bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A99: DCQ is a hypoxia-activated quinoxaline 1,4-dioxide that reduces breast cancer metastasis
Authors: Ghattass Khaled I. , Sitt Sally El , Zibara Kazem , Haddadin Makhlouf MJ , El-Sabban Marwan , Ghali-Muhtasib Hala 
Published: August 2014

Abstract
Although tumor hypoxia is associated with the complex processes of tumor metastasis and resistance, and poses significant challenges against traditional cancer treatments, it provides a target for therapy by bioreductive drugs with enhanced cytotoxic activity in the reduced microenvironment of tumors. We identified a potent synthetic quinoxaline di-N-oxide (DCQ) which preferentially targets hypoxic tumors. Here we show that DCQ: 1) Reduces the viability of breast cancer cell lines (MDA-MB-231, MCF-7), 2) Induces reactive oxygen species (ROS)-dependent p53-independent apoptosis, 3) Inhibits the accumulation of hypoxia inducible factor (HIF-1α) via distinct mechanisms in the two cell lines and 4) Significantly reduces hypoxia-induced invasion of breast cancer cell lines in vitro and in vivo. DCQ-induced ROS was associated with increased DNA damage in MDA-MB-231 and MCF-7 cells. The inhibition of HIF-1α accumulation in MCF-7 was in part via the activation of p53 and was accompanied by a decrease in the levels of phosphorylated mTOR, indicating that DCQ-induced reduction of HIF-1α is possibly occurring at the translational level of the protein. HIF-1α reduction was associated with a decrease in p21 and a reversal of the hypoxia-induced VEGF secretion and invasion, which are key processes in tumor metastasis. In MDA-MB-231 cells; however, DCQ reduced HIF-1α through proteasomal degradation, which was accompanied by a reduction of TWIST, a major player in epithelial to mesenchymal transition (EMT). The inhibitory effect of DCQ on hypoxia induced breast cancer invasion was validated in the xenograft model of subdermally injected MDA-MB-231 cells in immune-compromised mice. DCQ significantly increased the survival rate of treated animals. This increase was associated with a reduction of the metastatic dissemination of breast cancer cells into the liver and lungs of DCQ treated mice.
Citation Format: Khaled I. Ghattass, Sally El Sitt, Kazem Zibara, Makhlouf MJ Haddadin, Marwan El-Sabban, Hala Ghali-Muhtasib. DCQ is a hypoxia-activated quinoxaline 1,4-dioxide that reduces breast cancer metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A99.
Abstract B1: Hypoxia inducible factor (HIF) promotes reductive carboxylation by regulating citrate levels and renders VHL-deficient and hypoxic cells sensitive to glutamine deprivation
Authors: Gameiro Paulo , Metelo Ana , Pérez-Carro Rojo , Alexandra Arreola , Wang Zongwei , Rathmell Kimryn W. , Olumi Aria , López-Larrubia Pilar , Stephanopoulos Gregory , Iliopoulos Othon 
Published: August 2014

