bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4959: Targeting pancreatic stellate cells (PSC) to treat pancreatic cancer.
Authors: Gonzalez-Villasana Vianey , Rodriguez-Aguayo Cristian , Arumugam Thiru , Cruz-Monserrate Zobeida , Deng Defeng , Fuentes-Mattei Enrique , Hwang Rosa F. , Wang Huamin , Pena Guillermo N. Armaiz , Aslan Burcu , Gutierrez-Puente Yolanda , Sood Anil K. , Logsdon Craig , Lopez-Berestein Gabriel 
Published: August 2014

Abstract
Pancreatic cancer (PC) is characterized by a prominent stromal reaction. Recently, the contribution of the stromal elements to the initiation and progression of the disease has come to be appreciated. In this context, targeting this tumor microenvironment represents a potential strategy to improve the delivery and efficacy of chemotherapeutic agents leading a better prognosis for the patients. Pancreatic stellate cells (PSC) have been recognized as the principal cells responsible for the production of fibrosis in pancreatic cancer. In the current study, we observed that PSC possess α-naphthyl acetate esterase (ANAE) activity, which is a specific marker enzyme for monocytes and macrophages, these cells can be differentiated/activated in a similar fashion as a monocytes/macrophages, suggesting that PSC behave in a similar fashion as macrophages, and hence can be treated as such. Based on these data we targeted PSC in vitro and in vivo by using bisphosphonates (BPs) that are macrophages inhibitors. BPs inhibited proliferation and inactivated PSC in vitro through inhibition of protein prenylation, and increased cell apoptosis and cell cycle arrest in G1. Furthermore, BPs inactivated PSC, inhibited tumor growth (p&lt;0.0005), tumor weight (p&lt;0.001) and number of nodules (p&lt;0.001) in an orthotopic animal model of pancreas. These antitumor effects were enhanced when BPs were combined with a taxane. These data suggest that BPs could disrupt the pancreatic cancer, which could offer a better prognosis to PC patients.
Citation Format: Vianey Gonzalez-Villasana, Cristian Rodriguez-Aguayo, Thiru Arumugam, Zobeida Cruz-Monserrate, Defeng Deng, Enrique Fuentes-Mattei, Rosa F. Hwang, Huamin Wang, Guillermo N. Armaiz Pena, Burcu Aslan, Yolanda Gutierrez-Puente, Anil K. Sood, Craig Logsdon, Gabriel Lopez-Berestein. Targeting pancreatic stellate cells (PSC) to treat pancreatic cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4959. doi:10.1158/1538-7445.AM2013-4959
Abstract 4968: Chemotherapy up-regulates RANK-RANKL signaling in breast cancer cells.
Authors: Sharma Bhawna , Varney Michelle L. , Singh Rakesh K. 
Published: August 2014

