bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A28: Impact of macrophage function on the efficacy of radiation therapy
Authors: Shiao Stephen L. , DeNardo David G. , Faddegon Bruce A. , Underhill David M. , Park Catherine C. , Coussens Lisa M. 
Published: May 2015

Abstract
In patients with locally advanced breast cancer, radiation therapy (RT) and chemotherapy following surgery has been a mainstay of treatment for breast cancer with demonstrated survival advantage in numerous randomized trials. However, despite recent advances in treatment, many women still ultimately succumb to this disease highlighting the need to improve our therapeutic options. Previous work from other groups demonstrated that the therapeutic effects of RT depend in part on activation of the immune system, but little is known about the details of this activation. To address this, we explored the effects of RT on the immune microenvironment in a syngeneic orthotopic murine transplantation model of breast cancer and found that 7 days following RT tumors had significantly increased numbers of CD11b+ macrophages compared to untreated tumors. When we depleted these macrophages using a CSF1 inhibitor or CSF1 blocking Ab following RT we found significantly delayed tumor growth compared to RT alone. Tumor-associated macrophages (TAMs) are key orchestrators of the tumor microenvironment and can be either classically-activated expressing cytotoxic molecules leading to tumor cell death (“anti-tumor”) or alternatively-activated in which they secrete proangiogenic, prosurvival, and proinvasive factors that foster tumor progression (“pro-tumor”). Given the delayed growth when TAMs were depleted following RT, we hypothesized that the infiltrating TAMs are predominantly of the pro-tumor phenotype and that a milieu that favors an anti-tumor phenotype would enhance the effect of RT. We tested this hypothesis using a blocking antibody against IL-4, the predominant cytokine which drives the alternatively-activated phenotype, and we observed significantly reduced tumor growth in mice treated with the combination of RT and IL-4 blockade compared to mice treated with either agent alone. These studies indicate that infiltrating macrophages following RT have a protumor function, and that conversion of these macrophages to a cytotoxic phenotype may improve the efficacy of RT.
Citation Format: Stephen L. Shiao, David G. DeNardo, Bruce A. Faddegon, David M. Underhill, Catherine C. Park, Lisa M. Coussens. Impact of macrophage function on the efficacy of radiation therapy. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr A28. doi:10.1158/1538-7445.CHTME14-A28
Abstract A30: MKP-1 negatively regulates Il-1beta in the oral tumor microenvironment
Authors: Zhang Xiaoyi , Yu Hong , Kirkwood Keith L. 
Published: May 2015

Abstract
Head and neck cancer accounts for approximately 6% of diagnosed malignancies in the United States, the most common form being head and neck squamous cell carcinoma (HNSCC). Cytokines and pro-inflammatory factors have been shown to play a critical role in various steps of malignant transformation, many of which are regulated by mitogen-activated protein kinases (MAPK). These kinases are negatively regulated by MAPK phosphatases (MKPs), the founding member of this class being mitogen-activated protein kinase phosphatase-1 (MKP-1). MKP-1 is often over-expressed in early stages of epithelial malignancies with levels of expression falling progressively in tumors of higher histological grade. As MKP-1 is a crucial negative regulator of innate immunity, we hypothesized MKP-1 inhibits tumor-promoting inflammation in the HNSCC microenvironment. MKP-1 deficient animals treated with 4-nitroquinoline 1-oxide to induce HNSCC formation showed a significant increase in tumor development, characterized by tumor onset, size, histological grade, and inflammation. Tumor tissues expressed increased levels of multiple inflammatory cytokines and chemokines by qPCR and altered MAPK activity by immunoblot and immunohistochemistry. In particular, Il-1beta was significantly increased in MKP-1 deficient tumors as well as primary bone marrow-derived macrophages. These data suggest MKP-1 inhibits oral cancer progression by regulating Il-1beta expression. Elucidating the regulation of this inflammatory mediator in the tumor microenvironment may reveal critical tumor suppressive interactions mediated by MKP-1 that are lost during cancer progression.
Citation Format: Xiaoyi Zhang, Hong Yu, Keith L. Kirkwood. MKP-1 negatively regulates Il-1beta in the oral tumor microenvironment. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr A30. doi:10.1158/1538-7445.CHTME14-A30
Abstract A41: Hypoxia-dependent modification of collagen networks promotes sarcoma metastasis
Authors: Eisinger-Mathason T.S. Karin , Zhang Minsi , Qiong Qiu , Skuli Nicolas , Nakazawa Michael S. , Karakasheva Tatiana , Mucaj Vera , Shay Jessica E.S. , Stangenberg Lars , Pure Ellen , Yoon Sam S. , Kirsch David G. , Simon M. Celeste 
Published: May 2015

