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tumor stromal microenvironment

Jack R Staunton, Wilfred Vieira, King Leung Fung, Ross Lake, Alexus Devine, Kandice Tanner
One of the hallmarks of the malignant transformation of epithelial tissue is the modulation of stromal components of the microenvironment. In particular, aberrant extracellular matrix (ECM) remodeling and stiffening enhances tumor growth and survival and promotes metastasis. Type I collagen is one of the major ECM components. It serves as a scaffold protein in the stroma contributing to the tissue's mechanical properties, imparting tensile strength and rigidity to tissues such as those of the skin, tendons, and lungs...
September 2016: Cellular and Molecular Bioengineering
Hiroaki Kasashima, Masakazu Yashiro, Hirohisa Nakamae, Kisyu Kitayama, Go Masuda, Haruhito Kinoshita, Tatsunari Fukuoka, Tsuyoshi Hasegawa, Takahiko Nakane, Masayuki Hino, Kosei Hirakawa, Masaichi Ohira
Tumor stromal cells play a critical role in the progression of diffuse-type gastric cancer (DGC). The aim of this study was to clarify where tumor stromal cells originate from and which factor(s) recruits them into the tumor stroma. Immunodeficient mice with bone marrow transplantation from the cytomegalovirus enhancer/chicken β-actin promoter-enhanced green fluorescent protein mice were used for the in vivo experiments. An in vitro study analyzed the chemotaxis-stimulating factor from DGC cells using bone marrow-derived mesenchymal cells (BM-MCs)...
October 8, 2016: American Journal of Pathology
Paul Macklin, Hermann B Frieboes, Jessica L Sparks, Ahmadreza Ghaffarizadeh, Samuel H Friedman, Edwin F Juarez, Edmond Jonckheere, Shannon M Mumenthaler
Tumors cannot be understood in isolation from their microenvironment. Tumor and stromal cells change phenotype based upon biochemical and biophysical inputs from their surroundings, even as they interact with and remodel the microenvironment. Cancer should be investigated as an adaptive, multicellular system in a dynamical microenvironment. Computational modeling offers the potential to detangle this complex system, but the modeling platform must ideally account for tumor heterogeneity, substrate and signaling factor biotransport, cell and tissue biophysics, tissue and vascular remodeling, microvascular and interstitial flow, and links between all these sub-systems...
2016: Advances in Experimental Medicine and Biology
Maria Celia Fernandez, Roni Rayes, Boram Ham, Ni Wang, France Bourdeau, Simon Milette, Martin Lllemann, Nigel Bird, Ali Majeed, Jun Xu, Tatiana Kisselova, Pnina Brodt
Hepatic stellate cells (HSC) play a major role in initiating the liver fibrogenic (wounding) response of the liver and can also orchestrate a pro-metastatic microenvironment in the liver in response to invading cancer cells. Here we explored the role of the hepatic stellate cells in colon carcinoma liver metastasis with emphasis on the contribution of the insulin-like growth factor (IGF) axis to their activation and function. To this end, we used mice with a Tamoxifen inducible liver IGF-I deficiency. We found that in mice with a sustained IGF-I deficiency, recruitment and activation of HSC into tumor-infiltrated areas of the liver were markedly diminished, resulting in decreased collagen deposition and reduced tumor expansion...
October 12, 2016: Oncotarget
Timothy Chao, Emma E Furth, Robert H Vonderheide
Tumor-associated neutrophils are increasingly recognized for their ability to promote tumor progression, mediate resistance to therapy, and regulate immunosuppression. Evidence from various murine models has shown that the chemokine receptor CXCR2 attracts neutrophil into tumors and, therefore, represents a tractable therapeutic target. Here, we report prominent expression of a neutrophil gene signature in a subset of human pancreatic adenocarcinoma (PDA). CXCL5 was the most prominently expressed CXCR2 ligand in human PDA, and its expression was higher in PDA than in any other common tumor represented in The Cancer Genome Atlas...
