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Breast Cancer Cancer associated Fibroblast

Shira Bernard, Megan Myers, Wei Bin Fang, Brandon Zinda, Curtis Smart, Diana Lambert, An Zou, Fang Fan, Nikki Cheng
With improved screening methods, the numbers of abnormal breast lesions diagnosed in women have been increasing over time. However, it remains unclear whether these breast lesions will develop into invasive cancers. To more effectively predict the outcome of breast lesions and determine a more appropriate course of treatment, it is important to understand the underlying mechanisms that regulate progression of non-invasive lesions to invasive breast cancers. A hallmark of invasive breast cancers is the accumulation of fibroblasts...
August 9, 2018: Journal of Mammary Gland Biology and Neoplasia
Benjamin D Landry, Thomas Leete, Ryan Richards, Peter Cruz-Gordillo, Hannah R Schwartz, Megan E Honeywell, Gary Ren, Alyssa D Schwartz, Shelly R Peyton, Michael J Lee
Due to tumor heterogeneity, most believe that effective treatments should be tailored to the features of an individual tumor or tumor subclass. It is still unclear, however, what information should be considered for optimal disease stratification, and most prior work focuses on tumor genomics. Here, we focus on the tumor microenvironment. Using a large-scale coculture assay optimized to measure drug-induced cell death, we identify tumor-stroma interactions that modulate drug sensitivity. Our data show that the chemo-insensitivity typically associated with aggressive subtypes of breast cancer is not observed if these cells are grown in 2D or 3D monoculture, but is manifested when these cells are cocultured with stromal cells, such as fibroblasts...
August 6, 2018: Molecular Systems Biology
Xiangdong Zhao, Faliang Xu, Nestor Prieto Dominguez, Yuanping Xiong, Zhongxun Xiong, Hong Peng, Chloe Shay, Yong Teng
Although genetic amplification and overexpression of the fibroblast growth factor 19 (FGF19) gene are found in human breast cancer, mechanisms that contribute to such functional alterations remain elusive. We report here that high expression of FGF19 is associated with the aggressive malignant behavior and poor survival outcome of breast cancer patients. FGF19 is particularly highly expressed in luminal molecular subtype of breast tumors and its expression levels are positively associated with its secretion levels from breast cancer cells...
August 3, 2018: Molecular Carcinogenesis
Tamara Muliaditan, Jonathan Caron, Mary Okesola, James W Opzoomer, Paris Kosti, Mirella Georgouli, Peter Gordon, Sharanpreet Lall, Desislava M Kuzeva, Luisa Pedro, Jacqueline D Shields, Cheryl E Gillett, Sandra S Diebold, Victoria Sanz-Moreno, Tony Ng, Esther Hoste, James N Arnold
Tumour-associated macrophages (TAMs) play an important role in tumour progression, which is facilitated by their ability to respond to environmental cues. Here we report, using murine models of breast cancer, that TAMs expressing fibroblast activation protein alpha (FAP) and haem oxygenase-1 (HO-1), which are also found in human breast cancer, represent a macrophage phenotype similar to that observed during the wound healing response. Importantly, the expression of a wound-like cytokine response within the tumour is clinically associated with poor prognosis in a variety of cancers...
July 27, 2018: Nature Communications
Elizabeth A Wellberg, Peter Kabos, Austin E Gillen, Britta M Jacobsen, Heather M Brechbuhl, Stevi J Johnson, Michael C Rudolph, Susan M Edgerton, Ann D Thor, Steven M Anderson, Anthony Elias, Xi Kathy Zhou, Neil M Iyengar, Monica Morrow, Domenick J Falcone, Omar El-Hely, Andrew J Dannenberg, Carol A Sartorius, Paul S MacLean
Obesity increases breast cancer mortality by promoting resistance to therapy. Here, we identified regulatory pathways in estrogen receptor-positive (ER-positive) tumors that were shared between patients with obesity and those with resistance to neoadjuvant aromatase inhibition. Among these was fibroblast growth factor receptor 1 (FGFR1), a known mediator of endocrine therapy resistance. In a preclinical model with patient-derived ER-positive tumors, diet-induced obesity promoted a similar gene expression signature and sustained the growth of FGFR1-overexpressing tumors after estrogen deprivation...
