bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1514: Proteomics of human dense breast stroma.
Authors: Fox Jay W. , Mikesh Leann , Aramadhaka Lavakumar R. , Moskulak Christopher A. 
Published: August 2014

Abstract
Dense breast contains glandular and connective tissue. Less dense breasts are mainly comprised of fat tissue. Dense breast tissue itself is a risk factor for breast cancer with the risk being 4-6 fold higher in women with extremely dense breasts compared to fatty breasts. Typically, breast cancer is more likely to develop in the denser areas of the breast. Furthermore, on mammogram, a tumor is more difficult to detect in dense tissue than in fatty tissue because the tumor looks similar to the tissue that surrounds it. Recognition of the important role of the stroma during the progression of breast cancer leads to the possibility of new targets for the prevention or treatment of the primary breast cancer. In addition, clinically useful biomarkers for the early detection of risk for breast cancer in dense breasts could lead to a significant reduction of mortality. In this investigation we describe a detailed analysis of normal and dense breast stroma using laser microdissection in combination with mass spectrometry and immunohistochemistry of normal and dense breast stroma. Using this approach several potential markers for dense breast were identified and compared to stromal markers associated with breast cancer.
Citation Format: Jay W. Fox, Leann Mikesh, Lavakumar R. Aramadhaka, Christopher A. Moskulak. Proteomics of human dense breast stroma. [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 1514. doi:10.1158/1538-7445.AM2013-1514
Abstract 1515: Epigenetic silencing of retinoblastoma gene regulates pathologic differentiation of myeloid cells in cancer.
Authors: Youn Je-In , Kumar Vinit , Collazo Michelle , Gabrilovich Dmitry I. 
Published: August 2014

Abstract
Myeloid-derived suppressor cells (MDSC) are one of the major factors negatively regulating immune responses in cancer and many other pathologic conditions. These cells consist of two distinct populations: monocytic MDSC (M-MDSC) and polymorphonuclear MDSC (PMN-MDSC). PMN-MDSC is the predominant group of MDSC accumulated in cancer. Under physiologic conditions, the normal counterpart of M-MDSC - Ly6ChiLy6G- inflammatory monocytes (Mon) differentiate in periphery tissues to macrophages (MΦ) and dendritic cells (DCs). In contrast, a large proportion of M-MDSC, in tumor-bearing mice, acquired phenotypic, morphological and functional features of PMN-MDSC. In human, CD14+HLA-DR-/low M-MDSC from patients with multiple myeloma also differentiated into CD66b+ PMN-MDSC. This effect was caused by soluble tumor-derived factors and mediated by transcriptional silencing of the retinoblastoma (Rb) gene. M-MDSC had an amount of Rb1 similar to that in mature myeloid cells (PMN, DCs) while Rb1 was barely detectable in PMN-MDSC. Lack of Rb1 in mice with conditional deletion of the gene promoted an expansion of splenic CD11b+Ly6G+Ly6Clo cells, similar to the phenotype of PMN-MDSC in tumor-bearing mice. Moreover, immunogeneic EG7 tumor grew much faster in Rb1-KO mice than in Rb1-WT littermates. Mon from Rb1-KO mice acquired significantly increased proportion of PMN after in vitro culture compared to Rb1-WT Mon. In contrast, the overexpression of Rb1 substantially reduced the proportion of PMN-MDSC differentiated from M-MDSC. Histone deacetylase 2 (HDAC-2) was directly involved in down-regulation of Rb1 expression. Inhibition of HDAC in MDSC resulted in the increase in their Rb1 expression, abrogated differentiation of M-MDSC to PMN-MDSC, and restored M-MDSC differentiation towards DCs and MΦ. These results suggest that down-regulation of Rb by epigenetic modification plays a major role in accumulation of MDSC in cancer by regulating PMN-MDSC differentiation from M-MDSC. HDAC may be considered as potential targets for therapeutic regulation of MDSC in cancer.
Citation Format: Je-In Youn, Vinit Kumar, Michelle Collazo, Dmitry I. Gabrilovich. Epigenetic silencing of retinoblastoma gene regulates pathologic differentiation of myeloid cells in 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 1515. doi:10.1158/1538-7445.AM2013-1515
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 1517: Pancreatic stellate cells and chemoresistant pancreatic cancer cells induce EMT gene expression in normal pancreatic ductal cells.
Authors: Kumar Krishan , Sahai Vaibhav , Ebine Kazumi , Munshi Hidayatullah G. 
Published: August 2014

