prevent the recurrence of cervical cancer.
Citation Format: Fabiola Mehta, Salil Ojha, Sang-Hyuk Chung. Recurrence of cervical cancer following PR agonist withdrawal in mice. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3131. doi:10.1158/1538-7445.AM2014-3131
Abstract 3136: X-MAN™ isogenic DualXenoTM models with KRAS mutation predicts the effect of anti-EGFR agents
Authors: Sun Yanmei , Zhang Songling , Li Nan , Astley Holly , Foster Rebecca , Schofield Christine , Torrance Chris Chris , Ning Jinying , Shi Qian 
Published: May 2015

Abstract
We have previously reported using cell lines generated with Horizon Discovery's rAAV-based GENESIS™ gene editing platform to establish a comprehensive list of isogenic cancer models for in vivo compound screening, with mutations in a wide variety of genes including KRAS, PIK3CA, PTEN, IDH1 and IDH2, and p53. These isogenic tumor models comprise pairs of cell lines which share the same genetic background, differing only by the mutation of interest, and therefore allow definitive studies of specific genetic variances to be performed.
In the current study we developed a DualXenoTM method where isogenic pairs of a colorectal cell line, one of each pair with a KRAS mutation, were inoculated simultaneously in the two flanks of the same mouse. The tumors were then treated with EGFR targeted therapeutics to address the question of resistant phenotypes elicited by different KRAS mutations. This design allows direct comparison of wild type and mutant isogenic pairs for treatment responses that are associated with the defined genetic variations. Our results demonstrated that tumors harboring the G12V mutation were resistant to both Cetuximab and Erlotinib treatment, while tumors harboring the G13D mutation remained sensitive to both agents. This is in consistent with clinical findings (De Roock, et al. JAMA 2010, 304(16), pp 1812), and our own findings with PDX mouse clinical trials in colon cancer, suggesting that the KRAS G13D mutation may establish a different signaling network to other KRAS mutations, and that colon cancer patients with the mutation should not be excluded from the EGFR targeted therapies.
Citation Format: Yanmei Sun, Songling Zhang, Nan Li, Holly Astley, Rebecca Foster, Christine Schofield, Chris Chris Torrance, Jinying Ning, Qian Shi. X-MAN™ isogenic DualXenoTM models with KRAS mutation predicts the effect of anti-EGFR agents. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3136. doi:10.1158/1538-7445.AM2014-3136
Abstract 3143: Sodium butyrate induced cellular senescence, inhibited invasion and modulated cellular metabolism in glioblastoma cells
Authors: Nakagawa Hidemitsu , Shindou Masahiro , Sasagawa Satoru , Itoh Kazuyuki 
Published: May 2015

Abstract
Sodium butyrate (SB) -C-4 saturated fatty acid (short-chain fatty acids) present in the human bowel membrane in the quite high concentration (2 mM) as food metabolites. It was previously reported that SB showed anti-tumor effect as HDAC inhibitor, however, the precise mechanism has not been elucidated yet. Here, we focused on the role of SB on cancer cell growth, motility and invasion. Physiological concentration of SB (0.25-4 mM) induced inhibition of cell growth, colony formation in soft agar, in vitro motility and invasiveness with Boyden chamber and wound healing assay in a dose-dependent fashion using human glioblastoma (A172) cells and rat mammary Walker 256 cells. SB also affected the morphology of both cells, namely spread out with marked stress fibers bridging focal adhesions. Phosphorylation levels of focal adhesion kinase (Y577 and Y397 sites) were increased but that of myosin light chain (S19 site) was not altered. All of these biological effects of SB were reversible, and recovered after withdrawal. In contrast, HDAC inhibitor trichostatin A inhibited cancer cell growth irreversibly but not affected motility, invasiveness and morphology. In addition, A172 cells treated with SB showed positivity for senescence-associated β-gal (SA-β gal) staining with elevated expression levels of p53 and p21 proteins in a time and dose-dependent manner. In contrast, mRNA level of p21 was sharply declined after the treatment with SB. Knocking down of p21 protein expression by siRNA reversed both the growth inhibition and positivity for SA-β gal staining but not the inhibition of invasiveness. Thus p21 was required for cellular senescence but not for the decrease in motility induced by SB. Further, SB increased the expression of isocitrate dehydrogenase 1 (IDH1), critical enzyme for glioblastoma progression and metabolism. Finally, intrathecal administration of SB effectively inhibited the invasion of Walker256 cells into the brain and elongated the animal (rat) survival in vivo. Collectively, SB inhibited growth with induced cellular senescence, inhibited invasion and modulated the expression of IDH-1, and thus would be a good candidate for anti-invasive therapy of brain tumor without severe adverse effects.
Citation Format: Hidemitsu Nakagawa, Masahiro Shindou, Satoru Sasagawa, Kazuyuki Itoh. Sodium butyrate induced cellular senescence, inhibited invasion and modulated cellular metabolism in glioblastoma cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3143. doi:10.1158/1538-7445.AM2014-3143
Abstract 3145: eIF4E, an adverse prognostic marker of melanoma patient survival, increases melanoma cell invasion
Authors: Khosravi Shahram , Ardekani Gholamreza Safaee , Martinka Magdalena , Ong Christopher John 
Published: May 2015

