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Breast Cancer Cancer associated Fibroblast

Samanta Makurat, Paulina Spisz, Witold Kozak, Janusz Rak, Magdalena Zdrowowicz
Nucleosides, especially pyrimidines modified in the C5-position, can act as radiosensitizers via a mechanism that involves their enzymatic triphosphorylation, incorporation into DNA, and a subsequent dissociative electron attachment (DEA) process. In this paper, we report 5-iodo-4-thio-2'-deoxyuridine (ISdU) as a compound that can effectively lead to ionizing radiation (IR)-induced cellular death, which is proven by a clonogenic assay. The test revealed that the survival of cells, pre-treated with 10 or 100 µM solution of ISdU and exposed to 0...
March 15, 2019: International Journal of Molecular Sciences
Marta Truffi, Serena Mazzucchelli, Arianna Bonizzi, Luca Sorrentino, Raffaele Allevi, Renzo Vanna, Carlo Morasso, Fabio Corsi
Cancer-associated fibroblasts (CAF) are the most abundant cells of the tumor stroma and they critically influence cancer growth through control of the surrounding tumor microenvironment (TME). CAF-orchestrated reactive stroma, composed of pro-tumorigenic cytokines and growth factors, matrix components, neovessels, and deregulated immune cells, is associated with poor prognosis in multiple carcinomas, including breast cancer. Therefore, beyond cancer cells killing, researchers are currently focusing on TME as strategy to fight breast cancer...
March 13, 2019: International Journal of Molecular Sciences
Maria Francesca Santolla, Adele Vivacqua, Rosamaria Lappano, Damiano Cosimo Rigiracciolo, Francesca Cirillo, Giulia Raffaella Galli, Marianna Talia, Giuseppe Brunetti, Anna Maria Miglietta, Antonino Belfiore, Marcello Maggiolini
The FGF2/FGFR1 paracrine loop is involved in the cross-talk between breast cancer cells and components of the tumor stroma as cancer-associated fibroblasts (CAFs). By quantitative PCR (qPCR), western blot, immunofluorescence analysis, ELISA and ChIP assays, we demonstrated that 17β-estradiol (E2) and the G protein estrogen receptor (GPER) agonist G-1 induce the up-regulation and secretion of FGF2 via GPER together with the EGFR/ERK/c-fos/AP-1 signaling cascade in (ER)-negative primary CAFs. Evaluating the genetic alterations from METABRIC and TCGA datasets, we then assessed that FGFR1 is the most frequently amplified FGFRs family member and its amplification/expression associates with shorter survival rates in breast cancer patients...
March 7, 2019: Cells
Xi Tang, Gang Tu, Guanglun Yang, Xing Wang, Linmin Kang, Liping Yang, Huan Zeng, Xueying Wan, Yina Qiao, Xiaojiang Cui, Manran Liu, Yixuan Hou
Cancer-associated fibroblasts (CAFs) remain active even in the absence of cancer cells. However, the molecular mechanism underlying the sustained active status of CAFs is largely unrevealed. We found that in CAFs, DNMT3B was not only a target of miR-200b, miR-200c and miR-221, but was able to induce DNA methylation of miR-200s promoters. DNMT3B eventually reached a stably high level by the counteracting effect of decreasing miR-200b/c and increasing miR-221 in normal fibroblasts (NFs) with long-term exogenous TGF-β1 treatment, and DNMT3B further led to a low level of miR-200s which established CAF activation...
March 6, 2019: Cancer Letters
Elin Sjöberg, Max Meyrath, Laura Milde, Mercedes Herrera, John Lövrot, Daniel Hägerstrand, Oliver Frings, Margarita Bartish, Charlotte Rolny, Erik Sonnhammer, Andy Chevigné, Martin Augsten, Arne Ostman
PURPOSE: Fibroblasts expressing the orphan chemokine CXCL14 have been previously shown to associate with poor breast cancer prognosis and promote cancer growth. This study explores the mechanism underlying the poor survival-associations of stromal CXCL14. EXPERIMENTAL DESIGN: Tumor cell EMT, invasion and metastasis were studied in in vitro and in vivo models together with fibroblasts overexpressing CXCL14. An approach for CXCL14-receptor identification included loss-of-function studies followed by molecular and functional endpoints...