Abstract
Pancreatic cancer, one of the deadliest of human cancers, is associated with a collagen-rich pronounced stromal reaction. Previously, we showed that the collagen microenvironment increased the motility of human pancreatic ductal epithelial (HPDE) cells (Ottaviano AJ et al, Cancer Research 2006). Since stellate cells are one of the major contributors to the stromal reaction, we examined the effect of stellate cells on HPDE cells. HPDE cells were labeled with cell tracking dye and then co-cultured stellate cells to allow intimate cell-cell contact. HPDE cells were then isolated 72 hours later using FACS and changes in gene expression analyzed by real time PCR. We found that HPDE cells upregulated expression of epithelial-mesenchymal transition (EMT) markers Zeb1, Snail and vimentin. Stellate cells also increased expression of these EMT markers in HPDE cells expression Kras (HPDE-Kras). However, no change in these EMT markers were seen when the HPDE and stellate cells were prevented from direct cell-cell contact using transwell co-culture system. Treatment with TGF-b type I receptor inhibitor SB431542 blocked the effect of stellate cells on HPDE gene expression. Since ductal cells also encounter malignant cells in vivo, we also examined the effect of co-culture of ductal cells with cancer cells. HPDE cells failed to upregulate EMT markers when they were co-cultured with HPAFII/CD18 cell. However, when HPDE cells were co-cultured with chemo-resistant CD18 cells (CD18-CR), HPDE cells upregulated EMT markers. The effect of CD18-CR cells on HPDE gene expression was only observed when there was intimate cell-cell contact. Also, treatment with SB431542 blocked the effect on HPDE gene expression. These results indicate that the tumor microenvironment may affect the behavior of peri-tumoral non-malignant cells and thereby contribute to tumor progression.
Citation Format: Krishan Kumar, Vaibhav Sahai, Kazumi Ebine, Hidayatullah G. Munshi. Pancreatic stellate cells and chemoresistant pancreatic cancer cells induce EMT gene expression in normal pancreatic ductal 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 1517. doi:10.1158/1538-7445.AM2013-1517
Abstract 1519: Identification and functional analysis of genes involved in cholesterol metabolism that are upregulated in prostate cancer stroma.
Authors: Ashida Shingo , Kawada Chiaki , Inoue Keiji , Shuin Taro 
Published: August 2014

Abstract
Recent studies have highlighted tumor microenvironment as important in carcinogenesis and progression. Especially in prostate cancer (PC), it has been suggested that tumor microenvironment plays an important role in progression, acquisition of androgen independence, and distant metastasis. However, little is known about the genetic basis of human PC microenvironment. To clarify the mechanism of PC progression and metastasis, we investigated cross-interaction of PC epithelial cells and stromal cells by analyzing genome-wide gene expression profiles. We hypothesized that PC cells could affect on stromal cells to change their characteristics into so-called cancer-associated fibroblasts (CAFs), which might contribute to cancer invasion and metastasis. We identified genes that were up-regulated in PC stroma by analyzing gene expression profiles of normal human prostate stromal cells (PrSC) co-cultured with human PC cells (LNCaP), which included some genes involved in cholesterol metabolism, such as 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR). HMGCR is the rate-limiting enzyme for cholesterol synthesis and the pharmalogical target for statins. We confirmed the overexpression of HMGCR in PC stroma by immunohistochemistry. Then we knocked down endogenous HMGCR in PC cells by small interfering RNA, which resulted in the significant reduction of PC cell viability. In contrast, HMGCR overexpression stimulated PC cell growth. These results provide clues to the molecular mechanisms underlying PC invasion and metastasis, and suggest candidate genes the products of which might serve as molecular targets for the treatment of PC.
Citation Format: Shingo Ashida, Chiaki Kawada, Keiji Inoue, Taro Shuin. Identification and functional analysis of genes involved in cholesterol metabolism that are upregulated in prostate cancer stroma. [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 1519. doi:10.1158/1538-7445.AM2013-1519
Abstract 1525: Nuclear homeoprotein SIX1 is associated with stage and grade of endometrial carcinoma.
Authors: Wobker Sara E. , Jefferson Wendy N. , Williams Carmen J. , Bae-Jump Victoria L. 
Published: August 2014

