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Carcinoma-Associated Fibroblasts

Linda Ziani, Salem Chouaib, Jerome Thiery
Among cells present in the tumor microenvironment, activated fibroblasts termed cancer-associated fibroblasts (CAFs), play a critical role in the complex process of tumor-stroma interaction. CAFs, one of the prominent stromal cell populations in most types of human carcinomas, have been involved in tumor growth, angiogenesis, cancer stemness, extracellular matrix remodeling, tissue invasion, metastasis, and even chemoresistance. During the past decade, these activated tumor-associated fibroblasts have also been involved in the modulation of the anti-tumor immune response on various levels...
2018: Frontiers in Immunology
Roshanak Derakhshandeh, Sonia Sanadhya, Kyu Lee Han, Haiyan Chen, Olga Goloubeva, Tonya J Webb, Rania H Younis
The search for stromal biomarkers in carcinoma patients is a challenge in the field. Semaphorin 4D (Sema4D), known for its various developmental, physiological and pathological effects, plays a role in pro and anti-inflammatory responses. It is expressed in many epithelial tumors including head and neck squamous cell carcinoma (HNSCC). Recently, we found that HNSCC-associated Sema4D modulates an immune-suppressive, tumor-permissible environment by inducing the expansion of myeloid derived suppressor cells. The purpose of this study was to determine the value of Sema4D as a biomarker for the peri-tumoral stromal phenotype in human HNSCC...
February 16, 2018: Oncotarget
Julien Daubriac, Shiwei Han, Jelena Grahovac, Eve Smith, Abdel Hosein, Marguerite Buchanan, Mark Basik, Yves Boucher
Carcinoma-associated fibroblasts (CAFs) can remodel the extracellular matrix to promote cancer cell invasion, but the paracrine signaling between CAFs and cancer cells that regulates tumor cell migration remains to be identified. To determine how the interaction between CAFs and cancer cells modulates the invasiveness of cancer cells, we developed a 3-dimensional co-culture model composed of breast cancer (BC) MDA-MB-231 cell spheroids embedded in a collagen gel with and without CAFs. We found that the crosstalk between CAFs and cancer cells promotes invasion by stimulating the scattering of MDA-MB-231 cells, which was dependent on RhoA/ROCK/phospho MLC signaling in cancer cells but independent of RhoA in CAFs...
February 13, 2018: Oncotarget
Anne-Marie Givel, Yann Kieffer, Alix Scholer-Dahirel, Philemon Sirven, Melissa Cardon, Floriane Pelon, Ilaria Magagna, Géraldine Gentric, Ana Costa, Claire Bonneau, Virginie Mieulet, Anne Vincent-Salomon, Fatima Mechta-Grigoriou
High-grade serous ovarian cancers (HGSOC) have been subdivided into molecular subtypes. The mesenchymal HGSOC subgroup, defined by stromal-related gene signatures, is invariably associated with poor patient survival. We demonstrate that stroma exerts a key function in mesenchymal HGSOC. We highlight stromal heterogeneity in HGSOC by identifying four subsets of carcinoma-associated fibroblasts (CAF-S1-4). Mesenchymal HGSOC show high content in CAF-S1 fibroblasts, which exhibit immunosuppressive functions by increasing attraction, survival, and differentiation of CD25+ FOXP3+ T lymphocytes...
March 13, 2018: Nature Communications
Pernilla Roswall, Matteo Bocci, Michael Bartoschek, Hong Li, Glen Kristiansen, Sara Jansson, Sophie Lehn, Jonas Sjölund, Steven Reid, Christer Larsson, Pontus Eriksson, Charlotte Anderberg, Eliane Cortez, Lao H Saal, Christina Orsmark-Pietras, Eugenia Cordero, Bengt Kristian Haller, Jari Häkkinen, Ingrid J G Burvenich, Elgene Lim, Akira Orimo, Mattias Höglund, Lisa Rydén, Holger Moch, Andrew M Scott, Ulf Eriksson, Kristian Pietras
Breast tumors of the basal-like, hormone receptor-negative subtype remain an unmet clinical challenge, as there is high rate of recurrence and poor survival in patients following treatment. Coevolution of the malignant mammary epithelium and its underlying stroma instigates cancer-associated fibroblasts (CAFs) to support most, if not all, hallmarks of cancer progression. Here we delineate a previously unappreciated role for CAFs as determinants of the molecular subtype of breast cancer. We identified paracrine crosstalk between cancer cells expressing platelet-derived growth factor (PDGF)-CC and CAFs expressing the cognate receptors in human basal-like mammary carcinomas...