Abstract
Chemotherapy has been the mainstay of cancer treatment for so many years and so do the increasing resistance to it. Recent studies emphasize the importance of cytokines in breast cancer therapy resistance and how targeting cytokines or their receptor may prove to be a better therapeutic regimen. This study focuses on the role of receptor activator of NFkB ligand (RANKL), recently been observed to provide survival benefits to cancer cells and helps in mammary stem cell maintenance. To the best of our knowledge the modulations of RANK and RANKL in response to chemotherapy has not been evaluated before. Our preliminary studies with drug-resistant cells showed higher expression of RANK and RANKL both in vitro in cells as well as in vivo in tumors formed by these cells, suggesting a role of this RANKL mediated signaling in breast cancer therapy resistance. Given that RANK and RANKL are expressed in aggressive breast tumors and this signaling provides survival benefits to cancer cells, we hypothesized that chemotherapy up-regulates RANK-RANKL signaling in breast cancer cells which eventually makes breast cancer cells resistant to further chemotherapy providing evasion to therapy. To investigate this, we monitored the expression of RANKL in murine 4T1, CL66 and MDA MB-231, MCF-7; human breast cancer cells lines after treatment with two commonly used drugs doxorubicin and paclitaxel for breast cancer treatment. We observed that both drugs up-regulate RANKL expression in these cells. To examine if the expression of RANK also changes after drug treatment in these cells, we treated 4T1 and Cl66 cells with paclitaxel for 4, 8 and 12 hours. We observed an increase in the expression of RANK in these cells in a dose- and duration-dependent manner. 4T1 and Cl66 along with MDA MB-231 and MCF-7 were also treated with both paclitaxel and doxorubicin to evaluate if the change in receptor and ligand expression was drug-dependent. Our data showed that both the drugs up-regulate RANKL at mRNA (qRT-PCR) and protein levels (Immunofluorescence) in Cl66 and 4T1 cells. This up-regulation was as early as 4hrs (at mRNA level) after drugs treatment and the expression decreases after 8 hrs, suggesting an early transcriptional up-regulation. Our data suggest that increased expression of both RANK and RANKL in the breast cancer cells following chemotherapy may contribute to the activation of RANK-RANKL signaling in breast cancer and targeting this signaling might provide a novel adjuvant therapeutic regimen.
Citation Format: Bhawna Sharma, Michelle L. Varney, Rakesh K. Singh. Chemotherapy up-regulates RANK-RANKL signaling in breast cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4968. doi:10.1158/1538-7445.AM2013-4968
Abstract 4974: Oligoclonal characterization of tumor-infiltrating plasma cells in breast cancer: Germ cell expansion and immunity .
Authors: Shukla Anurag , Sun Yu-Jing , Krag David 
Published: August 2014

Abstract
Breast cancer is the most common invasive cancer in women in the United States and many other parts of the world. About 80% of all the breast cancers are Invasive Ductal Carcinomas (IDC). Breast cancers often show detectable lymphocytic infiltrates, and only about one-fourth of them contain moderate to heavy infiltration of B-cells and plasma cells. B cells are the effector cells of humoral immunity and can terminally differentiate into antibody secreting plasma cells. In the present study, we have analyzed the immunoglobulin variable genes of tumor-infiltrating plasma cells from IDC patients. This was done to determine the clonal character of the plasma cells and their possible role in the tumor immunity. Fresh malignant breast tumors were obtained following surgery, and their frozen sections were screened for the lymphocytic infiltration. The tumor samples from patients which showed good plasma cell-infiltration were used for this study. Both malignant breast tumors, A55 (estrogen receptor-positive 80%; progesterone receptor-positive &gt;90%) and A91 (estrogen receptor positive 70%; progesterone receptor positive 90%), were categorized as invasive ductal carcinomas. Using a laser capture microdissection technique (PALM Microlaser Technologies AG, Bernried, Germany), single and small clusters of plasma cells in the tumors were collected. The tumor plasma cells were processed for human immunoglobulin variable gene analysis using appropriate RT-PCR primer sets for heavy and light chains. A set of B- cells from healthy volunteer blood was also run as a RT-PCR quality control. The analyses of variable regions (VHeavy and VLight) of immunoglobulin genes show a very limited number of plasma cell clones in both the tumors. These results indicate their origin from a possible B-cell germ center within the tumor. These plasma cells may be secreting antibodies relevant to the tumor antigens. In order to confirm this, we plan to clone these VH and VL genes and produce antibodies in vitro and examine their binding to the tumor from which they were derived. The work will be extended to study the effects of these antibodies on breast cancer cell proliferation.
Citation Format: Anurag Shukla, Yu-Jing Sun, David Krag. Oligoclonal characterization of tumor-infiltrating plasma cells in breast cancer: Germ cell expansion and immunity . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4974. doi:10.1158/1538-7445.AM2013-4974
Abstract 4980: Myeloid cells display immunosuppression activities during pregnancy, participating to the establishment of pre-metastatic niches.
Authors: Le Bitoux Marie-Aude , Waeber Sabine , Stamenkovic Ivan 
Published: August 2014