Abstract
Hypoxia is a hallmark of tumor microenvironment. We showed before that exposure of cells to hypoxia reprograms cell metabolism and directs an IDH1-mediated reductive carboxylation (RC) of glutamine-derived alpha-ketoglutarate (a-KG) for lipogenesis. In addition Von Hippel-Lindau (VHL)-deficient renal cell carcinoma cells use glutamine to generate citrate and lipids through RC of a-KG. To gain insights into the role of HIF and the molecular mechanisms underlying RC we took advantage of a panel of disease-associated VHL mutants and showed that HIF expression is necessary and sufficient for the induction of RC in human renal cell carcinoma (RCC) cells. HIF expression drastically reduces intracellular citrate levels. Feeding VHL-deficient RCC cells with acetate or citrate, or knocking-down PDK-1 and ACLY enzymes restored intracellular citrate levels and suppressed RC. These data suggest that HIF-induced low intracellular citrate levels promote the reductive flux by mass action, to maintain lipogenesis. Expression of HIF renders hypoxic and VHL-deficient cells addicted to glutamine in vitro. VHL-deficient cells displayed significantly less growth than their isogenic counterparts in media containing low glutamine concentration or in the presence of a glutaminase inhibitor. Systemic administration of a glutaminase inhibitor (BPTES) suppressed the growth of VHL-deficient human RCC cell lines as xenografts in nude mice. Lastly, we investigated whether RC occurs in vivo. We metabolically labeled mice bearing VHL-deficient tumors by infusing them with 13C-1-Glutamine for up to 6 hours and we detected the early formation of labeled citrate in the tumors; thus we showed for the first time RC in vivo. Our data provide mechanistic insights into the signaling events that mediate hypoxia-induced RC, strongly suggest that RC is an in vivo phenomenon in growing tumors and highlight potential novel therapeutic approaches for treatment of hypoxic and VHL-deficient tumors based on their metabolic signature.
Citation Format: Paulo Gameiro, Ana Metelo, Rojo Pérez-Carro, Arreola Alexandra, Zongwei Wang, Kimryn W. Rathmell, Aria Olumi, Pilar López-Larrubia, Gregory Stephanopoulos, Othon Iliopoulos. Hypoxia inducible factor (HIF) promotes reductive carboxylation by regulating citrate levels and renders VHL-deficient and hypoxic cells sensitive to glutamine deprivation. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr B1.
Abstract B103: Proinflammatory signaling by cancer-associated fibroblasts co-evolves during mammary carcinogenesis
Authors: Sharon Yoray , Raz Yael , Alon Lina , Erez Neta 
Published: August 2014

Abstract
Cancer-associated fibroblasts (CAFs) support tumorigenesis by stimulating angiogenesis, cancer cell proliferation, and invasion. We demonstrated that CAFs also mediate tumor-enhancing inflammation: CAFs isolated from pre-neoplastic and tumor tissue expressed a pro-inflammatory gene signature and functioned to recruit macrophages and enhance tumor angiogenesis in a mouse model of squamous carcinoma. Moreover, we demonstrated that pro-inflammatory signaling by CAFs is operative also in mouse and human breast carcinogenesis. Although breast cancer is one of the major tumor types where CAFs were shown to be tumor promoting, there is no detailed analysis of CAF characteristics and function in correlation with tumor progression. We therefore set out to characterize the dynamic changes in CAFs during progression of mammary carcinogenesis, in a transgenic mouse model of human breast cancer, the MMTV-PyMT mice. We show that normal mammary fibroblasts can be “educated” by mammary carcinoma cells to become activated, pro-inflammatory CAFs. Furthermore, transcriptome profiling of fibroblasts isolated from normal mammary glands, or from mammary glands of transgenic mice at defined tumorigenic stages (hyperplasia, early carcinoma, invasive adenocarcinoma) revealed distinct CAF gene expression signatures that correspond to different tumor stages, with only partial overlap between the stages, suggesting co-evolution of the microenvironment with tumorigenic progression. Interestingly, the gene signature of fibroblasts isolated from hyperplastic lesions is inverse to that in CAFs from neoplastic stages, and has a putative growth inhibitory phenotype, while CAFs from early and late carcinoma express pro-inflammatory and tumor promoting gene signatures. Elucidating the molecular mechanisms by which CAFs mediate cancer-related inflammation in breast cancer will greatly increase our understanding of stromal pathways that contribute to tumorigenesis, in an effort to identify novel stromal molecular targets for combinatorial therapeutic approaches to combat breast cancer progression.
Citation Format: Yoray Sharon, Yael Raz1,2, Lina Alon, Neta Erez. Proinflammatory signaling by cancer-associated fibroblasts co-evolves during mammary carcinogenesis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr B103.
Abstract B13: Porphyromonas gingivalis-induced autophagy suppresses cell proliferation through G1 arrest in oral cancer cells
Authors: Cho Tae Jin , Woo Vok Hee , Choi Jeom Il , Kim Seung Jo , Shin Hong In , Park Bong Soo , Park Dae Geun , Park Hae Ryoun 
Published: August 2014