March 12, 2018: Nature Medicine
Johannes Breyer, Ralph M Wirtz, Philipp Erben, Thomas S Worst, Robert Stoehr, Markus Eckstein, Simone Bertz, Danijel Sikic, Stefan Denzinger, Maximilian Burger, Arndt Hartmann, Wolfgang Otto
BACKGROUND: A recent study on the comprehensive genomic profile of advanced urothelial bladder cancer (UBC) showed cyclin-dependent kinase inhibitor 2A (CDKN2A) and fibroblast growth factor receptor 3 (FGFR3) as the most often clinically relevant genomic alterations. Therefore, the prognostic role of FGFR3 and CDKN2A/p16 for pT1 UBC was studied. PATIENTS AND METHODS: Clinical data and formalin-fixed paraffin-embedded tissues of pT1 UBC treated with an organ-preserving approach was analyzed retrospectively...
February 2, 2018: Clinical Genitourinary Cancer
Marta Giussani, Elena Landoni, Giuseppe Merlino, Federica Turdo, Silvia Veneroni, Biagio Paolini, Vera Cappelletti, Rosalba Miceli, Rosaria Orlandi, Tiziana Triulzi, Elda Tagliabue
Changes in amount and composition of extracellular matrix (ECM) are considered a hallmark of tumor development. We tested the hypothesis that abnormal production of ECM components leads to blood-released ECM molecules representing tumor circulating biomarkers. Candidate genes were selected through class comparison in two publicly available datasets and confirmed in paired normal and tumor associated fibroblasts from breast carcinoma (BC) specimens. Production and release of ECM molecules were evaluated in normal human dermal fibroblasts (NHDFs) treated with conditioned media from three BC cell lines...
March 9, 2018: Journal of Cellular Physiology
Si Xiong, Ronghua Wang, Qian Chen, Jing Luo, Jinlin Wang, Zhenxiong Zhao, Yawen Li, Yun Wang, Xiju Wang, Bin Cheng
In this study, we investigated the role of cancer-associated fibroblasts (CAFs) in hepatocellular carcinoma (HCC) progression. We showed that CAFs secrete high levels of IL-6, which promoted stem cell-like properties in HCC cells by activating Notch signaling through STAT3 Tyr705 phosphorylation. These effects were abolished by Notch1 shRNA knockdown in HCC cells or treatment with an IL-6 neutralizing antibody or the p-STAT3 (Tyr705) inhibitor cryptotanshinone. Xenografted liver tumors were larger in nude mice injected with HCC cells and CAFs than in those receiving HCC cells alone...
2018: American Journal of Cancer Research
Nathaniel Edward Bennett Saidu, Marie Bretagne, Audrey Lupo Mansuet, Pierre-Alexandre Just, Karen Leroy, Olivier Cerles, Sandrine Chouzenoux, Carole Nicco, Diane Damotte, Marco Alifano, Bruno Borghese, François Goldwasser, Frédéric Batteux, Jérôme Alexandre
KRAS mutation, one of the most common molecular alterations observed in adult carcinomas, was reported to activate the anti-oxidant program driven by the transcription factor NRF2 (Nuclear factor-erythroid 2-related factor 2). We previously observed that the antitumoral effect of Dimethyl fumarate (DMF) is dependent of NRF2 pathway inhibition. We used in vitro methods to examine the effect of DMF on cell death and the activation of the NRF2/DJ-1 antioxidant pathway. We report here that DMF is preferentially cytotoxic against KRAS mutated cancer cells...
February 6, 2018: Oncotarget
Marcel F Glaas, Constanze Wiek, Linda-Maria Wolter, Katharina Roellecke, Vera Balz, Vera Okpanyi, Martin Wagenmann, Thomas Karl Hoffmann, Rene Grässlin, Christian Plettenberg, Jörg Schipper, Helmut Hanenberg, Kathrin Scheckenbach
BACKGROUND/AIM: Head and neck squamous cell carcinomas (HNSCCs) form a heterogeneous tumor entity located throughout the oral cavity, pharynx and larynx that is caused predominantly by chemically or virally induced carcinogenesis. Heterozygous germline mutations in cancer susceptibility genes might also lead to increased incidence of HNSCCs. As DNA stability is typically impaired in HNSCC cells and genes of the Fanconi anemia/BRCA DNA repair pathway can be mutated or down-regulated in HNSCCs, we investigated here whether germline mutations occur in the X-chromosomal FANCB as candidate gene...