October 13, 2016: Cancer Immunology Research
Dieter Zopf, Iduna Fichtner, Ajay Bhargava, Wolfram Steinke, Karl-Heinz Thierauch, Konstanze Diefenbach, Scott Wilhelm, Frank-Thorsten Hafner, Michael Gerisch
Regorafenib is an orally administered inhibitor of protein kinases involved in tumor angiogenesis, oncogenesis, and maintenance of the tumor microenvironment. Phase III studies showed that regorafenib has efficacy in patients with advanced gastrointestinal stromal tumors or treatment-refractory metastatic colorectal cancer. In clinical studies, steady-state exposure to the M-2 and M-5 metabolites of regorafenib was similar to that of the parent drug; however, the contribution of these metabolites to the overall observed clinical activity of regorafenib cannot be investigated in clinical trials...
October 13, 2016: Cancer Medicine
T Yu, G Yang, Y Hou, X Tang, C Wu, X-A Wu, L Guo, Q Zhu, H Luo, Y-E Du, S Wen, L Xu, J Yin, G Tu, M Liu
Multiple drug resistance is a challenging issue in the clinic. There is growing evidence that the G-protein-coupled estrogen receptor (GPER) is a novel mediator in the development of multidrug resistance in both estrogen receptor (ER)-positive and -negative breast cancers, and that cancer-associated fibroblasts (CAFs) in the tumor microenvironment may be a new agent that promotes drug resistance in tumor cells. However, the role of cytoplasmic GPER of CAFs on tumor therapy remains unclear. Here we first show that the breast tumor cell-activated PI3K/AKT (phosphoinositide 3-kinase/AKT) signaling pathway induces the cytoplasmic GPER translocation of CAFs in a CRM1-dependent pattern, and leads to the activation of a novel estrogen/GPER/cAMP/PKA/CREB signaling axis that triggers the aerobic glycolysis switch in CAFs...
October 10, 2016: Oncogene
Elisabeth Naschberger, Andrea Liebl, Vera S Schellerer, Manuela Schütz, Nathalie Britzen-Laurent, Patrick Kölbel, Ute Schaal, Lisa Haep, Daniela Regensburger, Thomas Wittmann, Ludger Klein-Hitpass, Tilman T Rau, Barbara Dietel, Valérie S Méniel, Alan R Clarke, Susanne Merkel, Roland S Croner, Werner Hohenberger, Michael Stürzl
Different tumor microenvironments (TMEs) induce stromal cell plasticity that affects tumorigenesis. The impact of TME-dependent heterogeneity of tumor endothelial cells (TECs) on tumorigenesis is unclear. Here, we isolated pure TECs from human colorectal carcinomas (CRCs) that exhibited TMEs with either improved (Th1-TME CRCs) or worse clinical prognosis (control-TME CRCs). Transcriptome analyses identified markedly different gene clusters that reflected the tumorigenic and angiogenic activities of the respective TMEs...
October 10, 2016: Journal of Clinical Investigation
Virginia Brancato, Alessandro Garziano, Filomena Gioiella, Francesco Urciuolo, Giorgia Imparato, Valeria Panzetta, Sabato Fusco, Paolo A Netti
: We fabricated three-dimensional microtissues with the aim to replicate in vitro the composition and the functionalities of the tumor microenvironment. By arranging either normal fibroblasts (NF) or cancer-activated fibroblasts (CAF) in two different three dimensional (3D) configurations, two kinds of micromodules were produced: spheroids and microtissues. Spheroids were obtained by means of the traditional cell aggregation technique resulting in a 3D model characterized by high cell density and low amount of extracellular proteins...
October 6, 2016: Acta Biomaterialia
Qinglin Zhang, Zhi Liang, Yongxiang Gao, Maikun Teng, Liwen Niu
It has been reported that tumor growth and proliferation correspond to mitochondrial dysfunction and that the tumor cellular microenvironment plays a key role in tumor progression, representing an area that might be manipulated to confer therapeutic anti-tumor benefits. In this article, we have identified mitochondrial genes, largely nuclear-encoded genes, which are differentially expressed in breast cancer epithelial and stromal cells compared to cells from normal breast tissues. We determined that gene expression of the mitochondrial membrane respiratory chain complex I and IV and ATP synthesis were reduced in both in epithelial and stromal cancer cells compared to normal breast cells...