Abstract
Human cutaneous melanoma is a life-threatening skin cancer due to its invasive nature and high metastatic potential, leading to poor prognosis for melanoma patients. However, the mechanisms for melanoma invasion and metastasis are poorly understood. Human eukaryotic translation initiation factor 4E (eIF4E) has been shown to be associated with tumor progression in multiple cancer types. However, the role of eIF4E in melanoma progression is not very well known. We examined eIF4E expression in 448 melanocytic lesions at different stages using tissue microarray and found that positive eIF4E staining was significantly increased in primary melanomas compared to dysplastic nevi (P&lt;0.001), and further increased in metastatic melanomas compared to primary melanomas (P=0.008). EIF4E expression was correlated with melanoma thickness (P&lt;0.001) and was inversely correlated with overall and disease-specific 5-year survival of all and primary melanoma patients especially those with tumor ≥4mm thick combined with metastatic melanoma patients. Furthermore, positive eIF4E expression was significantly higher in AJCC stage I-II melanomas compared to stage III-IV melanomas. Multivariate Cox regression analysis also revealed that eIF4E is an independent prognostic marker. FACS analysis and sulforhodamine B (SRB) cell proliferation assay showed that eIF4E knockdown in melanoma cells resulted in a significant increase and decrease in apoptosis and cell proliferation, respectively. EIF4E knockdown in melanoma cells also resulted in a down regulation of mesenchymal markers such as vimentin, N-cadherin, α-smooth muscle actin (α-SMA) and the EMT inducing transcription factor Twist. Additionally eIF4E knockdown in melanoma cells led to a decrease in the expression of c-Myc and Bcl2 and an increase in the expression of cleaved PARP and cleaved Caspase3. Moreover, down regulation of eIF4E resulted in a decrease in both melanoma cell invasion and MMP-2 activity. Taken together our data suggests the eIF4E may promote melanoma cell invasion and metastasis by inducing EMT and preventing apoptosis and also by increasing MMP-2 activity. EIF4E may also serve as a promising prognostic marker and a potential therapeutic target for melanoma.
Citation Format: Shahram Khosravi, Gholamreza Safaee Ardekani, Magdalena Martinka, Christopher John Ong. eIF4E, an adverse prognostic marker of melanoma patient survival, increases melanoma cell invasion. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3145. doi:10.1158/1538-7445.AM2014-3145
Abstract 3149: Targeting ERBB2-induced, lysosome-mediated invasion
Authors: Kallunki Tuula , Brix Ditte M. , Rafn Bo , Bundgaard Clemmensen Knut Kristoffer , Andersen Sofie Hagel , Ambartsumian Noona , Jäättelä Marja 
Published: May 2015

