bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3286: Interleukin-17 receptor c (IL-17RC) knockout mice developed fewer and smaller prostate tumors compared to the wild-type mice in Pten-deficient context
Authors: You Zongbing , Zhang Qiuyang , Liu Sen , Ge Dongxia , Zhang Qingsong , Xue Yun 
Published: August 2012

Abstract
Introduction: Interleukinα17 (ILα17) is a key cytokine in inflammatory and immune diseases. ILα17 may promote or inhibit tumor growth. Several studies have linked ILα17 with prostate cancer. ILα17's role in prostate cancer is unknown. The objective of this study is to investigate ILα17's role in formation and growth of prostate adenocarcinoma. Methods: ILα17 receptor C (ILα17RC) knockout mice were crossed with Pten conditional knockout mice (using ProbasinαCre). Ptenα/β male mice with intact ILα17 signaling (named RC+ mice, including ILα17RC+/+ and ILα17RC+/−) were compared with Ptenα/β male mice without ILα17 signaling (ILα17RCα/α, named RCβ mice). Results: There was no difference between the weight of genitourinary bloc of RC+ mice and that of RCβ mice at 4, 6 and 9 weeks. At 12 and 30 weeks, the GUαbloc weight of RC+ mice was 14% and 47% heavier than that of RCβ mice, respectively (P = 0.005, N = 54, and P = 0.004, N = 32, respectively). We found similar prostatic epithelial hyperplasia at 4 weeks and prostatic intraepithelial neoplasia (PIN) at 6 weeks in both RC+ and RCβ mice, suggesting that ILα17RC knockout did not affect PIN formation. At 9 weeks, invasive cancer was formed in 87% of RC+ prostate lobes, but only in 25% of RCβ prostate lobes (P &lt; 0.001). At 30 weeks, 100% of RC+ prostate lobes formed invasive cancer, whereas only 70% of RCβ prostate lobes showed invasive cancer (P &lt; 0.005). This suggests that ILα17RC knockout decreased progression of PIN to invasive cancer. The RCβ PINs were surrounded with a thick layer of fibromuscular stroma, whereas the stroma layer was significantly thinner in RC+ prostate glands, suggesting that failure of PIN to invade stroma was a critical deficit in RCβ mice. We found that MMP7 expression was significantly decreased in RCβ prostates compared to RC+ prostates, suggesting that lack of MMP7 expression is likely responsible for the observed phenotype. Furthermore, we found that ILα17 treatment induced MMP7 mRNA and protein expression in exαvivo cultured RC+ prostate tissues but not in RCβ prostate tissues, suggesting that MMP7 is a downstream target gene of ILα17 signaling. Conclusions: ILα17 promotes prostate adenocarcinoma formation and growth through induction of MMP7 expression in mouse prostate. Funding provided by NIH/NCRR COBRE Grant (2P20RR020152α06), DoD (W81XWHα05α1α0567 and W81XWHα10α1α0937), Tulane Cancer Center, Louisiana Cancer Research Consortium, and Tulane Framework for Global Health Seed Grant.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3286. doi:1538-7445.AM2012-3286
Abstract 3295: Systematic in vivo analysis of PI3K pathway aberrations in a mouse model for invasive lobular carcinoma
Authors: van Miltenburg Martine H. , Klarenbeek Sjoerd , Braumuller Tanya , Henneman Linda , Ali Rahmen Bin , Huijbers Ivo , Krimpenfort Paul , Berns Anton , Jonkers Jos 
Published: August 2012