Abstract
Introduction: SIX1 is a member of the homeoprotein gene family encoding transcription factors involved in normal embryogenesis. These proteins function in the cell nucleus to regulate transcription of genes that drive differentiation. SIX1 is also aberrantly expressed in numerous human malignancies, including breast, ovarian and cervical carcinomas. In a mouse model, SIX1 initiates transformation of mammary epithelial cells to diverse histologic types of carcinoma. SIX1 has not yet been studied in endometrial carcinoma, which is the most common gynecologic malignancy in the United States. Thus, our goal was to evaluate SIX1 in clinical samples of endometrial carcinoma and determine if there was an association with stage and grade.
Methods: A tissue microarray (TMA) was created using endometrial carcinoma cases (n=55) and benign controls (i.e. proliferative, secretory and atrophic endometrium) (n=12). Endometrioid and serous histologic types were included in the carcinoma cases. The TMA was stained using a rabbit polyclonal anti-SIX1 antibody (Sigma). The TMA was then scored in a blinded manner by a single pathologist, using presence versus absence of nuclear staining for the stromal cells and the epithelial cells. Clinical data was collected on these samples to include height, weight, BMI, grade (FIGO 1, 2 or 3) and stage (1A, 1B-2B, 3A-4B).
Results: Few controls had nuclear SIX1 in epithelial cells while all controls had nuclear SIX1 in stromal cells. In endometrial cancer samples, there was significantly increased nuclear SIX1 staining in the epithelial cells compared to controls, while there was less nuclear SIX1 in stromal cells. This finding was more pronounced with increasing grade and stage of tumor (Table 1).
Conclusions: Nuclear SIX1 expression is associated with increased grade and stage of endometrial cancer. These findings suggest that SIX1 may play a role in the progression of this common cancer and have utility as a marker of more aggressive disease.
Table 1. Percentage of uterine samples with nuclear SIX1 staining in epithelial and stromal cells Grade Stage Epithelial Stromal Epithelial Stromal Control 3/12 (25) 12/12 (100) Control 3/12 (25) 12/12 (100) Grade 1 16/22 (72) 13/22 (59) 1A 5/11 (46) 10/11 (91) Grade 2 15/16 (94) 6/16 (38) 1B-2B 26/31 (84) 13/31 (42) Grade 3 14/17 (82) 7/17 (41) 3A-4B 12/13 (92) 3/13 (23)
Citation Format: Sara E. Wobker, Wendy N. Jefferson, Carmen J. Williams, Victoria L. Bae-Jump. Nuclear homeoprotein SIX1 is associated with stage and grade of endometrial carcinoma. [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 1525. doi:10.1158/1538-7445.AM2013-1525
Abstract 1526: Evaluation of the novel tumor suppressor gene, β-Defensin-1, in colorectal cancer cell line models.
Authors: Layton Austin , Bohanes Pierre O. , Zhang Wu , Lenz Heinz-Josef , Labonte Melissa J. 
Published: August 2014