March 8, 2019: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Betul Gok Yavuz, Gurcan Gunaydin, M Emre Gedik, Kemal Kosemehmetoglu, Derya Karakoc, Figen Ozgur, Dicle Guc
Fibroblasts turn into cancer associated fibroblasts (CAFs) in the tumour microenvironment. CAFs have recently attracted attention for their function as a regulator of immune cell recruitment and function in addition to their tumour-promoting roles. In this study, we aimed to determine the role of CAFs on monocyte recruitment and macrophage polarization in breast cancer. CAFs, which were α-SMA expressing fibroblasts in contrast to normal fibroblasts (NFs), effectively recruited monocytes. Recruitment of monocytes by CAFs might be mediated by monocyte chemotactic protein-1 (MCP-1) as well as stromal cell-derived factor-1 (SDF-1) cytokines...
February 28, 2019: Scientific Reports
Marwa S Salem, Rasha A Hussein, Wael M El-Sayed
BACKGROUND AND METHODS: In a continuous combat against cancer which is one of the leading causes of mortality now, chalcone and Schiff bases moieties have been incorporated and their antiproliferative activities and associated mechanisms against liver (HepG2) and breast (MCF-7) cell lines in addition to normal fibroblasts (WI-38) have been examined. RESULTS: Derivatives 4 and 5 of Schiff bases only and chalcone derivatives of Schiff bases 1 and 2 were devoid of any antiproliferative activity...
February 25, 2019: Anti-cancer Agents in Medicinal Chemistry
Kexin Sun, Shifu Tang, Yixuan Hou, Lei Xi, Yanlin Chen, Jiali Yin, Meixi Peng, Maojia Zhao, Xiaojiang Cui, Manran Liu
BACKGROUND: Cancer-associated fibroblasts (CAFs) are the predominant residents in the breast tumor microenvironment. In our work, we found activation of DNA damage-independent ATM (oxidized ATM), enhanced glycolysis and aberrant metabolism-associated gene expressions in breast CAFs. Nevertheless, whether and how oxidized ATM regulates the glycolytic activity of CAFs keep in unveil. Recently, a reverse Warburg effect was observed in tumor tissues, in which host cells (such as CAFs, PSCs) in the tumor microenvironment have been found to "fuel" the cancer cells via metabolites transfer...
February 21, 2019: EBioMedicine
Brock A Humphries, Johanna M Buschhaus, Yu-Chih Chen, Henry R Haley, Tonela Qyli, Benjamin Chiang, Nathan Shen, Shrila Rajendran, Alyssa Cutter, Yu-Heng Cheng, Yu-Ting Chen, Jason Cong, Phillip C Spinosa, Euisik Yoon, Kathryn E Luker, Gary D Luker
Migration and invasion of cancer cells constitute fundamental processes in tumor progression and metastasis. Migratory cancer cells commonly upregulate expression of plasminogen activator inhibitor 1 (PAI1), and PAI1 correlates with poor prognosis in breast cancer. However, mechanisms by which PAI1 promotes migration of cancer cells remain incompletely defined. Here we show that increased PAI1 drives rearrangement of the actin cytoskeleton, mitochondrial fragmentation, and glycolytic metabolism in triple-negative breast cancer (TNBC) cells...
February 4, 2019: Molecular Cancer Research: MCR
Ben Yi Tew, Christophe Legendre, Gerald C Gooden, Kyle N Johnson, Rae Anne Martinez, Jeff Kiefer, Mark Bernstein, Jennifer Glen, Loren Butry, Aleksander Hinek, Steven A Toms, Bodour Salhia
The functional role of human derived stromal cells in the tumor microenviornment of CNS metastases (CM) remain understudied. The purpose of the current study was to isolate and characterize stromal cells of the tumor microenvironment in CM. Four different patient-derived cell lines (PDCs) of stromal and one PDC of tumorigenic origin were generated from breast or lung CM. PDCs were analyzed by DNA/RNA sequencing, DNA methylation profiling, and immunophenotypic assays. The stromal derived PDCs were termed CNS metastasis-associated stromal cells (cMASCs)...
January 30, 2019: Oncogene
Ivy X Chen, Vikash P Chauhan, Jessica Posada, Mei R Ng, Michelle W Wu, Pichet Adstamongkonkul, Peigen Huang, Neal Lindeman, Robert Langer, Rakesh K Jain
Metastatic breast cancers (mBCs) are largely resistant to immune checkpoint blockade, but the mechanisms remain unclear. Primary breast cancers are characterized by a dense fibrotic stroma, which is considered immunosuppressive in multiple malignancies, but the stromal composition of breast cancer metastases and its role in immunosuppression are largely unknown. Here we show that liver and lung metastases of human breast cancers tend to be highly fibrotic, and unlike primary breast tumors, they exclude cytotoxic T lymphocytes (CTLs)...