Abstract
Invasive lobular carcinoma (ILC) is a form of breast cancer that develops in the milk-producing glands (lobules) of the breast. ILC is an aggressive form of breast cancer due to its ability to spread to other parts of the body, both by bloodstream as well as lymphatic system. One of the key features found in ILC is loss of E-cadherin, encoding CDH1. Mammary-gland specific deletion of E-cadherin does not lead to tumour formation indicating that other factors are involved in the induction of ILC. Indeed, combined tissue-specific inactivation of E-cadherin and p53 induces development of invasive and metastatic mammary tumours resembling human ILC. However, a limitation of the current conditional mouse models is that human ILCs rarely contain p53 mutations. In contrast, PI3K pathway mutations are frequently found in human ILCs. Currently we are developing novel mouse ILC models to systematically examine the contribution of PI3K pathway components such as PIK3CA, AKT and PTEN to ILC development. To reduce time spent on generating a genetically engineered mouse (GEM) tumour cohort expressing three or more transgenes we set-up embryonic stem (ES) cell derivation and targeting of ES cells from validated GEM models, the so-called GEMM-ESC strategy. WapCre-Cdh1F/F ES cells targeted with PIK3CA or AKT mutants are now being used to generate the elaborate PI3K pathway tumour cohort. These advanced models will allow us to study the role of the PI3K pathway in the pathogenesis of ILC. Moreover, we can use these advanced mouse models which recapitulate key hallmarks of human ILC to perform refined and realistic preclinical prevention and intervention studies for ILC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3295. doi:1538-7445.AM2012-3295
Abstract 3296: SRC-3 is a critical mediator in the development of castration-resistant prostate cancer
Authors: Tien Jean C. , Liu Zhaoliang , Gao Li , Wang Fen , Xu Jianming 
Published: August 2012

Abstract
Androgen ablation therapy is the standard treatment for advanced prostate cancer. While tumors initially respond to androgen deprivation, they almost always recur with an androgen-independent phenotype termed castration-resistant prostate cancer (CRPC). Castration-resistant tumors are incurable with current therapy regimens and account for most prostate cancer mortality. Better understanding of their biology is therefore critical for devising novel treatment options. Steroid Receptor Coactivator 3 (SRC-3) is a nuclear receptor coactivator that promotes growth of endocrine tissues. It enhances proliferation of prostate cancer cell lines and is highly expressed in advanced human prostate tumors. Despite this, the role of SRC-3 in CRPC is not well studied. PTEN is a tumor suppressor gene mutated in most human prostate cancers. Mice harboring PTEN deletion in prostatic epithelial cells develop cancer that arises from progenitors in the luminal epithelial and basal compartments. Tumors histologically mimic advanced human disease and are castration-resistant. We hypothesized that, in prostate tumors caused by PTEN deletion, SRC-3 is a critical mediator for accelerating the development of CRPC. To test this hypothesis, we generated mice in which floxed PTEN and SRC-3 genes were concomitantly deleted in prostate epithelial cells via a Cre recombinase driven by the Probasin promoter. We first compared tumor mass, histology and biomarkers in these PTENf/f/SRC-3f/f/ARR2PBiCre (pten3cko) mice vs. PTENf/f/ARR2PBiCre (ptencko) mice. We found that while tumor growth in pten3cko mice was slightly inhibited at 9 wks of age, tumor histology and cellular composition were not markedly different. We then castrated mice of both genotypes at 9-wks-old and harvested tumors at 12wks. Interestingly, castrated ptencko mice had significantly worsened tumor aggressiveness–as indicated by increased proliferation index, reduced differentiation (increased p63; decreased K5 and K8) and increased reactive stroma (double staining of SMA and vimentin)–versus their non-castrated counterparts. Amazingly, in addition to significantly reducing tumor size, SRC-3 ablation reversed all changes comprising the aggressive phenotype seen in the post-castration tumors. Further investigation showed SRC-3 deletion decreased mTOR signaling. Together, these data show that castration induces a worse tumor phenotype in the setting of PTEN deletion and that SRC-3 promotes this process by inducing epithelial cell proliferation and enhancing the growth-promoting effect of these cells on the stroma. Therefore, SRC-3 may serve as a potential target for controlling CRPC development.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3296. doi:1538-7445.AM2012-3296
Abstract 3298: Arsenic induces human bronchial epithelial cell transformation featured with tumor-initiating cells
Authors: Chang Qingshan , Chen Fei , Lu Yongju 
Published: August 2012