March 2018: Anticancer Research
Miki Young, Darren Rodenhizer, Teresa Dean, Elisa D'Arcangelo, Bin Xu, Laurie Ailles, Alison P McGuigan
Cancer-associated fibroblasts (CAFs) are a key component of the tumour microenvironment and have been shown to play an important role in the progression of cancer. To probe these tumour-stroma interactions, we incorporated CAFs derived from head and neck cancer patients and squamous carcinoma cells of the hypopharynx (FaDu) into the Tissue Roll for the Analysis of Cellular Environment and Response (TRACER) platform to establish a co-culture platform that simulates the CAF-tumour microenvironmental interactions in head and neck tumours...
February 19, 2018: Biomaterials
W Shang, Q Zhang, Y Huang, R Shanti, F Alawi, A Le, C Jiang
Head and neck cancer is one of the most frequent human malignancies worldwide, with a high rate of recurrence and metastasis. Head and neck squamous cell carcinoma (HNSCC) is cellularly and molecularly heterogeneous, with subsets of undifferentiated cancer cells exhibiting stem cell-like properties, called cancer stem cells (CSCs). Epithelial-mesenchymal transition, gene mutation, and epigenetic modification are associated with the formation of cellular plasticity of tumor cells in HNSCC, contributing to the acquisition of invasive, recurrent, and metastatic properties and therapeutic resistance...
February 1, 2018: Journal of Dental Research
Song-Ming Ding, Ai-Li Lu, Wu Zhang, Lin Zhou, Hai-Yang Xie, Shu-Sen Zheng, Qi-Yong Li
Background: Our previous study showed that cancer-associated fibroblast MRC-5 promoted hepatocellular carcinoma progression by enhancing migration and invasion capability. However, few studies have explored the role of MRC-5 in pancreatic cancer (PC). In this study, we examined the exact role and associated mechanisms of MRC-5. Methods: The conditioned media for MRC-5 was used to culture PC cell lines SW1990 and PANC-1. Cell proliferation was compared based on colony formation assays of PC cells in normal media and of PC cells cultured with conditioned media of MRC-5...
2018: Journal of Cancer
R D Coletta, T Salo
In oral cancer, acquisition of α-smooth muscle actin (α-SMA)-positive fibroblasts, known as myofibroblasts or carcinoma-associated fibroblasts (CAF), is an important event for progression and metastasis. However, the contribution of myofibroblasts in oral potentially malignant disorders (OPMD) remains controversial. This systematic review provides evidence that immunodetection of myofibroblasts may identify oral submucous fibrosis (OSMF) with high risk of malignant transformation, but does not represent an auxiliary tool to predict the malignant potential of leukoplakia and erythroplakia, the most common OPMD...
March 2018: Oral Diseases
Sofia P Rebelo, Catarina Pinto, Tatiana R Martins, Nathalie Harrer, Marta F Estrada, Pablo Loza-Alvarez, José Cabeçadas, Paula M Alves, Emilio J Gualda, Wolfgang Sommergruber, Catarina Brito
The tumour microenvironment (TME) shapes disease progression and influences therapeutic response. Most aggressive solid tumours have high levels of myeloid cell infiltration, namely tumour associated macrophages (TAM). Recapitulation of the interaction between the different cellular players of the TME, along with the extracellular matrix (ECM), is critical for understanding the mechanisms underlying disease progression. This particularly holds true for prediction of therapeutic response(s) to standard therapies and interrogation of efficacy of TME-targeting agents...