Abstract
During pregnancy, major physiological changes occur that include inflammation and reduced immunity, conditions that are both implicated in promoting tumor growth. Tumors are indeed more aggressive during pregnancy and have greater metastatic proclivity. To gain insight into the mechanisms that may render pregnancy permissive for tumor growth, we addressed the biological and functional properties of myeloid-derived suppressor cells (MDSC), a heterogeneous population of hematopoietic cells of variable plasticity and immunoregulatory properties, during mouse and human gestation.
Gene expression profiling of mouse MDSC has been shown to differ in pregnant and virgin mice, and the gene expression profile of pregnant animal-derived MDSC bears similarity to that observed in MDSC of tumor bearing mice. Common induced genes include Fibronectin1 and Olfactomedin4, which are known to be involved in extracellular matrix remodeling and tissue permissiveness to tumor cell implantation.
In human pregnancy, CD33+ myeloid cells isolated from peripheral blood mononuclear cells (PBMC) are shown to be more strongly inhibitory of T cell proliferation in pregnant than in non-pregnant women. We also observed reduced natural killer cell numbers in the circulation of pregnant women, but which was not linked to a decrease in their cytotoxic activity, even after co-culture with CD33+ PBMC.
Our observations suggest that mouse MDSC, as well as human CD33+ cell populations that arise during the physiological state of gestation, mimic tumor progression-associated MDSC and participate in the constitution of a permissive soil, often referred to as the pre-metastatic niche.
Citation Format: Marie-Aude Le Bitoux, Sabine Waeber, Ivan Stamenkovic. Myeloid cells display immunosuppression activities during pregnancy, participating to the establishment of pre-metastatic niches. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4980. doi:10.1158/1538-7445.AM2013-4980
Abstract 4987: Immunoscore of CD8/CD45RO in pre-operative biopsy specimens predicts TNM-stage in primary colorectal cancer.
Authors: Koelzer Viktor H. , Lugli Alessandro , Dawson Heather , Borner Markus , Inderbitzin Daniel , Zlobec Inti 
Published: August 2014

Abstract
Background:
Colonoscopy and biopsy are the standard procedure for primary diagnosis of colorectal cancer (CRC), but prognostic biomarkers based on biopsy material are still missing. The tumor microenvironment has been shown to play a major role in the pathogenesis of CRC. Therefore, we hypothesized that an immunoscore of CD8+ T-effector and CD45RO+ memory T-cell infiltrates in pre-operative biopsy specimens could have an impact on the pre-operative management of CRC patients by predicting TNM-stage.
Methods:
Intraepithelial (i) and stromal (s)CD8+ and CD45RO+ T-cells were visualized in biopsy specimens of 134 well characterized CRC patients by immunohistochemistry and quantified in 5 high-power-fields each of the highest density of immune cell infiltration. Cut-off scores for prediction of pN, pM and pT in the matched resection specimen were established using Classification and Regression Tree (CART) analysis. Infiltration of CD8+ and CD45RO+ T-cells in each compartment was assessed for prediction of TNM stage, lymphovascular invasion and tumor grade.
Results:
High numbers of infiltrating sCD45RO T-cells in biopsy material were associated with earlier T-stage in the matched resection specimen(p&lt;0.0001) as well as with earlier tumor grade (p=0.0223) and absence of distant metastasis (p=0.0177; specificity=62.5% and positive predictive value (PPV)=93%). High total (t) numbers of infiltrating CD8-T cells in biopsy material were strongly predictive of absence of nodal metastasis (p=0.0182) as well as absence of lymphatic invasion (p=0.0201). Combined analysis of tCD8 and tCD45RO with pN led to 100% specificity and PPV. No association of CD8+ and CD45R0+ T-cell-infiltration with vascular invasion was observed. In contrast, absence of both CD8+ and CD45RO+ T-cells in pre-operative biopsies predicted frequent nodal and distant metastatic spread, advanced T-stage and lymphovascular invasion in the matched resection specimen.
Conclusion:
Total CD8 counts and sCD45RO in pre-operative biopsy specimens allows prediction of essential clinical characteristics of primary CRC in the matched resection specimen including full TNM-stage and lymphatic invasion. Analysis of total CD8+ and sCD45RO+ in pre-operative biopsies may thereby provide a decisive indicator for risk stratification of CRC patients in the preoperative setting.
Citation Format: Viktor H. Koelzer, Alessandro Lugli, Heather Dawson, Markus Borner, Daniel Inderbitzin, Inti Zlobec. Immunoscore of CD8/CD45RO in pre-operative biopsy specimens predicts TNM-stage in primary colorectal cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4987. doi:10.1158/1538-7445.AM2013-4987
Abstract 4990: Complement promotes growth of ovarian cancer.
Authors: Cho Min Soon , Vasquez Hernan G. , Han Hee Dong , Pradeep Sunila , Rupaimoole Rajesh , Zand Behrouz , Kroll Michael , Sood Anil K. , Afshar-Kharghan Vahid 
Published: August 2014