Abstract
Epidemiological studies have shown that chronic inflammation predisposes individuals to different types of cancer and that microbial infections can trigger chronic inflammation. Porphyromonas gingivalis is a major microbial pathogen in periodontitis, which is a chronic inflammatory condition of the oral cavity and one of the most common infectious diseases. In this study, we examined the effect of P. gingivalis on oral cancer cells to define the role of chronic periodontitis on the development and/or progression of oral cancers. P. gingivalis-infected cells showed reduced proliferation rates and a concomitant G1 arrest compared with non-infected cells. One mechanism through which P. gingivalis blocked cell cycle progression in oral cancer cells was through ROS production, which induced autophagy. We conclude that the suppression of cell proliferation and cell cycle progression through autophagy may serve as an alternative to apoptosis to eliminate transformed cells. Autophagy represents a survival strategy against environmentally stressful conditions, such as the pathogenic invasion of P. gingivalis, and the prolonged survival of P. gingivalis-infected cells may contribute to the malignant progression of oral cancer cells.
Citation Format: Tae Jin Cho, Vok Hee Woo, Jeom Il Choi, Seung Jo Kim, Hong In Shin, Bong Soo Park, Dae Geun Park, Hae Ryoun Park. Porphyromonas gingivalis-induced autophagy suppresses cell proliferation through G1 arrest in oral cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr B13.
Abstract B15: Invasive breast cancer amplifies lymphangiogenic signals in tumor microenvironment through integrin beta4 expressing cancer-associated fibroblasts
Authors: Kim Baek Gil , Choi Yoon Pyo , Kang Suki , Lee Joo Hyun , Cho Nam Hoon 
Published: August 2014

Abstract
Lymphangiogensis is widely acknowledged as a major route of breast cancer metastasis and a critical alteration of tumor microenvironment (TME) for tumor progression. But, most of it has remained still unknown. Previously, we found that invasive ductal carcinoma (IDC), not ductal carcinoma in situ (DCIS), upregulates integrin alpha6beta4 in the fibrosis adjacent to tumor burden, and that MDA-MB-231 induces integrin beta4 neoexpression in cancer-associated fibroblasts (CAFs) via cell-to-cell contract. Integrin (alpha6)beta4 overexpression is often detected in malignant tumors and negatively associated with patient survivor. In addition, integrin alpha6beta4 was reported to regulate eIF-4E activity leading to vascular endothelial growth factor (VEGF) translation in cancer cells. It is, therefore, plausible that invasive breast cancer cells increase lymphangiogenic signals in TME through driving integrin beta4 expression in CAFs. To verify our hypothesis, we induced integrin beta4 overexpression in CAFs using co-culture with MDA-MB-231 or transfection with pRK5_beta4 plasmid, and then observed tube formation of human dermal lymphatic endothelial cells (HDLEC) by integrin beta4-expressing CAFs in 3D co-culture model. VEGF-D, known as a major factor of lymphangiogenesis, was highly upregulated in integrin beta4-expressing CAFs, which promoted tube formation of HDLEC compared to normal CAFs and MDA-MB-231. Interestingly, the level of VEGF-D expression in MDA-MB-231 was much lower than that of integrin beta4-expressing CAFs before and after co-culture. Taken together, invasive breast cancer may amplify lymphangiogenic signals in TME by inducing integrin beta4-expressing CAFs, and integrin beta4 neoexpression in CAFs by breast cancer may be a pivotal process for lymphangiogensis.
Citation Format: Baek Gil Kim, Yoon Pyo Choi, Suki Kang, Joo Hyun Lee, Nam Hoon Cho. Invasive breast cancer amplifies lymphangiogenic signals in tumor microenvironment through integrin beta4 expressing cancer-associated fibroblasts. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr B15.
Abstract B16: Extracellular S100A4 as an inducer of a cytokine network that mediates tumor-stroma crosstalk: Potential implications for metastases
Authors: Bettum Ingrid J. , Vasiliauskaite Kotryna , Pettersen Solveig J. , Malandsmo Gunhild M. , Prasmickaite Lina 
Published: August 2014

