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fibroblast cancer cell secretomes

T Kryza, L M Silva, N Bock, R A Fuhrman-Luck, C R Stephens, J Gao, H Samaratunga, M G Lawrence, J D Hooper, Y Dong, G P Risbridger, J A Clements
The reciprocal communication between cancer cells and their microenvironment is critical in cancer progression. Although involvement of cancer-associated fibroblasts (CAF) in cancer progression is long established, the molecular mechanisms leading to differentiation of CAFs from normal fibroblasts are poorly understood. Here, we report that kallikrein-related peptidase-4 (KLK4) promotes CAF differentiation. KLK4 is highly expressed in prostate epithelial cells of premalignant (prostatic intra-epithelial neoplasia) and malignant lesions compared to normal prostate epithelia, especially at the peri-stromal interface...
May 16, 2017: Molecular Oncology
Benjamin Yaw Owusu, Robert Galemmo, James Janetka, Lidija Klampfer
The tumor microenvironment plays a key role in tumor development and progression. Stromal cells secrete growth factors, cytokines and extracellular matrix proteins which promote growth, survival and metastatic spread of cancer cells. Fibroblasts are the predominant constituent of the tumor stroma and Hepatocyte Growth Factor (HGF), the specific ligand for the tyrosine kinase receptor c-MET, is a major component of their secretome. Indeed, cancer-associated fibroblasts have been shown to promote growth, survival and migration of cancer cells in an HGF-dependent manner...
April 17, 2017: Cancers
Jee San Lee, Jeong Eun Yoo, Haeryoung Kim, Hyungjin Rhee, Myoung Ju Koh, Ji Hae Nahm, Jin Sub Choi, Kee-Ho Lee, Young Nyun Park
Senescence secretome was recently reported to promote liver cancer in an obese mouse model. Steatohepatitic hepatocellular carcinoma (SH-HCC), a new variant of HCC, has been found in metabolic syndrome patients, and pericellular fibrosis, a characteristic feature of SH-HCC, suggests that alteration of the tumor stroma might play an important role in SH-HCC development. Clinicopathological characteristics and tumor stroma showing senescence and senescence-associated secretory phenotype (SASP) were investigated in 21 SH-HCCs and 34 conventional HCCs (C-HCCs)...
2017: PloS One
Juan R Hernandez-Fernaud, Elena Ruengeler, Andrea Casazza, Lisa J Neilson, Ellie Pulleine, Alice Santi, Shehab Ismail, Sergio Lilla, Sandeep Dhayade, Iain R MacPherson, Iain McNeish, Darren Ennis, Hala Ali, Fernanda G Kugeratski, Heba Al Khamici, Maartje van den Biggelaar, Peter V E van den Berghe, Catherine Cloix, Laura McDonald, David Millan, Aoisha Hoyle, Anna Kuchnio, Peter Carmeliet, Stella M Valenzuela, Karen Blyth, Huabing Yin, Massimiliano Mazzone, Jim C Norman, Sara Zanivan
The secretome of cancer and stromal cells generates a microenvironment that contributes to tumour cell invasion and angiogenesis. Here we compare the secretome of human mammary normal and cancer-associated fibroblasts (CAFs). We discover that the chloride intracellular channel protein 3 (CLIC3) is an abundant component of the CAF secretome. Secreted CLIC3 promotes invasive behaviour of endothelial cells to drive angiogenesis and increases invasiveness of cancer cells both in vivo and in 3D cell culture models, and this requires active transglutaminase-2 (TGM2)...
February 15, 2017: Nature Communications
Vida Farsam, Abhijit Basu, Martina Gatzka, Nicolai Treiber, Lars A Schneider, Medhanie A Mulaw, Tanja Lucas, Stefan Kochanek, Reinhard Dummer, Mitchell P Levesque, Meinhard Wlaschek, Karin Scharffetter-Kochanek
Aging is associated with a rising incidence of cutaneous squamous cell carcinoma (cSCC), an aggressive skin cancer with the potential for local invasion and metastasis. Acquisition of a senescence-associated secretory phenotype (SASP) in dermal fibroblasts has been postulated to promote skin cancer progression in elderly individuals. The underlying molecular mechanisms are largely unexplored. We show that Chemerin, a previously unreported SASP factor released from senescent human dermal fibroblasts, promotes cSCC cell migration, a key feature driving tumor progression...
December 13, 2016: Oncotarget
G M Sizemore, S Balakrishnan, A M Hammer, K A Thies, A J Trimboli, J A Wallace, S T Sizemore, R D Kladney, S A Woelke, L Yu, S A Fernandez, A Chakravarti, G Leone, M C Ostrowski
Fibroblasts within the mammary tumor microenvironment are active participants in carcinogenesis mediating both tumor initiation and progression. Our group has previously demonstrated that genetic loss of phosphatase and tensin homolog (PTEN) in mammary fibroblasts induces an oncogenic secretome that remodels the extracellular milieu accelerating ErbB2-driven mammary tumor progression. While these prior studies highlighted a tumor suppressive role for stromal PTEN, how the adjacent normal epithelium transforms in response to PTEN loss was not previously addressed...