Abstract
Intratumoral hypoxia and expression of Hypoxia Inducible Factor 1α (HIF1α) correlate with metastasis and poor survival in sarcoma patients. We demonstrate here that hypoxia controls sarcoma metastasis through a novel mechanism wherein HIF1α enhances expression of the intracellular enzyme procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2). We show that loss of HIF1α or PLOD2 expression disrupts collagen modification, cell migration and pulmonary metastasis (but not primary tumor growth) in allograft and autochthonous LSL-KrasG12D/+; Trp53fl/fl murine sarcoma models. Biochemical analyses revealed that overexpression of HIF1α and PLOD2 in sarcoma cells alters collagen structure and organization. The increase in lysyl hydroxylation and concomitant loss of prolyl hydroxylation, promotes adherence of tumor cells, collagen-associated migration and tumor cell dissemination. Furthermore, ectopic PLOD2 expression restores migration and metastatic potential in HIF1α-deficient tumors, and analysis of human sarcomas reveal elevated HIF1α and PLOD2 expression in metastatic primary lesions. Pharmacological inhibition of PLOD enzymatic activity suppresses metastases. Collectively, these data indicate that HIF1α controls sarcoma metastasis through PLOD2-dependent collagen modification and organization in primary tumors. We conclude that PLOD2 is a novel therapeutic target in sarcomas and successful inhibition of this enzyme may reduce tumor cell dissemination.
Citation Format: T.S. Karin Eisinger-Mathason, Minsi Zhang, Qiu Qiong, Nicolas Skuli, Michael S. Nakazawa, Tatiana Karakasheva, Vera Mucaj, Jessica E.S. Shay, Lars Stangenberg, Ellen Pure, Sam S. Yoon, David G. Kirsch, M. Celeste Simon. Hypoxia-dependent modification of collagen networks promotes sarcoma metastasis. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr A41. doi:10.1158/1538-7445.CHTME14-A41
Abstract A52: Paracrine apoptotic effect of the tumor suppressor p53 is mediated by secreted Par-4
Authors: Shrestha-Bhattarai Tripti , Burikhanov Ravshan , Hebbar Nikhil , Qiu Shirley , Zhao Yanming , Zambetti Gerard P. , Rangnekar Vivek M. 
Published: May 2015

Abstract
The guardian of the genome, p53, is mutated or functionally inactivated in a majority of human cancers. However, p53 in normal cells is intact and functional. In the present study, we tested the potential of wild-type p53 in normal tissues to inhibit the growth of p53-deficient cancer cells. Co-culture experiments of normal fibroblasts with cancer cells revealed that specific activation of p53 in normal fibroblasts selectively induced apoptosis in p53-deficient cancer cells. Moreover, this paracrine apoptotic effect of p53 was attributed to an enhanced secretion of the tumor suppressor Par-4 in response to p53 activation. Mechanistically, p53 represses the expression of UACA, a binding partner of Par-4, by directly binding to its signature motif in the UACA gene. Down-regulation of UACA expression liberates Par-4 from sequestration, and thus induces its secretion. Consistent with our cell culture studies, animal experiments also show that activation of p53 results in an elevation of systemic Par-4 levels in p53+/+ mice, which can induce apoptosis in p53-deficient cancer cells in ex vivo experiments. By contrast, p53 activators failed to induce this paracrine effect in p53-/- or Par-4-/- mice. Thus, by activating wild-type p53, normal cells can be empowered to inhibit tumor growth, progression, and metastasis.
Citation Format: Tripti Shrestha-Bhattarai, Ravshan Burikhanov, Nikhil Hebbar, Shirley Qiu, Yanming Zhao, Gerard P. Zambetti, Vivek M. Rangnekar. Paracrine apoptotic effect of the tumor suppressor p53 is mediated by secreted Par-4. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr A52. doi:10.1158/1538-7445.CHTME14-A52
Abstract A58: Characterized herbal extract of Wedelia chinensis suppresses prostate cancer growth and metastasis by targeting multiple intrinsic pathways and modulating immune cells
Authors: Tsai Chin-Hsien , Tzeng Sheue-Fen , Hsiao Pei-Wen 
Published: May 2015