October 6, 2016: Gene
Sandy Liu, Radu M Cadaneanu, Baohui Zhang, Lihong Huo, Kevin Lai, Xinmin Li, Colette Galet, Tristan R Grogan, David Elashoff, Stephen J Freedland, Matthew Rettig, William J Aronson, Beatrice S Knudsen, Michael S Lewis, Isla P Garraway
BACKGROUND: Benign human prostate tubule-initiating cells (TIC) and aggressive prostate cancer display common traits, including tolerance of low androgen levels, resistance to apoptosis, and microenvironment interactions that drive epithelial budding and outgrowth. TIC can be distinguished from epithelial and stromal cells that comprise prostate tissue via cell sorting based upon Epcam, CD44, and CD49f antigenic profiles. Fetal prostate epithelial cells (FC) possess a similar antigenic profile to adult TIC and are capable of inducing tubule formation...
2016: PloS One
Julie Leca, Sébastien Martinez, Sophie Lac, Jérémy Nigri, Véronique Secq, Marion Rubis, Christian Bressy, Arnauld Sergé, Marie-Noelle Lavaut, Nelson Dusetti, Céline Loncle, Julie Roques, Daniel Pietrasz, Corinne Bousquet, Stéphane Garcia, Samuel Granjeaud, Mehdi Ouaissi, Jean Baptiste Bachet, Christine Brun, Juan L Iovanna, Pascale Zimmermann, Sophie Vasseur, Richard Tomasini
The intratumoral microenvironment, or stroma, is of major importance in the pathobiology of pancreatic ductal adenocarcinoma (PDA), and specific conditions in the stroma may promote increased cancer aggressiveness. We hypothesized that this heterogeneous and evolving compartment drastically influences tumor cell abilities, which in turn influences PDA aggressiveness through crosstalk that is mediated by extracellular vesicles (EVs). Here, we have analyzed the PDA proteomic stromal signature and identified a contribution of the annexin A6/LDL receptor-related protein 1/thrombospondin 1 (ANXA6/LRP1/TSP1) complex in tumor cell crosstalk...
October 4, 2016: Journal of Clinical Investigation
David L Marks, Rachel Lo Olson, Martin E Fernandez-Zapico
Stromal cells of the tumor microenvironment have been shown to play important roles in both supporting and limiting cancer growth. The altered phenotype of tumor-associated stromal cells (fibroblasts, immune cells, endothelial cells etc.) is proposed to be mainly due to epigenetic dysregulation of gene expression; however, only limited studies have probed the roles of epigenetic mechanisms in the regulation of stromal cell function. We review recent studies demonstrating how specific epigenetic mechanisms (DNA methylation and histone post-translational modification-based gene expression regulation, and miRNA-mediated translational regulation) drive aspects of stromal cell phenotype, and discuss the implications of these findings for treatment of malignancies...
October 4, 2016: Epigenomics
Xavier Catteau, Philippe Simon, Frédéric Buxant, Jean-Christophe Noël
Cancer- associated fibroblasts (CAFs) are actively involved in breast carcinoma. Our previous study demonstrated that the majority of these CAFs were smooth muscle actin (SMA) positive and were therefore termed peritumoral myofibroblast (PMY). Glucocorticoid, linked or not with its receptor (GR), has been postulated to serve a major role in normal breast and breast carcinoma; however, their role in CAFs remains poorly understood. The aim of the present study was to assess the presence of GR in breast CAFs and particularly in PMY in 56 cases of invasive breast carcinoma in correlation with clinicopathological parameters, by immunohistochemistry...
October 2016: Molecular and Clinical Oncology
David Chiron, Céline Bellanger, Antonin Papin, Benoit Tessoulin, Christelle Dousset, Sophie Maiga, Anne Moreau, Julie Esbelin, Valérie Trichet, Selina Chen-Kiang, Philippe Moreau, Cyrille Touzeau, Steven Le Gouill, Martine Amiot, Catherine Pellat-Deceunynck
Mantle cell lymphoma (MCL) accumulates in lymphoid organs but disseminates early on in extranodal tissues. Although proliferation remains located in lymphoid organs only, suggesting a major role of the tumor ecosystem, few studies have assessed MCL microenvironment. We therefore cocultured primary circulating MCL cells from 21 patients several weeks ex vivo with stromal or lymphoid-like (CD40L) cells to determine which interactions could support their proliferation. We showed that coculture with lymphoid-like cells, but not stromal cells, induced cell-cycle progression, which was amplified by MCL-specific cytokines (IGF-1, BAFF, IL-6, IL-10)...