July 25, 2018: JCI Insight
Aurélie S Cazet, Mun N Hui, Benjamin L Elsworth, Sunny Z Wu, Daniel Roden, Chia-Ling Chan, Joanna N Skhinas, Raphaël Collot, Jessica Yang, Kate Harvey, M Zahied Johan, Caroline Cooper, Radhika Nair, David Herrmann, Andrea McFarland, Niantao Deng, Manuel Ruiz-Borrego, Federico Rojo, José M Trigo, Susana Bezares, Rosalía Caballero, Elgene Lim, Paul Timpson, Sandra O'Toole, D Neil Watkins, Thomas R Cox, Michael S Samuel, Miguel Martín, Alexander Swarbrick
The cellular and molecular basis of stromal cell recruitment, activation and crosstalk in carcinomas is poorly understood, limiting the development of targeted anti-stromal therapies. In mouse models of triple negative breast cancer (TNBC), Hedgehog ligand produced by neoplastic cells reprograms cancer-associated fibroblasts (CAFs) to provide a supportive niche for the acquisition of a chemo-resistant, cancer stem cell (CSC) phenotype via FGF5 expression and production of fibrillar collagen. Stromal treatment of patient-derived xenografts with smoothened inhibitors (SMOi) downregulates CSC markers expression and sensitizes tumors to docetaxel, leading to markedly improved survival and reduced metastatic burden...
July 24, 2018: Nature Communications
Giuseppe Curigliano
Chest wall inflammatory and lymphangitic breast cancer represents a clinical spectrum and a model disease. Inflammation and the immune response have a role in the natural history of this special clinical presentation. Preclinical models and biomarker studies suggest that inflammatory breast cancer comprises a more important role for the tumour microenvironment, including immune cell infiltration and vasculogenesis, especially lympho-angiogenesis. Across this clinical continuum of the chest wall disease there is an important role of the inflammation cascade...
August 2018: European Journal of Surgical Oncology
Zhu-Yue Chen, Ying-Ying Hu, Xiao-Fan Hu, Long-Xian Cheng
Recently, multipotent mesenchymal stromal cell (MSC) treatment has attracted special attention as a new alternative strategy for stimulating regeneration. Irradiation myocardial fibrosis (IMF) is a major complication associated with total body irradiation for hematopoietic stem cell transplantation, nuclear accidents, and thoracic radiotherapy for lung cancer, esophageal cancer, proximal gastric cancer, breast cancer, thymoma, and lymphoma. The aim of the present study was to assess the therapeutic paracrine effects of human umbilical cord-derived mesenchymal stromal cells (UC-MSCs) in the cell model of IMF...
July 12, 2018: Journal of Radiation Research
Tao Jiang, Jose Munguia-Lopez, Salvador Flores-Torres, Joel Grant, Sanahan Vijayakumar, Antonio De Leon-Rodriguez, Joseph M Kinsella
The cellular, biochemical, and biophysical heterogeneity of the native tumor microenvironment is not recapitulated by growing immortalized cancer cell lines using conventional two-dimensional (2D) cell culture. These challenges can be overcome by using bioprinting techniques to build heterogeneous three-dimensional (3D) tumor models whereby different types of cells are embedded. Alginate and gelatin are two of the most common biomaterials employed in bioprinting due to their biocompatibility, biomimicry, and mechanical properties...
July 2, 2018: Journal of Visualized Experiments: JoVE
Long Yuan, Fan Zhang, Xiaowei Qi, Yongjun Yang, Chang Yan, Jun Jiang, Jun Deng
BACKGROUND: Autophagy regulation through exogenous materials has aroused intensive attention to develop treatment protocols according to diverse human diseases. However, to the best of our knowledge, few examples have been reported to selectively control autophagy process and ultimately achieve efficient therapeutic potential. RESULTS: In this study, monolayers of poly (acryloyl-L, D and racemic valine) (L-PAV-AuNPs, D-PAV-AuNPs and L/D-PAV-AuNPs) chiral molecules were anchored on the surfaces of gold nanoparticles (PAV-AuNPs), and the subsequent chirality-selective effects on autophagy activation were thoroughly studied...