May 2018: Biomaterials
Sumera Rizvi, Samantha R Fischbach, Steven F Bronk, Petra Hirsova, Anuradha Krishnan, Renumathy Dhanasekaran, James B Smadbeck, Rory L Smoot, George Vasmatzis, Gregory J Gores
Deregulated Hippo pathway signaling is associated with aberrant activation of the downstream effector yes-associated protein (YAP), an emerging key oncogenic mediator in cholangiocarcinoma (CCA). In our prior work, we have demonstrated that biliary transduction of YAP along with Akt as a permissive factor induces CCA in mice. To further delineate the mechanisms associated with YAP-associated biliary oncogenesis, we have established seven malignant murine cell lines from our YAP-driven murine CCA model. These cells express the CCA markers SRY (Sex Determining Region Y)-Box 9 (SOX9), cytokeratin (CK)-7 and 19 but lack hepatocyte nuclear factor 4 alpha and alpha-smooth muscle actin, markers of hepatocellular carcinoma and cancer-associated fibroblasts, respectively...
January 19, 2018: Oncotarget
Ana Costa, Yann Kieffer, Alix Scholer-Dahirel, Floriane Pelon, Brigitte Bourachot, Melissa Cardon, Philemon Sirven, Ilaria Magagna, Laetitia Fuhrmann, Charles Bernard, Claire Bonneau, Maria Kondratova, Inna Kuperstein, Andrei Zinovyev, Anne-Marie Givel, Maria-Carla Parrini, Vassili Soumelis, Anne Vincent-Salomon, Fatima Mechta-Grigoriou
Carcinoma-associated fibroblasts (CAF) are key players in the tumor microenvironment. Here, we characterize four CAF subsets in breast cancer with distinct properties and levels of activation. Two myofibroblastic subsets (CAF-S1, CAF-S4) accumulate differentially in triple-negative breast cancers (TNBC). CAF-S1 fibroblasts promote an immunosuppressive environment through a multi-step mechanism. By secreting CXCL12, CAF-S1 attracts CD4+ CD25+ T lymphocytes and retains them by OX40L, PD-L2, and JAM2. Moreover, CAF-S1 increases T lymphocyte survival and promotes their differentiation into CD25High FOXP3High , through B7H3, CD73, and DPP4...
February 12, 2018: Cancer Cell
Qianqian Zhang, Wen Liu, Yang Yang, Zhenzhen Zhao, Bing Luo
BACKGROUND: Epstein-Barr virus (EBV) is etiologically linked to nasopharyngeal carcinoma, lymphoma and gastric carcinoma. The aim of this study was to assess the association of TM2 domain containing 3 (TM2D3) and fibroblast growth factor receptor 2 (FGFR2) SNPs rs675436 and rs755793 with susceptibility to EBV-associated tumors in Chinese Han population. MATERIALS AND METHODS: Genomic DNA of 415 patients with cancer and 99 healthy controls was assessed using a MALDI-TOF mass spectrometer, and was genotyped in EBV-associated/-negative gastric cancer (EBVa/nGC), EBV-associated/-negative nasopharyngeal carcinoma (EBVa/nNPC), EBV-associated/ -negative lymphoma (EBVa/nL) and normal controls (NC)...
February 15, 2018: Journal of Medical Virology
Yae Ohata, Maiko Tsuchiya, Hideaki Hirai, Satoshi Yamaguchi, Takumi Akashi, Kei Sakamoto, Akira Yamaguchi, Tohru Ikeda, Kou Kayamori
The interaction between cancer cells and the cancer stroma plays a crucial role in tumor progression and metastasis in diverse malignancies, including oral cancer. However, the mechanism underlying this interaction remains incompletely elucidated. Here, to investigate the interaction between oral cancer cells and fibroblasts, which are major cellular components of the tumor stroma, we conducted an in vitro study by using human oral squamous cell carcinoma (OSCC) cell lines and normal human dermal fibroblasts (NHDFs)...
2018: PloS One
Matheus Oliveira da Silva, Marcella Lemos Brettas Carneiro, Joseílma Luciana Neves Siqueira, Sônia Nair Báo, Aparecido Ribeiro de Souza
In this study, we report the synthesis and characterization of a new rhodium(II) succinate complex (Rh2(suc)4) and its immobilization on lauric acid bilayer-coated maghemite nanoparticles (MGH-2L/Rh2(suc)4) and subsequent adsorption with bovine serum albumin (MGH-2L/Rh2(suc)4/BSA). Rh2(suc)4 has been characterized by elemental analysis, potentiometric titration, TGA, MS, FTIR and UV-Vis analysis. The maghemite phase was confirmed by XRD, and a diameter of 10 nm was obtained by Sherrer equation. The VSM experiment showed superparamagnetic properties...
June 1, 2018: Journal of Nanoscience and Nanotechnology
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