Abstract
Arsenic is a well-known human carcinogen. Chronic exposure to arsenic is associated with cancers in various tissues, including skin, urinary bladder, lung, liver, kidney and prostate. However, the mechanism underlying arsenic-induced carcinogenesis remains elusive. Here, we demonstrate that long-term (six month) exposure to low levels of sodium arsenite (0.25 µ M) in human bronchial epithelial cell line (BEAS-2B) results in altered morphology, increased cell proliferation and anchorage-independent colony formation in soft agar, indicative of malignant transformation of these cells. Moreover, tumorigenesis analysis revealed that s.c. inoculation of the arsenic-transformed cells can induce tumors in nude mice. The tumors can be observed after 2-3 weeks even only 500 arsenic-transformed cells were injected, suggesting that these transformed cells induced by long-term and low-dose arsenic treatment are highly tumorigenic. Additional studies indicated that some of these arsenic-transformed cells exhibit characteristics of tunor-initiating cells (TICs) or cancer stem cells (CSCs), such as overexpression of Oct3/4, Nanog, Sox2, Klf4, and C-myc. Tumor sphere formation assay, a general procedure in defining TICs or CSCs, suggested that about 5% of these arsenic-transformed cells can form tumor spheres in non-adherent plates. The tumor sphere forming cells were enriched through serial passage of the cells collected from tumor spheres. Flow cytometry sorting showed that 90% of these sphere cells are CD49f positive, whereas CD133, CD44, EpCAM, and c-kit were not detected. Overexpression of CD49f was confirmed by immunoblotting, which indicated an increased CD49f level in the arsenic-transformed cells relative to the non-transformed BEAS-2B cells. Finally, the ability of sphere formation and colony formation in soft agar was compared between the cells showed the strongest and the weakest CD49f expression and suggested that the cells with the strongest CD49f expression are more capable of forming tumor spheres and colonies. In conclusion, our data suggested that the transformed cells induced by arsenic have features of TICs or CSCs.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3298. doi:1538-7445.AM2012-3298
Abstract 3299: Hematopoietic chimerism in liver transplantation patients and hematopoietic stem/progenitor cells in adult human liver
Authors: Wang Xiao Qi , Lo Chung Mau , Chen Lin , Cheung Cindy KY , Fan Sheung Tat 
Published: August 2012

Abstract
Liver transplantation (LT) is a cure for many liver diseases. Blood chimerism of donor origin can develop after LT, which raises the possibility of existence of hematopoietic stem/progenitor cells (HSPCs) in liver. We characterized the blood chimerism in a large cohort of 226 LT patients and analyzed putative HSPCs in adult human livers. The overall incidence of chimerism was 6.19%, of which 10.3% was among short-term (one day to six months) and 3.6% was among long-term (six months to eight years) LT patients. Hematopoietic LinαCD34+CD38αCD90+ population has been demonstrated to generate long-term multipotent grafts in transplantations. In human adult livers, we detected LinαCD34+CD38αCD90+ population accounting for 0.056% ± 0.05% of the total single liver cells and for 0.06% ± 0.05% of CD45+ liver cells. Both LinαCD34+ and LinαCD45+ liver cells from extensive perfused human liver graft were capable of forming hematopoietic myeloid-lineage and erythroid-lineage methylcellulose colonies. More importantly, LinαCD45+ or CD45+ liver cells could be engrafted into hematopoietic cells in an immunodeficient mouse model. These results are the first evidence of presence of the putative HSPC population in adult human liver, where liver is a good ectopic niche. The discovery of existence of HSPCs in adult liver will have new implications for understanding of extra-marrow hematopoiesis, liver regeneration, mechanisms of tolerance in organ transplantation and de novo cancer recurrence in LT patients. Conclusion: Human adult liver contains small population of HSPCs. In LT patients, there are two types of chimerism: transient chimerism resulting from mature leucocytes and long-term chimerism deriving from putative HSPCs in the liver graft.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3299. doi:1538-7445.AM2012-3299
Abstract 3302: Roles of cortical and subventricular GFAP+ astrocytes in initiation of astrocytomas
Authors: Schmid Ralf S. , Bash Ryan E. , Werneke Andrea M. , Miller C. Ryan 
Published: August 2012