Abstract
Background: Human defensins are antimicrobial linear peptides with broad anti-microbial activity, organized into two classes, α- and β-defensins. Human β-Defensin 1 (hBD-1) is encoded by the DEFB1 gene located on chromosome 8p23 and functions as an antimicrobial peptide involved in the innate immune response. It is most often expressed in epithelial cells, including those in the large intestines. Previous experiments have shown that hBD-1 exhibits tumor suppressor functions in urothelial and kidney cancer cells. Previous evaluation of germline single nucleotide polymorphisms in the promoter region of DEFB1 demonstrated CRC stage specific effects of rs1800972 and rs179946 in predicting time-to-tumor recurrence in CRC patients. This study examined the cancer specific expression of hBD-1 in CRC compared to normal cells and further evaluated the cellular mechanism associated with the effects of hBD-1 expression in CRC proliferation, cell cycle progression and apoptosis.
Methods: Twenty-two patients colon tissue samples were subjected to immunohistochemistry (IHC) specific for hBD-1 to examine its expression in both normal and tumor cells. To gain insight into the effects of hBD-1 expression in CRC, CaCo2, HCT116, HT29 and SW620 CRC cell lines were transfected with pCMV6-XL4-DEFB1, alongside a control empty vector, to compare the effect of hBD-1 overexpression on cell viability and apoptosis at 24 and 48 hr. In addition, recombinant hBD-1 was exogenously added to CRC cells and analyzed for the effect on cell viability.
Results: Examination of hBD-1 expression from patients’ colon tissue samples by IHC demonstrated that hBD-1 expression was present in the normal colon cells, but its expression was lost in CRC cells. Induction of hBD-1 expression in CRC cell lines resulted in a significant change in cell viability, membrane permeability and induction of apoptosis. Further, the exogenous addition of recombinant hBD-1 to CRC cells resulted in a significant reduction in cell number at 48 hr.
Conclusion: These results demonstrate evidence of loss of hBD-1 expression in CRC cells and further provide evidence for hBD-1’s potential role as a tumor suppressor. Further studies are being conducted to determine the pathway of apoptosis that is induced and to better understand the hBD-1 affects in the CRC cells development and progression and further evaluate the potential utility of targeting hBD-1 as a therapeutic strategy.
Citation Format: Austin Layton, Pierre O. Bohanes, Wu Zhang, Heinz-Josef Lenz, Melissa J. Labonte. Evaluation of the novel tumor suppressor gene, β-Defensin-1, in colorectal cancer cell line models. [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 1526. doi:10.1158/1538-7445.AM2013-1526
Abstract 1530: Alveolar macrophage depletion decreases lung cytokines and decreases mouse lung tumor growth.
Authors: Fritz Jason , Tennis Meredith A. , Malkinson Alvin , Dwyer-Nield Lori 
Published: August 2014

Abstract
While anti-inflammatory therapies are being evaluated in lung cancer, the role of specific immune effector cells and their products in lung carcinogenesis is unclear. Alveolar macrophage numbers increase as lung tumors progress, and subsequent changes in macrophage function are linked to increased growth factor production, accelerated tumor proliferation, enhanced angiogenesis, depressed immune response, and metastasis. However, the signaling molecules linking alveolar macrophages to advanced lung tumor growth are not well defined. To examine how macrophages drive lung tumorigenesis, clodronate-encapsulated liposomes were used to specifically deplete alveolar macrophages in mice bearing chemically-induced lung tumors. Treatment efficacy was assessed by evaluating tumor burden, multiplicity, proliferation index and histologic stage. Alveolar macrophage populations decreased to ≤ 50% of control levels during six weeks of liposomal clodronate treatment. This was associated with significantly decreased pulmonary levels of IGF-1, KC, IL-6 and CCL2. The concentrations of these cytokines strongly correlated with decreased macrophage numbers in lung lavage fluid. Tumor burden and Ki-67 index was reduced by 50% in clodronate-treated mice, corresponding with the 50% decrease in macrophage numbers and cytokine content. Therefore, macrophage depletion attenuates lung tumor proliferation in vivo, consistent with our previous observations linking macrophage IGF-1 production and lung tumor proliferation in vitro. These cytokines appear to mediate macrophage-stimulated lung tumorigenesis, and are thus potential therapeutic targets in lung cancer and chronic inflammatory lung disease.
Citation Format: Jason Fritz, Meredith A. Tennis, Alvin Malkinson, Lori Dwyer-Nield. Alveolar macrophage depletion decreases lung cytokines and decreases mouse lung tumor growth. [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 1530. doi:10.1158/1538-7445.AM2013-1530
Abstract 1531: Macrophage FLT1 signaling activates an inflammatory response that promotes breast cancer distal metastasis.
Authors: Qian Bin-Zhi , Lang Richard A. , Pollard Jeffrey W. 
Published: August 2014