January 30, 2019: Proceedings of the National Academy of Sciences of the United States of America
Jing Sun, Dan Yang, Shi-He Cui, Hai-Tao Zhang, Yu Fu, Jian-Cheng Wang, Qiang Zhang
Gemcitabine (Gem) as an anti-cancer agent has been limited by its short circulation time and rapid metabolism that reflects in low tumor uptake and low therapeutic efficiency. To improve its anti-tumor activity, a novel FAPα enzyme-activated prodrug of Z-GP-Gem modified at 4-amino group of Gem was developed, which could effectively release parent Gem based on the specific cleavage via FAPα enzyme-activation in tumor microenvironment. Compared to Gem, the Z-GP-Gem prodrug exhibited significantly enhanced inhibition of both tumor growth and pulmonary metastasis in BALB/c mice bearing orthotopic breast 4T1 tumors...
January 21, 2019: International Journal of Pharmaceutics
K Louault, T L Bonneaud, C Séveno, P Gomez-Bougie, F Nguyen, F Gautier, N Bourgeois, D Loussouarn, O Kerdraon, S Barillé-Nion, P Jézéquel, M Campone, M Amiot, P P Juin, F Souazé
Selective inhibition of BCL-2 is expected to enhance therapeutic vulnerability in luminal estrogen receptor-positive breast cancers. We show here that the BCL-2 dependency of luminal tumor cells is nevertheless mitigated by breast cancer-associated fibroblasts (bCAFs) in a manner that defines MCL-1 as another critical therapeutic target. bCAFs favor MCL-1 expression and apoptotic resistance in luminal cancer cells in a IL-6 dependent manner while their own, robust, survival also relies on MCL-1. Studies based on ex vivo cultures of human luminal breast cancer tissues further argue that the contribution of stroma-derived signals to MCL-1 expression shapes BCL-2 dependency...
January 10, 2019: Oncogene
Nicola Ferrari, Romana Ranftl, Ievgeniia Chicherova, Neil D Slaven, Emad Moeendarbary, Aaron J Farrugia, Maxine Lam, Maria Semiannikova, Marie C W Westergaard, Julia Tchou, Luca Magnani, Fernando Calvo
Aggressive behaviours of solid tumours are highly influenced by the tumour microenvironment. Multiple signalling pathways can affect the normal function of stromal fibroblasts in tumours, but how these events are coordinated to generate tumour-promoting cancer-associated fibroblasts (CAFs) is not well understood. Here we show that stromal expression of Dickkopf-3 (DKK3) is associated with aggressive breast, colorectal and ovarian cancers. We demonstrate that DKK3 is a HSF1 effector that modulates the pro-tumorigenic behaviour of CAFs in vitro and in vivo...
January 10, 2019: Nature Communications
Marie Nguyen, Adele De Ninno, Arianna Mencattini, Fanny Mermet-Meillon, Giulia Fornabaio, Sophia S Evans, Mélissande Cossutta, Yasmine Khira, Weijing Han, Philémon Sirven, Floriane Pelon, Davide Di Giuseppe, Francesca Romana Bertani, Annamaria Gerardino, Ayako Yamada, Stéphanie Descroix, Vassili Soumelis, Fatima Mechta-Grigoriou, Gérard Zalcman, Jacques Camonis, Eugenio Martinelli, Luca Businaro, Maria Carla Parrini
A major challenge in cancer research is the complexity of the tumor microenvironment, which includes the host immunological setting. Inspired by the emerging technology of organ-on-chip, we achieved 3D co-cultures in microfluidic devices (integrating four cell populations: cancer, immune, endothelial, and fibroblasts) to reconstitute ex vivo a human tumor ecosystem (HER2+ breast cancer). We visualized and quantified the complex dynamics of this tumor-on-chip, in the absence or in the presence of the drug trastuzumab (Herceptin), a targeted antibody therapy directed against the HER2 receptor...