July 11, 2018: Journal of Nanobiotechnology
Ernestina M De Francesco, Marcello Maggiolini, Anna Maria Musti
The Notch signaling pathway acts in both physiological and pathological conditions, including embryonic development and tumorigenesis. In cancer progression, diverse mechanisms are involved in Notch-mediated biological responses, including angiogenesis and epithelial-mesenchymal-transition (EMT). During EMT, the activation of cellular programs facilitated by transcriptional repressors results in epithelial cells losing their differentiated features, like cell⁻cell adhesion and apical⁻basal polarity, whereas they gain motility...
July 10, 2018: International Journal of Molecular Sciences
Junqiang Wu, Yuhang Wang, Jing Liu, Qianlin Chen, Da Pang, Yongdong Jiang
BACKGROUND/AIMS: Fibroblast growth factor receptor 1 (FGFR1) is widely considered to play an important role in mammary carcinogenesis. Some common variants in FGFR1 might be associated with its expression, and further affect breast cancer risk. The aim of this study was to investigate effects of single-nucleotide polymorphisms (SNPs) in FGFR1 on breast cancer susceptibility and FGFR1 protein expression. METHODS: SNPs rs17182023, rs17175624 and rs10958704 in FGFR1 were genotyped in 747 breast cancer cases and 716 healthy controls by SNaPshot method...
2018: Cellular Physiology and Biochemistry
Manoj Kumar Jena, Jagadeesh Janjanam
Evidence is increasing on the crucial role of the extracellular matrix (ECM) in breast cancer progression, invasion and metastasis with almost all mortality cases owing to metastasis. The epithelial-mesenchymal transition is the first signal of metastasis involving different transcription factors such as Snail, TWIST, and ZEB1. ECM remodeling is a major event promoting cancer invasion and metastasis; where matrix metalloproteinases (MMPs) such as MMP-2, -9, -11, and -14 play vital roles degrading the matrix proteins for cancer spread...
2018: F1000Research
Dana Koslawsky, Marianna Zaretsky, Ron Alcalay, Ohad Mazor, Amir Aharoni, Niv Papo
The cytokine IL-17A is associated with the progression of various cancers, but little is known about the molecular cross-talk between IL-17A and other tumor-promoting factors. Previous studies have shown that the IL-17A-mediated invasion of breast cancer cells can be inhibited by selective antagonists of the matrix metalloproteinase 9 (MMP-9), suggesting that the cross-talk between IL-17A and MMP-9 may promote cancer invasiveness and metastasis. Here, we present a novel strategy for developing cancer therapeutics, based on the simultaneous binding and inhibition of both IL-17A and MMP-9...
June 19, 2018: Oncotarget
Ang Li, Ping Chen, Ye Leng, Jiuhong Kang
Cancer-associated fibroblasts (CAFs) are important components in breast tumors and essential for tumor progression and metastasis. However, the role of epigenetic modification in driving the function of CAFs within breast tumors is only marginally known. Herein, we reported that histone deacetylase 6 (HDAC6), one of class II histone deacetylases, was frequently upregulated in the CAFs of breast tumor and promotes an immunosuppressive microenvironment. The genetic or pharmacologic disruption of HDAC6 in CAFs delays tumor growth, inhibits the tumor recruitment of myeloid-derived suppressor cells and regulatory T cells, alters the macrophage phenotype switch, and increases the CD8+ and CD4+ T-cell activation in vivo...