Abstract
Objective: The complement system is a component of innate immunity against invading pathogens, but also mediates the cell-cell communication in organ regeneration, angiogenesis, epithelial-mesenchymal transition (EMT) and cell migration. We studied whether the complement system affect tumor growth in ovarian cancer.
Materials & Methods: Complement C3 mRNA level was quantified using qRT-PCR in ovarian cancer cell lines and in tumor specimens from patients with ovarian cancer. Small interfering RNA (siRNA) was used to investigate the consequences of C3 gene silencing in vitro and in vivo.
Results: C3 was expressed in ovarian cancer cell lines and tumor tissues from patients. Silencing of the C3 gene decreased ovarian cancer cell proliferation, migration and invasion in vitro. In orthotopic murine models of ovarian cancer, C3 siRNA reduced growth of implanted tumors by 60% as was evident by lower number and smaller size of tumor nodules in C3-siRNA treated mice in comparison to those in scrambled siRNA treated control mice (average tumor weight of 0.19 g in C3 siRNA vs. 0.61 g in scrambled siRNA, n=8 in each group, p=0.017; average nodule number of 4.4 in C3 siRNA vs. 11.4 in scrambled siRNA, n=8 in each group, p=0.05; t-test). Consistent with our in vitro and animal studies, ovarian cancer patients with a higher C3 mRNA level in their tumors had a worse prognosis with overall survival rates compared to those with a lower C3 mRNA level (n=75, p=0.03).
Conclusion: Our studies revealed a novel role for complement in cancer biology. Cancer cell-derived C3 promotes tumor growth and progression. Our studies might identify the complement system as a new target for the development of new anti-tumor reagents.
Citation Format: Min Soon Cho, Hernan G. Vasquez, Hee Dong Han, Sunila Pradeep, Rajesh Rupaimoole, Behrouz Zand, Michael Kroll, Anil K. Sood, Vahid Afshar-Kharghan. Complement promotes growth of ovarian cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4990. doi:10.1158/1538-7445.AM2013-4990
Abstract 4998: NFAT signaling modulates tumor microenvironment.
Authors: Kaunisto Aura , Toker Alex 
Published: August 2014

Abstract
Nuclear factor of activated T cells (NFAT) transcription factors regulate several cancer-related processes, such as migration and invasion. We have shown that NFAT is both necessary and sufficient to drive invasive migration of breast carcinoma cells. NFAT target genes that contribute to this phenotype encode cyclo-oxygenase-2, the enzyme required for the production of prostaglandin E2, and autotaxin, which catalyzes the synthesis of lysophosphatidic acid. NFAT also promotes tumor progression downstream of vascular endothelial growth factors and contributes to angiogenesis and lymphangiogenesis, though the underlying molecular mechanisms that control these phenotypes have remained unknown. In our present studies, we have identified novel NFAT target genes whose products are likely to modify tumor microenvironment through paracrine signaling to immune cells. We have generated stable pools of breast cancer cells with inducible lentiviral silencing or overexpression of NFAT and performed quantitative real-time RT-PCR to identify NFAT-responsive genes that code for soluble factors. This approach yielded several novel candidates, including those encoding cytokines and chemokines. The contribution of these NFAT-regulated gene products to tumor-stromal interactions is currently under investigation. Our studies propose a central role for NFAT in modulating tumor microenvironment.
Citation Format: Aura Kaunisto, Alex Toker. NFAT signaling modulates tumor microenvironment. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4998. doi:10.1158/1538-7445.AM2013-4998
Abstract 500: Role of R-spondin4 in Wnt/β-catenin signaling and cell proliferation in breast cancer.
Authors: Lu Wenyan , Lin Cuihong , King Taj K. , Li Yonghe 
Published: August 2014