Abstract
Among soluble factors that appear to be of high importance for metastasis progression are chemokines from the S100 family. One such factor is S100A4, a small calcium binding protein linked to metastasis and poor prognosis in several cancer types. The protein is expressed in and secreted from not only tumor cells, but also various stroma cells, suggesting that S100A4 might be an important factor in the tumor microenvironment. Recently we have revealed that in vivo S100A4-positive stroma cells are tightly associated with the metastatic nodules in the brain and lungs, suggesting the role of S100A4 in facilitating metastatic growth in these microenvironments. How S100A4 executes its metastasis-promoting functions is however not fully elucidated. Here we hypothesize that the extracellular S100A4 can trigger a cytokine network that mediates the tumor-stroma crosstalk and thereby facilitates metastases progression in malignant melanoma. We have shown that extracellular S100A4 stimulates melanoma cells to secrete various cytokines and growth factors, including IL-8, IL-6, CXCL2, sICAM-1 and VEGF, molecules playing a role in cancer progression and angiogenesis in particular. Since cytokines can act in a paracrine manner, they can mediate interactions between tumor cells and stroma cells. Thus, we have shown that conditioned medium from melanoma cells treated with extracellular S100A4 modulates the angiogenic functions of endothelial cells making them more migratory and more proned to make vascular-like networks in vitro. Among factors induced by S100A4 were also pro-inflammatory cytokines associated with macrophage recruitment and/or activation. Currently we are investigating whether the S100A4-triggered cytokines modulate the properties of macrophages making them support tumor cells. Altogether, our results indicate a potential role of S100A4 in stimulating tumor-stoma crosstalk which might mimic the formation of a metastatic niche-like milieu facilitating metastases.
Citation Format: Ingrid J. Bettum, Kotryna Vasiliauskaite, Solveig J. Pettersen, Gunhild M. Malandsmo, Lina Prasmickaite. Extracellular S100A4 as an inducer of a cytokine network that mediates tumor-stroma crosstalk: Potential implications for metastases. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr B16.
Abstract B17: A microscale 3-D in vitro model of the breast cancer progression from DCIS to IDC: Deciphering the role of the stromal fibroblasts
Authors: Sung Kyung Eun , Pehlke Carolyn , Berthier Erwin , Eliceiri Kevin W. , Friedl Andreas , Beebe David J. 
Published: August 2014

Abstract
Breast cancer progression from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) is a critical step in breast cancer. This invasive transition of DCIS is defined by stromal invasion and is a life-threatening step accompanied by a dramatic drop in prognosis. In addition, the invasive transition of DCIS is largely driven by stromal alteration; thus it is critical to understand how DCIS alters the surrounding microenvironment, thus causing the cancer cells to become invasive. This study investigates the role of stromal fibroblasts in the vicinity of DCIS during the invasive transition using an innovative multidisciplinary approach that combines 3D cancer biology, microfluidics, and high-resolution imaging. We recently developed an efficient 3D microfluidic system that supports the transition from DCIS to IDC. The in vitro system employs microchannels with two inputs and one output enabling MCF10-DCIS.com cells (MCF-DCIS) and human mammary fibroblasts (HMF) to be loaded in two adjacent (side-by-side) compartments. This platform allows investigations of effects of spatial organization on the transition by independently analyzing their morphology and the modifications to the surrounding collagen architecture. Importantly, the compartmentalized platform enables monitoring of both MCF-DCIS and HMF independently including quantitative measures of the collagen architecture associated with each cell type. We observed that the HMF near MCF-DCIS became more protrusive versus HMF relatively far from MCF-DCIS. We have also begun to identify how the HMF become activated and protrusive when co-cultured with MCF-DCIS and to understand the biological function and impact of protrusive HMF during DCIS progression to IDC. We verified that the signaling based on Cathepsin D produced from MCF-DCIS and low-density lipoprotein receptor-related protein-1 (LRP1) from HMF is involved in regulation of the protrusive activity of HMF. Additionally, knocking down LRP1 in HMF inhibited the invasive transition of MCF-DCIS. This study demonstrates one possible route through which MCF-DCIS activate pre-existing fibroblasts and subsequently, leads to the modification of the ECM and the progression to IDC.
Citation Format: Kyung Eun Sung, Carolyn Pehlke, Erwin Berthier, Kevin W. Eliceiri, Andreas Friedl, David J. Beebe. A microscale 3-D in vitro model of the breast cancer progression from DCIS to IDC: Deciphering the role of the stromal fibroblasts. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr B17.
Abstract B23: Tumor-associated macrophages in human papillary thyroid cancer
Authors: Cho Sun Wook , Min Hye Sook , Kim Seunwhan , Kim Kyung Won , Park Do Joon , Park Young Joo 
Published: August 2014