July 6, 2018: Oncogene
Nádia Ribeiro, Roberto E Di Paolo, Adelino M Galvão, Fernanda Marques, João Costa Pessoa, Isabel Correia
A new ZnL2 complex containing two molecules of a tridentate Schiff base derived from 5-methyl-1H-pyrazole (HL) is synthesized and characterized. The photophysical properties of HL and ZnL2 are disclosed and supported by CAMB3LYP DFT/TDDFT calculations. It is shown that there is keto-tautomer stabilization upon excitation with an energetically accessible triplet state in HL, not present in ZnL2 , this explaining the differences found in the emissions of the compounds. The intrinsic fluorescence of ZnL2 is used as probe for a detailed study of its binding to human serum albumin...
June 15, 2018: Spectrochimica Acta. Part A, Molecular and Biomolecular Spectroscopy
C Coulson-Gilmer, M P Humphries, S Sundara Rajan, A Droop, S Jackson, A Condon, G Cserni, L B Jordan, J L Jones, R Kanthan, A Di Benedetto, M Mottolese, E Provenzano, J Kulka, A M Shaaban, A M Hanby, V Speirs
Breast cancer can arise in either gender; however, it is rare in men, accounting for <1% of diagnosed cases. In a previous transcriptomic screen of male and female breast cancer we observed that Stanniocalcin 2 (STC2) was overexpressed in the former. The aim of this study was to confirm the expression of STC2 in male breast cancer, and to investigate whether this had an impact on patient prognosis. Following an earlier transcriptomic screen, STC2 gene expression was confirmed by RT-qPCR in matched male and female BC samples as well as in tumour-associated fibroblasts derived from each gender...
June 28, 2018: Journal of Pathology. Clinical Research
Ana Sahores, Virginia Figueroa, María May, Marcos Liguori, Adrián Rubstein, Cynthia Fuentes, Britta M Jacobsen, Andrés Elía, Paola Rojas, Gonzalo R Sequeira, Michelle M Álvarez, Pedro González, Hugo Gass, Stephen Hewitt, Alfredo Molinolo, Claudia Lanari, Caroline A Lamb
Endocrine resistance may develop as a consequence of enhanced growth factor signaling. Fibroblast growth factor 2 (FGF2) consists of a low and several high molecular weight forms (HMW-FGF2). We previously demonstrated that antiprogestin-resistant mammary carcinomas display lower levels of progesterone receptor A isoforms (PRA) than B isoforms (PRB). Our aim was to evaluate the role of FGF2 isoforms in breast cancer progression. We evaluated FGF2 expression, cell proliferation, and pathway activation in models with different PRA/PRB ratios...
June 28, 2018: Hormones & Cancer
Christos Sazeides, Anne Le
Cancer-associated fibroblasts (CAFs), a major component of the tumor microenvironment (TME), play an important role in cancer initiation, progression, and metastasis. Recent findings have demonstrated that the TME not only provides physical support for cancer cells, but also directs cell-to-cell interactions (in this case the interaction between cancer cells and CAFs). As cancer progresses, the CAFs also co evolve—transitioning from an inactivated state to an activated state. The elucidation and understanding of the interaction between cancer cells and CAFs will pave the way for new cancer therapies [1–3]...
2018: Advances in Experimental Medicine and Biology
Xinyan Wu, Muhammad Saddiq Zahari, Santosh Renuse, Nandini A Sahasrabuddhe, Raghothama Chaerkady, Min-Sik Kim, Mary Jo Fackler, Martha Stampfer, Edward Gabrielson, Saraswati Sukumar, Akhilesh Pandey
Background: Cancer-associated fibroblasts (CAFs) are one of the most important components of tumor stroma and play a key role in modulating tumor growth. However, a mechanistic understanding of how CAFs communicate with tumor cells to promote their proliferation and invasion is far from complete. A major reason for this is that most current techniques and model systems do not capture the complexity of signal transduction that occurs between CAFs and tumor cells. Methods: In this study, we employed a stable isotope labeling with amino acids in cell culture (SILAC) strategy to label invasive breast cancer cells, MDA-MB-231, and breast cancer patient-derived CAF this has already been defined above cells...
2018: Clinical Proteomics
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