Abstract
R-spondin 4 (Rspo4) is a member of the Rspo protein family, which is another group of secreted proteins that can activate Wnt/β-catenin signaling. Although it is well recognized that Wnt/β-catenin signaling is important for breast cancer development and progression, the role of Rspo4 in breast cancer is unclear. In the present study, we found that Rspo4 was expressed in breast cancer cell lines, but absent in normal mammary epithelial cells (HMECs). We also found that Rspo4 expression was up-regulated in human malignant breast tissues. Moreover, Rspo4 acted synergistically with Wnt3A to activate Wnt/β-catenin signaling in breast cancer cells. Conversely, reducing endogenous Rspo4 with siRNAs in human breast cancer cell lines suppressed Wnt/β-catenin signaling and cell proliferation. These data suggest that Rspo4 functions as a positive regulator of breast cancer proliferation by activating Wnt/β-catenin signaling.
Citation Format: Wenyan Lu, Cuihong Lin, Taj K. King, Yonghe Li. Role of R-spondin4 in Wnt/β-catenin signaling and cell proliferation in breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 500. doi:10.1158/1538-7445.AM2013-500
Abstract 5002: Intermittent hypoxia selects for increased carcinogenicity in breast epithelial cells.
Authors: Verduzco Daniel , Gatenby Robert , Gillies Robert 
Published: August 2014

Abstract
The hypoxic regions of solid tumors are hotbeds of drug resistance and selection. Tumors with highly hypoxic regions correlate with poor prognosis and increased aggressiveness. The exact molecular mechanisms of selection have not been elucidated. Recent studies have demonstrated that reoxygenation causes widespread DNA damage. Additionally, hypoxia suppresses the DNA damage machinery. Because cells within a solid tumor do not receive a consistent amount of oxygen, cycles of acute hypoxia and reoxygenation occur, a phenomenon termed intermittent hypoxia (IH). We predict that this may lead to widespread unrepaired DNA damage that consistently selects for populations adapted to survive within harsh tumor microenvironmental conditions.
We tested three breast cell lines - one aggressive carcinoma (MB 231), one DCIS line, and one non-transformed epithelial cell line (MCF10A) - for DNA damage and transformation after multiple cycles of IH. Cells were incubated under 0.2% hypoxia for 16 hours and reoxygenated for 8, for multiple cycles. Multiple clones of each cell line selected under IH conditions were then isolated. MCF10A IH-selected clones exhibit increased resistance to etoposide relative to unselected clones. Two of these clones were selected for additional phenotyping, and exhibited constituitive carbonic anhydrase 9 expression, as measured by qRT-PCR. Resistance to methotrexate, docetaxel, and hypoxia induced cell death was also observed, but growth-factor independent proliferation was not detected. Additionally, genomic analyses have revealed loss of the tp53 and e-cadherin loci after intermittent hypoxia. Consistent with this, we detect loss of p53 and e-cadherin mRNA levels and anchorage independent growth. These data increase our understanding of why hypoxia creates more aggressive cancers and poorer prognoses, and how de novo drug resistance arises.
Citation Format: Daniel Verduzco, Robert Gatenby, Robert Gillies. Intermittent hypoxia selects for increased carcinogenicity in breast epithelial cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5002. doi:10.1158/1538-7445.AM2013-5002