October 3, 2016: Blood
Makito Miyake, Shunta Hori, Yosuke Morizawa, Yoshihiro Tatsumi, Yasushi Nakai, Satoshi Anai, Kazumasa Torimoto, Katsuya Aoki, Nobumichi Tanaka, Keiji Shimada, Noboru Konishi, Michihiro Toritsuka, Toshifumi Kishimoto, Charles J Rosser, Kiyohide Fujimoto
Tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) are reported to be associated with poor prognosis, depending on their pro-tumoral roles. Current knowledge of TAMs and CAFs in the tumor microenvironment of urothelial cancer of the bladder (UCB) is limited. Therefore, we investigated the paracrine effect induced by TAMs and CAFs in the tumor microenvironment of human UCB. For this, we first carried out immunohistochemical analysis for CXCL1, CD204 (TAM marker), αSMA (CAF marker), E-cadherin, and MMP2 using 155 UBC tissue samples...
October 2016: Neoplasia: An International Journal for Oncology Research
Catalin Vlad, Paul Kubelac, Andrea Onisim, Bogdan Fetica, Annamaria Fulop, Alexandru Irimie, Patriciu Achimas-Cadariu
PURPOSE: The tumor microenvironment in ovarian cancer (OC) seems to play an important role, and besides tumor cells, biomarkers can derive from endothelial cells. We investigated CDCP1 and ADAM12 expression in relation with other clinical and pathological characteristics in OC patients. METHODS: We retrospectively evaluated patient files between 2006-2011. A histochemical score was developed to evaluate tumor staining, the microvessel density (MVD), and stromal expression patterns for both ADAM12 and CDCP1...
July 2016: Journal of B.U.ON.: Official Journal of the Balkan Union of Oncology
Jason D Domogauer, Sonia M de Toledo, Edouard I Azzam
Understanding the early heterotypic interactions between cancer cells and the surrounding non-cancerous stroma is important in elucidating the events leading to stromal activation and establishment of the tumor microenvironment (TME). Several in vitro and in vivo models of the TME have been developed; however, in general these models do not readily permit isolation of individual cell populations, under non-perturbing conditions, for further study. To circumvent this difficulty, we have employed an in vitro TME model using a cell growth substrate consisting of a permeable microporous membrane insert that permits simple generation of highly enriched cell populations grown intimately, yet separately, on either side of the insert's membrane for extended co-culture times...
2016: Journal of Visualized Experiments: JoVE
Amy A Lubik, Mannan Nouri, Sarah Truong, Mazyar Ghaffari, Hans H Adomat, Eva Corey, Michael E Cox, Na Li, Emma S Guns, Parvin Yenki, Steven Pham, Ralph Buttyan
Despite the substantial benefit of androgen deprivation therapy (ADT) for metastatic prostate cancer (mPCa), patients often progress to castration-resistant disease (CRPC) that is more difficult to treat. CRPC is associated with renewed androgen receptor (AR) activity in tumor cells and restoration of tumor androgen levels through acquired intratumoral steroidogenesis (AIS). While prostate cancer (PCa) cells have been shown to have steroidogenic capability in vitro, we previously found that benign prostate stromal cells (PrSCs) can also synthesize testosterone (T) from an adrenal precursor, DHEA, when stimulated with a hedgehog (Hh) pathway agonist, SAG...
September 27, 2016: International Journal of Cancer. Journal International du Cancer
Andriy Marusyk, Doris Tabassum, Michalina Janiszewska, Andrew Place, Anne Trinh, Andrii I Rozhok, Saumyadipta Pyne, Jennifer Guerriero, Shaokun Shu, Muhammad Ekram, Alexander Ishkin, Daniel P Cahill, Yuri Nikolsky, Timothy A Chan, Mothaffar F Rimawi, Susan G Hilsenbeck, Rachel Schiff, C Kent Osborne, Anthony Letai, Kornelia Polyak
Using a 3D co-culture model, we identified significant sub-type-specific changes in gene expression, metabolic, and therapeutic sensitivity profiles of breast cancer cells in contact with cancer-associated fibroblasts (CAFs). CAF-induced gene expression signatures predicted clinical outcome and immune-related differences in the microenvironment. We found that fibroblasts strongly protect carcinoma cells from lapatinib, attributable to its reduced accumulation in carcinoma cells and an elevated apoptotic threshold...
September 26, 2016: Cancer Research
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