Abstract
Macrophages are abundantly found in the tumor microenvironment enhance malignancy. At distal metastatic sites a distinct population of metastasis associated macrophages (MAMs) promotes tumor cell extravasation, seeding and persistent growth. Compared with lung resident macrophages, MAMs associated with breast cancer lung metastasis in pre-clinical models express high levels of cell surface FMS-like tyrosine kinase 1 (Flt1). Blockade of FLT1 signaling using specific inhibitory antibodies significantly inhibited the metastatic seeding and persistent growth of both human and murine breast tumor cell. This was confirmed using a genetic model of Flt1 tyrosine kinase domain (TK) ablation. Using bone marrow transplantation techniques, we further showed that this metastasis inhibitory effect was due to the lack of FLT1 signaling in hematopoietic cells. Furthermore, macrophage specific ablation of the tyrosine kinase domain of Flt1 by crossing Flt1 flox/flox mice with macrophage restricted Cre mice (Csf1r-Cre) also significantly inhibited tumor cell metastatic potential. Since Flt1 is not expressed by other hematopoietic cells and FLT1 inhibition did not affect the recruitment of MAMs, it indicated that specific FLT1 signaling in MAMs are important for their metastasis promoting functions. FLT1 regulated genes were identified by comparing gene expression profiles using microarray techniques of FACS sorted MAMs from mice treated with control and anti-FLT1 inhibitory antibody. Bioinformatics analysis showed that inflammatory response genes were highly enriched in these genes. Together, our studies indicated that FLT1 signaling is required for the activation of metastasis associated macrophages and regulates a set of inflammatory genes that promote breast tumor distal metastasis.
Citation Format: Bin-Zhi Qian, Richard A. Lang, Jeffrey W. Pollard. Macrophage FLT1 signaling activates an inflammatory response that promotes breast cancer distal metastasis. [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 1531. doi:10.1158/1538-7445.AM2013-1531
Abstract 1534: CD163-expressing macrophages constitute a distinct malignancy-promoting phenotype in melanoma facilitating tumor development, progression, and metastasis: Implications for novel anticancer therapy.
Authors: Maniecki Maciej B. , Etzerodt Anders , Damsky William E. , Rafique Aisha , Gonzalez David , Dyrskjøt Lars , Møller Holger J. , Bosenberg Marcus W. , Moestrup Søren K. 
Published: August 2014

Abstract
Tumor-infiltrating macrophages are recruited to the tumor microenvironment and believed to play a key role in tumor development, progression, and metastasis by producing growth factors and promoting neoangiogenesis. Here, we show that CD163-expressing macrophages express a distinct gene expression signature capable of facilitating tumor development and progression. This supports our earlier findings showing significant correlation between CD163+ macrophage density, tumor grade, and poor prognosis in patients with melanoma. Selective eradication of CD163-expressing tumor-associated macrophages through receptor-mediated delivery of nanoparticles encapsulating the cytotoxic agent doxorubicin significantly inhibited tumor formation and prolonged survival in an immune-competent conditional mouse model of BrafV600E-induced, Pten-deficient metastatic melanoma. High-resolution dynamic intravital imaging showed specific targeting of a subpopulation of tumor-infiltrating macrophages expressing the scavenger receptor CD163, including Tie2-expressing macrophages recently identified as being highly proangiogenic.
In conclusion, our findings identify CD163-expressing macrophages as a distinct malignancy-promoting phenotype and indicate a novel therapeutic target in cancer.
Citation Format: Maciej B. Maniecki, Anders Etzerodt, William E. Damsky Jr., Aisha Rafique, David Gonzalez, Lars Dyrskjøt, Holger J. Møller, Marcus W. Bosenberg, Søren K. Moestrup. CD163-expressing macrophages constitute a distinct malignancy-promoting phenotype in melanoma facilitating tumor development, progression, and metastasis: Implications for novel anticancer therapy. [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 1534. doi:10.1158/1538-7445.AM2013-1534