Abstract
ErbB2 overexpression is strongly associated with invasive cancer with high recurrence and poor prognosis. Similarly, increased expression of lysosomal proteases, cysteine cathepsins, is observed in several cancers and correlates with enhanced angiogenesis, invasion and metastasis. We recently showed that ErbB2 level correlates positively with cysteine cathepsin B and L levels in primary breast cancer and that ErbB2 regulates the expression of cathepsins B and L leading to their increased activity in several ErbB2-positive breast cancer cell lines. The increased cysteine cathepsin activity is essential for the invasion of ErbB2 overexpressing breast cancer cells in 3-dimensional (3D) Matrigel cultures and is mediated by novel signaling network that involves TGFβR, ERK2-MAPK, PAK4, PKCα and CDC42bpβ kinases and two transcription factors, MZF1 and ETS1.
With a pharmacological protein kinase inhibitor screen, using the ErbB2 inhibitor Lapatinib as positive control, we have now identified three inhibitors putatively targeting this novel ErbB2-induced signaling network. Our data shows that the treatment of ErbB2-positive, highly invasive breast or ovarian cancer cells with any of these inhibitors specifically reduces cysteine cathepsin expression, activity and invasion of these cancer cells in 3D Matrigel cultures. It also reverses lysosomal distribution from the invasion supporting pericellular position to less-invasive perinuclear position, where the lysosomal exocytosis and secretion of lysosome contents to extracellular space to assist extracellular matrix proteolysis becomes less likely. In this study we have identified novel inhibitors for ErbB2-induced invasion and discovered a novel, function for clinically used ErbB2 inhibitor Lapatinib in the regulation of lysosomal function and trafficking.
Citation Format: Tuula Kallunki, Ditte M. Brix, Bo Rafn, Knut Kristoffer Bundgaard Clemmensen, Sofie Hagel Andersen, Noona Ambartsumian, Marja Jäättelä. Targeting ERBB2-induced, lysosome-mediated invasion. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3149. doi:10.1158/1538-7445.AM2014-3149
Abstract 3155: Tks adaptor proteins and invadopodia formation in the growth and metastasis of melanoma
Authors: Iizuka Shinji , Gould Christine M. , Buschman Matthew D. , Begoña Diaz , Abdullah Christopher , Courtneidge Sara 
Published: May 2015

Abstract
Invadopodia are actin-based proteolytic structures which facilitate cancer cell invasion and metastasis. While it was previously believed that invadopodia are not required for tumor cell growth, based on studies in monolayer cell culture, more recently we have noted a role for invadopodia proteins in growth in more physiological 3-dimensional (3D) extracellular matrix contexts. From previous work in our lab, the Tks adaptor proteins with 5 (Tks5) and 4 (Tks4) SH3 domains, respectively, were identified as Src kinase substrates and both are essential molecules for functional invadopodia formation in mouse and human cancer cells.
Here, we assess the roles of the Tks adaptors in melanoma tumor growth and invasion both in vivo and in vitro. To address the mechanism as to how the Tks adaptors control tumor growth and invasion, in vitro 3D growth assays in collagen I were performed. Knockdown of either Tks4 or Tks5 in C8161.9 or A375 melanoma cells decreased 3D growth in collagen I, a process that also appeared to be dependent upon metalloproteinase (MMP) activity. Interestingly, knockdown of either Tks4 or Tks5 in A375 melanoma cells decreased cell-surface expression of MT1-MMP, a key protease involved in tumor growth and metastasis. In vivo tumor growth and metastasis assays in mice using human and mouse melanoma cells depleted of Tks4 or Tks5 by shRNA revealed roles for the Tks adaptors in both the size and the number of lung metastases. Finally, analysis of a human melanoma tissue array with a Tks5 antibody, and RNAseq data, indicates that Tks5 expression is increased in lymph node and other metastases in comparison to nevi and primary sites.
These data suggest that the Tks adaptors control melanoma tumor growth and invasion by regulating invadopodia formation and perhaps also cell surface expression of MT1-MMP, and thus contribute to melanoma progression.
Citation Format: Shinji Iizuka, Christine M. Gould, Matthew D. Buschman, Diaz Begoña, Christopher Abdullah, Sara Courtneidge. Tks adaptor proteins and invadopodia formation in the growth and metastasis of melanoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3155. doi:10.1158/1538-7445.AM2014-3155