Abstract
We previously demonstrated that the principal active compounds (wedelolectone, luteolin, and apigenin) in the ethanol extract of Wedelia chinensis synergistically inhibit human prostate carcinoma 22Rv1 cell growth and that this extract therefore has potential for use as a prostate cancer (PCa) therapy. Here, we developed a standardized preparation for a W. chinensis ethanol extract that is enriched in the principal active compounds. A comparison of the effect of herbal treatment, androgen ablation therapy, and a combination of the two on the development of androgen-dependent LNCaP tumors in a mouse model showed that the herbal extract alone decreased androgen-induced tumor growth and when in combination with androgen ablation therapy, resulted in more potent inhibition of both tumor growth and cancer metastasis. Our study demonstrated this herbal remedy simultaneously inhibited androgen receptor, NFκB and HER2/3-AKT signaling pathways to induce cell apoptosis. Importantly, our herbal remedy diminished androgen receptor overexpression and AKT activation induced by androgen ablation thus preventing castration-resistant PCa development. Moreover, the herbal remedy standing-alone curbed chemokine expression from hormone-refractory PC-3 tumor and consequently restrained the mobilization of CD11b+Gr1+ myeloid cells in tumor-bearing mice, which effectively inhibited PCa growth and metastasis. In conclusion, this standardized preparation of W. chinensis ethanol extract improved the outcome of PCa therapy either as an add-on to hormonal therapy for androgen-dependent disease or as a monotherapy for hormone-refractory disease.
Citation Format: Chin-Hsien Tsai, Sheue-Fen Tzeng, Pei-Wen Hsiao. Characterized herbal extract of Wedelia chinensis suppresses prostate cancer growth and metastasis by targeting multiple intrinsic pathways and modulating immune cells. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr A58. doi:10.1158/1538-7445.CHTME14-A58
Abstract A64: Cell-extrinsic effects of metformin in the breast cancer microenvironment
Authors: Williams Christopher Charles , Miller Kabrina 
Published: May 2015