Abstract
Introduction: Tumor associated macrophages (TAMs) play a pivotal role in tumoriogenesis of human cancers, including advanced thyroid cancers. A recent study demonstrated that the increased density of TAMs was positively associated with lymph node (LN) metastasis in papillary thyroid cancer (PTC). The purpose of this study was to investigate the functional role of TMA in PTC. Method: Immunohistochemistry with anti-CD68 antibody was performed in 35 PTC patients who had LN metastasis. Co-culture of human PTC (SNU-790) cells and activated human monocytes (THP-1) by macrophage-colony stimulating factor (M-CSF, 50ng/ml) were performed and cell survival rates were analyzed by MTT assay. Result: Among 35 patients, 9 were male and 26 were females. Mean age was 48.9 ± 13.4 years and mean tumor size was 0.94 ± 0.51 cm. Twenty six (74.2%) patients had extrathyroidal invasion. Immunohistochemical staining of primary tumor showed that the expression of CD68 was presence in 3~15% of the peri- and intratumoral areas in all cases, while there was no positivity in normal thyroid tissue adjacent to tumors. In vitro stimulation of THP-1 cells with M-CSF showed significant increase of IL-10 by 7~8 fold compared to vehicle treated cells. Co-culture of SNU-790 cells with M-CSF stimulated THP-1 cells showed higher survival rates than control. Conclusions: TAMs exist in invasive human PTC specifically in intratumoral areas. Activated human monocytes, representing TAM phenotypes support tumor cell survival. Collectively, TAMs may have a functional role in tumor microenvironment of human PTC.
Citation Format: Sun Wook Cho, Hye Sook Min, Seunwhan Kim, Kyung Won Kim, Do Joon Park, Young Joo Park. Tumor-associated macrophages in human papillary thyroid cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr B23.
Abstract B28: Signaling by PDGF-CC in the maintenance of a protumorigenic breast cancer microenvironment
Authors: Roswall Pernilla , Haller Kristian , Petersson Annika , Anderberg Charlotte , Li Hong , Norum Jens-Henrik , Toftgård Rune , Eriksson Ulf , Pietras Kristian 
Published: August 2014

Abstract
It is increasingly appreciated that cancer results from the concerted performance of genetically altered tumor cells interacting with ostensibly normal cells in the microenvironment. As the cancer progresses, the surrounding stroma co-evolves into an activated state through continuous paracrine communication, thus creating a dynamic signaling circuitry that promotes cancer initiation and growth, and ultimately leads to a fatal disease. We aim to molecularly map the support functions performed by the various cell types comprising the tumor stroma. Specifically we will focus on, cancer-associated fibroblasts (CAFs), which are known to support many aspects of tumor progression. Based on our previous finding that paracrine signaling by Platelet-derived growth factor (PDGF)-CC serves to recruit CAFs into tumors we have generated Pdgfc-deficient genetically engineered mouse models of breast cancer. Our results show a significant reduction in the tumor burden followed by prolonged survival in the absence of PDGF-CC, in agreement with the recent finding that PDGF-CC expression is an indicator of poor prognosis for breast cancer patients. Upon transplantation of small tumor pieces from wildtype and Pdgfc-deficient tumors respectively into the mammary fatpad of wildtype mice, Pdgfc-deficient tumors show substantial growth retardation with massive hemorrhage and necrosis, indicative of malfunctional vessels and insufficient blood supply. qPCR arrays on total RNA from wildtype and Pdgfc-deficient tumors respectively, suggest that lack of PDGF-CC causes perturbed differentiation yielding a less advanced tumor. Furthermore, we are currently investigating the differences observed in the recruited fibroblasts and/or MSCs in wildtype and Pdgfc-deficient tumors, by performing proteomics on isolated PDGFR-α positive cells. Tumor morphology in combination with proteomics suggests that the lack of PDGF-CC causes an impaired migration and/or guidance of the recruited fibroblasts from the periphery of the tumor. Thus, our studies suggest a novel role for PDGF-CC in creating a pro-tumorigenic microenvironment and identify PDGF-CC as a valid and promising therapeutic target in breast cancer.
Citation Format: Pernilla Roswall, Kristian Haller, Annika Petersson, Charlotte Anderberg, Hong Li, Jens-Henrik Norum, Rune Toftgård, Ulf Eriksson, Kristian Pietras. Signaling by PDGF-CC in the maintenance of a protumorigenic breast cancer microenvironment. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr B28.