Abstract
Astrocytomas, including glioblastomas (GBM), are characterized by cellular, molecular, and morphological heterogeneity, which raises the question from which cells astrocytomas originate. Research with many different types of cancer has established that tumor initiating cells share molecular characteristics and gene expression signatures with stem cells; however, the origin of glioma initiating cells and their relationship to adult neural stem cells remains unclear. Using conditional, inducible genetically-engineered mouse models (GEMM) with inactivated RB (GFAP-driven transgenic expression of N-terminal SV40 large T mutant (T121), T) and/or PTEN (P) and/or constitutively activated KRAS (R, KRAS(G12D)), we show that tumorigenesis was initiated in both parenchymal GFAP+ astrocytes as well as GFAP+ NSC/progenitor cells in the subventricular zone (SVZ) within two weeks of induction in adult mice. The induced GFAP+ cells proliferated (measured by EDU incorporation) and expressed multiple neural stem cell (NSC) markers such as Sox2, nestin and CD133, which persisted in developing astrocytomas over several months. Primary cortical astrocytes from TRP-/- mice cultured in vitro under NSC conditions displayed self-renewal and multi-lineage differentiation potential and expressed multiple NSC markers. When stereotactically injected in the diencephalon of syngeneic recipient mice, astrocytomas formed within 3 weeks, which histopathologically and genetically resembled human glioblastoma and proved to be fatal with a median survival of 25 days. To further evaluate the relationship between adult neural stem/progenitor cells in the SVZ and astrocytoma initiating cells, we crossed TRP GEMM with knock-in Sox2-GFP reporter mice to purify TRP neural stem cells from the SVZ. These cells were then stereotactically injected into the diencephalon of syngeneic recipient mice. Allograft cells, identified by GFP expression, were found proliferating around the injection site several weeks after injection, suggestive of developing astrocytomas. Some cells also migrated along white matter tracks and infiltrated the stem cell niche in the subventricular zone. These results suggest that GFAP+ NSC within the SVZ, and potentially GFAP+ astrocytes elsewhere in the neuraxis, may serve as the cell-of-origin for diffuse astrocytomas in the adult murine brain.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3302. doi:1538-7445.AM2012-3302
Abstract 3304: Hyaluronan mediates interactions between CD44+ MSCs and CD34+ fibrocytes in Desmoid Tumors.
Authors: Rizvi Hira , Carothers Adelaide M. , Bertagnolli Monica M. , Cho Nancy L. 
Published: August 2012

Abstract
We reported that 16/16 sporadic and familial desmoid tumors (DTs) contained CD44+CD73+CD90+Bmi1+ mesenchymal stromal cells (MSCs) and CD34+CD105+ALK1+ monocyte-derived fibrocytes. Hematopoietic stem cells (HSCs) and MSCs reside in the same bone marrow niche, and MSCs regulate HSC progenitor release into the circulation. Numerous signaling pathways maintain chemotactic and physical crosstalk between these types of stem cells (c-Kit/SCF, CXCR4/SDF-1, Notch/Jagged1, etc). HSC and MSC progenitors are both recruited to sites of tissue injury to aid in wound healing. We were interested to learn what crosstalk engages these multipotent cells in DTs. Hyaluronan (HA) is a long charged chain of repeating glucuronate and N-acteylglucosamine disaccharides that is synthesized by HA synthases (HAS 1, 2, 3) and degraded by hyaluronidases (HYAL1, 2). HA binds to receptors CD44, TLR2/4 and Hyaluronan binding protein (HABP). Immunofluorescent histochemistry was performed on our tumor collection to determine the expression of both metabolic and catabolic HA enzymes. All of our DTs contained cells expressing HA, HYAL2, HAS2, and HABP2. HABP2 attenuates hyaluronan-receptor interactions. Double staining showed that all MSCs expressed HA and HAS2, confirming the functional significance of the CD44+ receptor in these cells. The majority of MSCs co-expressed HABP2. CD34+ fibrocytes but not CD44+ MSCs co-expressed HYAL2. CD44 expression by MSCs is stimulated by PDGF-BB, and in DTs, CD44+ MSCs co-expressed PDGFRα. These results suggest that paracrine regulation of HA signaling in these tumors may be another way in which MSCs and fibrocytes crosstalk.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3304. doi:1538-7445.AM2012-3304
Abstract 3308: Axl is required for EMT-induced stem cell traits and metastasis in breast cancer
Authors: Tiron Crina , Stefansson Ingunn , Haugen Hallvard , Sandal Tone , McCormack Emmet , Gjertsen Bjørn Tore , Micklem David , Ivaska Johanna , Akslen Lars , Lorens James 
Published: August 2012