Abstract
Currently, few drugs have been formulated to disturb the autocrine/paracrine communication circuits which maintain the tumor-supportive microenvironment as a method of cancer chemoprevention. PGE2 (Prostaglandin E2) plays an important role in mediating the production of pro-inflammatory cytokines associated with tumor progression and metastasis. Recently, the anti-diabetic drug metformin has been associated with decreased incidence of several solid cancers among diabetic patients and has previously been shown to reduce expression of systemic inflammatory markers. However, few studies have detailed the intersection of metformin-mediated chemoprevention and chronic inflammation. As such, we investigated whether metformin impacts the inflammatory microenvironment in breast cancer to disrupt tumorigenesis and cancer progression. We hypothesize that metformin disrupts pro-neoplastic autocrine/paracrine inflammatory signaling by BCCs and its associated stroma. We have previously published that metformin inhibits proliferation of breast cancer cells, and that this impairment was associated with increased expression of growth differentiation factor 15 (GDF15) and repression of cyclooxygenase 1 mRNA expression. Here, we confirm that metformin decreases the intracellular and secreted GDF15 levels, and causes a reduction in the expression of proinflammatory annexin A2 protein, a component of the plasminogen receptor. Furthermore, exposure of breast cancer cells to metformin resulted in decreased PGE2 synthesis. Significantly, metformin mediated cell death was abrogated by addition of exogenous PGE2, suggesting that metformin at least in part elicits its antineoplastic function through PGE2 dependent mechanisms. Together these findings suggest a model in which metformin represses annexin A2 and cyclooxygenase expression, culminating in the loss of tumor-associated PGE2, induction of GDF15, and impaired breast cancer cell survival and invasiveness. As such, metformin may function to condition the pre-cancerous microenvironment/stroma to render it inhospitable toward further cancer progression.
Citation Format: Christopher Charles Williams, Kabrina Miller. Cell-extrinsic effects of metformin in the breast cancer microenvironment. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr A64. doi:10.1158/1538-7445.CHTME14-A64
Abstract A67: Stromal expression of microRNA-21 identifies high-risk group in triple negative breast cancer
Authors: MacKenzie Todd , Schwartz Gary , Wells Wendy , Sempere Lorenzo 
Published: May 2015

Abstract
Introduction: Triple negative breast cancer (TNBC) is an aggressive subtype defined by lack of ER, PR and HER2 expression. There are few specific prognostic markers and no effective targeted therapies for TNBC. microRNA diagnostics is an emerging area of novel biomarkers in cancer medicine. Expression of tumor promoting miR-21 is frequently altered in BC. Since tumor lesions are a complex mixture of different cell types, we hypothesized that analysis of miR-21 expression at single cell resolution could provide more accurate information to assess risk of disease recurrence and BC-related death.
Experimental procedure: We implemented a fully-automated tissue slide-based staining assay in a CLIA-certified environment to detect miR-21 expression in a cohort of 988 BC patients, whose tumors were represented in the NCI CDP Stage I/II Prognostic tissue microarrays. 901 cases provided adequate tissue to determine levels and cellular compartment (cancer vs. stroma) of miR-21 expression.
Results: The miR-21High group had a shorter recurrence-free (RFS; HR=1.71, p&lt;0.001) and BC-specific (CSS; HR=1.96, p&lt;0.001) survival in multivariate regression analyses, adjusted for standard clinicopathologic characteristics. Subdivision of the miR-21High group by cellular compartment of expression revealed that cancer cell-specific expression in ER+ and/or PR+ HER2- cases (HR=3.67, p=0.006 for RFS; HR=5.13, p=0.002 for CSS) and stromal cell expression in ER-PR-HER2- cases ( HR=2.59, p=0.013 for RFS; HR=3.37, p=0.003 for CSS) were associated with very poor clinical outcome.
Conclusions: These findings indicate that levels and cellular compartment of miR-21 expression provide clinically-relevant information in different intrinsic molecular BC subtypes. Importantly, miR-21 expression is predominantly upregulated in the stroma and not cancer cells. This suggests a regulatory role of miR-21 in cellular elements of the tumor microenvironment, including tumor-associated fibroblasts. miR-21 could become a useful functional biomarker to further refine individual risk and offer a new therapeutic avenue to improve management of TNBC.
Citation Format: Todd MacKenzie, Gary Schwartz, Wendy Wells, Lorenzo Sempere. Stromal expression of microRNA-21 identifies high-risk group in triple negative breast cancer. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr A67. doi:10.1158/1538-7445.CHTME14-A67
Abstract A68: GPCRs as potential therapeutic targets in pancreatic cancer-associated fibroblasts
Authors: Zhou Shu , French Randall , Lowy Andrew M. , Insel Paul A. 
Published: May 2015