December 26, 2018: Cell Reports
Jing Zhou, Xiao-Hua Wang, Yi-Xin Zhao, Cheng Chen, Xin-Yun Xu, Qi Sun, Hong-Yan Wu, Ming Chen, Jian-Feng Sang, Lei Su, Xiao-Qiao Tang, Xian-Biao Shi, Yin Zhang, Qiao Yu, Yong-Zhong Yao, Wei-Jie Zhang
Background: Cancer-associated fibroblasts (CAFs) have been shown to be among the most prominent cells in tumor microenvironment and play a significant role in accelerating tumor metastasis by interacting with other type of cells. Tumor-associated macrophages (TAMs), the predominant tumor-infiltrating immune cells, also play important roles in cancer progression. Here, we aimed to evaluate the effects of CAFs on infiltration of TAMs and lymphatic metastasis in triple-negative breast cancer (TNBC). Material and methods: The study included 278 patients with histologically confirmed TNBC...
2018: Journal of Cancer
Sara Gagno, Mario Rosario D'Andrea, Mauro Mansutti, Chiara Zanusso, Fabio Puglisi, Eva Dreussi, Marcella Montico, Paola Biason, Erika Cecchin, Donatella Iacono, Stefania Russo, Marika Cinausero, Silvana Saracchini, Giampietro Gasparini, Donata Sartori, Mario Bari, Elena Collovà, Rosa Meo, Ghassan Merkabaoui, Ilaria Spagnoletti, Arianna Pellegrino, Lorenzo Gianni, Paolo Sandri, Elisabetta Cretella, Emanuela Vattemi, Andrea Rocca, Patrizia Serra, Maria Agnese Fabbri, Giovanni Benedetti, Laura Foghini, Michele Medici, Umberto Basso, Vito Amoroso, Ferdinando Riccardi, Anna Maria Baldelli, Mario Clerico, Salvatore Bonura, Chiara Saggia, Federico Innocenti, Giuseppe Toffoli
INTRODUCTION: Approximately 50% of locally advanced or metastatic breast cancer (MBC) patients treated with first-line exemestane do not show objective response and currently there are no reliable biomarkers to predict the outcome of patients using this therapy. The constitutive genetic background might be responsible for differences in the outcome of exemestane-treated patients. We designed a prospective study to investigate the role of germ line polymorphisms as biomarkers of survival...
November 24, 2018: Clinical Breast Cancer
Caitlin E Jones, Anisha M Hammer, YouJin Cho, Gina M Sizemore, Edna Cukierman, Lisa D Yee, Samir N Ghadiali, Michael C Ostrowski, Jennifer L Leight
The organization of the extracellular matrix has a profound impact on cancer development and progression. The matrix becomes aligned throughout tumor progression, providing "highways" for tumor cell invasion. Aligned matrix is associated with breast density and is a negative prognostic factor in several cancers; however, the underlying mechanisms regulating this reorganization remain poorly understood. Deletion of the tumor suppressor Pten in the stroma was previously shown to promote extracellular matrix expansion and tumor progression...
December 11, 2018: Neoplasia: An International Journal for Oncology Research
Yongfang Xie, Mingling Wang, Min Cheng, Zhiqin Gao, Guohui Wang
The purpose of this study was to investigate the viscoelastic behaviors of cancer cells and normal cells using the micropipette aspiration technique combined with the standard linear viscoelastic solid model. The viscoelastic behaviors of pairs of cell lines (human skin cells and human skin cancer cells, human fetal lung fibroblasts and human lung cancer cells, human mammary fibroblasts and human breast cancer cells, and human hepatocyte cells and human hepatocellular carcinoma cells) were tested by the micropipette aspiration technique...
November 30, 2018: Journal of the Mechanical Behavior of Biomedical Materials
Xinyi Wang, Jing Ai, Hongyan Liu, Xia Peng, Hui Chen, Yi Chen, Yi Su, Aijun Shen, Xun Huang, Jian Ding, Meiyu Geng
Acquired resistance severely hinders the application of small molecule inhibitors. Our understanding of acquired resistance related to fibroblast growth factor receptors (FGFRs) is limited. Here, to explore the underlying mechanism of acquired resistance in FGFR-aberrant cancer cells, we generated cells resistant to multiple FGFR inhibitors and investigated the potential mechanisms underlying acquired resistance. We discovered that reprogramming of the secretome is closely associated with acquired resistance to FGFR inhibitors...
December 6, 2018: Molecular Cancer Therapeutics
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