Abstract
Epithelial-to-mesenchymal transition (EMT) endows carcinoma cells with migratory, survival and stem cell-like attributes that facilitate metastasis. We have shown that expression of the receptor tyrosine kinase Axl in primary breast cancer is a strong independent predictor of poor overall survival and is further enhanced in matched patient metastases. Axl is upregulated by EMT-induction in mammary epithelial cells and establishes an autocrine signaling loop with its ligand, Gas6. Axl signaling is required to maintain the mesenchymal and stem cell-like phenotype induced by EMT-transcription factors. Axl-inhibition downregulated mesenchymal and stem cell marker expression, blocked invasiveness, inhibited mammosphere formation and reversed drug resistance. Axl knockdown completely prevented the spread of metastatic breast carcinoma cells from the mammary gland and increased overall survival in two different orthotopic breast cancer models. Axl was also required for breast cancer cells to extravasate into the lung following intravenous injection. These results suggest that Axl signaling is necessary for metastasis, stem cell and therapy resistance traits in breast cancer. Hence, Axl-inhibition represents a novel therapeutic opportunity to target stem-like and drug resistant breast cancer cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3308. doi:1538-7445.AM2012-3308
Abstract 3309: Blocking the Notch pathway inhibits the epithelial-mesenchymal transition (EMT) status in lung cancer and alters chemoresistance
Authors: Hassan Khaled A. , Wang Luo , O'Dowd Paige , Kim Gwangil , Korkaya Hasan , Davis April , Liu Suling , Kalemkerian Gregory P. , Wicha Max 
Published: August 2012

Abstract
Background: The Epithelial-Mesenchymal Transition (EMT) is a key developmental program that is often activated during cancer invasion and metastasis. EMT cells have stem cells properties and possess the characteristics of cell motility, invasiveness and chemotherapy resistance. EMT expression profile correlates with poor outcome in multiple tumors and there is evidence suggesting an integral role of Notch pathway in mediating EMT. In this study, we investigated Notch activity and EMT status and the correlation with chemoressitance in non-small cell lung cancer (NSCLC). Results: Transduction of multiple NSCLC cell lines, NCI-H1299, NCI-H460, NCI-H358, NCI-H441 with a Notch GFP-reporter construct identified a subset of cells with high Notch activity (GFP-pos). We compared the tumor invasivness capacity of GFP-pos and GFP-neg cells utilizing a transwell invasion assay. Cells with high Notch activity, as evidenced by GFP expression, had multiple fold higher invasion capability compared to GFP-neg cells (p=0.0001). To evaluate whether Notch activity correlates with resistance to chemotherapy, we treated GFP-pos and GFP-neg cells with docetaxel or cisplatin and assessed Annexin V expression using flow cytometry. GFP-pos cells had five fold less apoptotic cells as compared to GFP-neg cells indicating resistance of GFP-pos cells to chemotherapy. When GFP-pos cells were exposed to a Notch signaling inhibitor inhibitor, gamma secretase inhibitor (GSI), these cells were rendered sensitive to cisplatin and docetaxel. RNA microarray analysis and RT-PCR analysis revealed an increased expression of EMT related genes (Vimentin, N-Cadherin, Snail-1,….) in GFP-pos cells as compared to GFP-neg cells. Furthermore, NOD/SCID mice with subcutaneous lung tumor xenografts treated with GSI showed decreased expression of downstream effectors of Notch as well as vimentin. This combination of GSI and docetaxel reduced tumor grwoth in mouse xenographs compared to GSI and docetaxel as single agents. Conclusion: These studies suggest that the Notch pathway is an important regulator of EMT status and that its inhibition may alter EMT chemo-resistance properties. The addition of a Notch inhibitor may enhance the efficacy of chemotherapy in the treatment of NSCLC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3309. doi:1538-7445.AM2012-3309