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense fibrotic stromal matrix, composed of activated fibroblasts/stellate cells, inflammatory cells and other cell types. This unique tumor microenvironment has been increasingly recognized as a key mediator of PDAC progression and drug resistance. Thus, targeting the tumor stroma may be a novel therapeutic approach for PDAC. We hypothesized that G protein-coupled receptors (GPCRs) expressed by pancreatic cancer-associated fibroblasts (CAFs) may be potential therapeutic targets for PDAC. To begin to test this hypothesis, we used an unbiased GPCRomic array approach to identify and quantify the GPCRs expressed by pancreatic CAFs. We found 125 GPCRs, whose expression was shared in CAFs obtained from the primary tumors of five patients. Among those GPCRs, 35 had at least two-fold higher expression in the CAFs compared to normal pancreatic fibroblasts and included GPCRs that link to each of the major classes of G proteins. RT-PCR analysis of the 10 most up-regulated GPCRs correlated well (r2=0.88) with the data from the GPCR array. We conclude that: 1) GPCRomic array analysis can identify and quantify the profile of GPCRs expressed by pancreatic CAFs; 2) the CAF-expressed profile differs from that of normal pancreatic fibroblasts and 3) GPCRs expressed by CAFs may have functional roles and be novel therapeutic targets for PDAC.
Citation Format: Shu Zhou, Randall French, Andrew M. Lowy, Paul A. Insel. GPCRs as potential therapeutic targets in pancreatic cancer-associated fibroblasts. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr A68. doi:10.1158/1538-7445.CHTME14-A68
Abstract B03: Hypoxia-induced carbonic anhydrase IX promotes MDSC recruitment and establishment of the breast cancer premetastatic niche by stimulating G-CSF production
Authors: Chafe Shawn C. , Lou Yuanmei , Sceneay Jaclyn , Vallejo Marylou , McDonald Paul C. , Möller Andreas , Dedhar Shoukat 
Published: May 2015

Abstract
The recruitment of bone marrow-derived cells (BMDCs) to distant tissue sites prior to the arrival of disseminated tumor cells has been shown to facilitate metastasis in a preclinical setting through the establishment of the pre-metastatic niche. Primary tumor hypoxia has been shown to play a pivotal role in the production of chemokines and cytokines responsible for the mobilization of these BMDCs, especially in breast cancer. Carbonic anhydrase IX (CAIX) expression is highly upregulated by breast cancer cells in hypoxia where its activity contributes to cell survival through the buffering of intracellular pH. Preclinically, CAIX has been demonstrated to be required for breast tumor growth and metastasis, whereas clinically, CAIX is an established indicator of poor prognosis and distant metastasis in breast cancer patients. However, the mechanism by which CAIX exerts its pro-metastatic function is incompletely understood. We investigated whether CAIX function in the hypoxic niche of the primary tumor was involved in establishment of the pre-metastatic niche through the production of soluble mediators of this process. Using shRNA-mediated depletion of CAIX in the metastatic 4T1 murine breast cancer cells and orthotopic tumors, we demonstrate that CAIX is required for the mobilization and recruitment of myeloid-derived suppressor cells (MDSCs) to pre-metastatic niches through the stimulation of granulocyte colony stimulating factor (G-CSF) production, a potent stimulator of MDSC mobilization and recruitment to pre-metastatic niches. We further demonstrate that CAIX expression is required for the activation of NF-κB by hypoxic breast cancer cells and that constitutive activation of the NF-κB pathway upon reducing CAIX expression by shRNA restores G-CSF secretion by hypoxic breast cancer cells. This is the first demonstration of a role for CAIX in the pre-metastatic phase of breast cancer metastasis and indicates that CAIX regulates the expression of G-CSF and recruitment of granulocytic MDSCs to pre-metastatic niches.
Citation Format: Shawn C. Chafe, Yuanmei Lou, Jaclyn Sceneay, Marylou Vallejo, Paul C. McDonald, Andreas Möller, Shoukat Dedhar. Hypoxia-induced carbonic anhydrase IX promotes MDSC recruitment and establishment of the breast cancer premetastatic niche by stimulating G-CSF production. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr B03. doi:10.1158/1538-7445.CHTME14-B03