April 20, 2017: Oncogene
Aihua Hou, Kai Pong Law, Min Qi Tin, Yoon Pin Lim, Louis Tong
Pterygium is a triangular shaped ocular fibrous surface lesion growing from conjunctiva towards central cornea, causing ocular irritation, astigmatism, and visual disturbance. The condition is characterized by epithelial proliferation, fibrovascular growth, chronic inflammation, and prominent extracellular matrix remodeling. Studies have suggested that aberrant extracellular proteins secreted by fibroblasts lead to abnormal matrix production and tissue invasion contributing to the development of the disease...
December 2016: Experimental Eye Research
David W Greening, Hong Ji, Maoshan Chen, Bruce W S Robinson, Ian M Dick, Jenette Creaney, Richard J Simpson
Malignant mesothelioma (MM) is a highly-aggressive heterogeneous malignancy, typically diagnosed at advanced stage. An important area of mesothelioma biology and progression is understanding intercellular communication and the contribution of the secretome. Exosomes are secreted extracellular vesicles shown to shuttle cellular cargo and direct intercellular communication in the tumour microenvironment, facilitate immunoregulation and metastasis. In this study, quantitative proteomics was used to investigate MM-derived exosomes from distinct human models and identify select cargo protein networks associated with angiogenesis, metastasis, and immunoregulation...
2016: Scientific Reports
Shashi K Gopal, David W Greening, Hong-Jian Zhu, Richard J Simpson, Rommel A Mathias
Epithelial-mesenchymal transition (EMT) enhances the migration and invasion of cancer cells, and is regulated by various molecular mechanisms including extracellular matrix metalloproteinase (MMP) activity. Previously, we reported transformation of epithelial Madin-Darby canine kidney (MDCK) cells with oncogenic H-Ras (21D1 cells) induces EMT, and significantly elevates MMP1 expression. To explore the biological significance, in this study we characterized 21D1 cells with knocked-down MMP1 expression (21D1(-MMP1))...
2016: Scientific Reports
S S Prime, N Cirillo, Y Hassona, D W Lambert, I C Paterson, M Mellone, G J Thomas, E N L James, E K Parkinson
There is now compelling evidence that the tumour stroma plays an important role in the pathogenesis of cancers of epithelial origin. The pre-eminent cell type of the stroma is carcinoma-associated fibroblasts. These cells demonstrate remarkable heterogeneity with activation and senescence being common stress responses. In this review, we summarise the part that these cells play in cancer, particularly oral cancer, and present evidence to show that activation and senescence reflect a unified programme of fibroblast differentiation...
February 2017: Journal of Oral Pathology & Medicine
Siham Moatassim-Billah, Camille Duluc, Rémi Samain, Christine Jean, Aurélie Perraud, Emilie Decaup, Stéphanie Cassant-Sourdy, Youssef Bakri, Janick Selves, Herbert Schmid, Yvan Martineau, Muriel Mathonnet, Stéphane Pyronnet, Corinne Bousquet
Pancreatic ductal adenocarcinoma (PDA) shows a rich stroma where cancer-associated fibroblasts (CAFs) represent the major cell type. CAFs are master secretors of proteins with pro-tumor features. CAF targeting remains a promising challenge for PDA, a devastating disease where treatments focusing on cancer cells have failed. We previously introduced a novel pharmacological CAF-targeting approach using the somatostatin analog SOM230 (pasireotide) that inhibits protein synthesis in CAFs, and subsequent chemoprotective features of CAF secretome...
July 5, 2016: Oncotarget
Robert Büttner, Alexander Berndt, Christina Valkova, Petra Richter, Alexander Korn, Christian Kosan, Claus Liebmann
INTRODUCTION: Receptors of the ErbB family belong to the key players in cancer development and are targets of several therapeutic approaches. Their functional dependency on the tumor microenvironment, especially on CAFs is albeit still poorly understood. Our objective was to investigate the impact of CAF secretome on ErbB receptor expression and signaling behavior in OSCC. METHODS: Stimulation of PE/CA-PJ15 OSCC cells with conditioned media of TGF-β1-activated fibroblasts was used as model system for CAF to cancer cell communication...
February 2017: Journal of Receptor and Signal Transduction Research
Takayuki Ishige, Motoi Nishimura, Mamoru Satoh, Mai Fujimoto, Masaki Fukuyo, Toshihisa Semba, Sayaka Kado, Sachio Tsuchida, Setsu Sawai, Kazuyuki Matsushita, Akira Togawa, Hisahiro Matsubara, Atsushi Kaneda, Fumio Nomura
Gastric cancer is classified into two subtypes, diffuse and intestinal. The diffuse-type gastric cancer (DGC) has poorer prognosis, and the molecular pathology is not yet fully understood. The purpose of this study was to identify functional secreted molecules involved in DGC progression. We integrated the secretomics of six gastric cancer cell lines and gene expression analysis of gastric cancer tissues with publicly available microarray data. Hierarchical clustering revealed characteristic gene expression differences between diffuse- and intestinal-types...
February 19, 2016: Scientific Reports
Ming Ding, Richard K Bruick, Yonghao Yu
The PI(3)K-Akt-mTORC1 pathway is a highly dynamic network that is balanced and stabilized by a number of feedback inhibition loops. Specifically, activation of mTORC1 has been shown to lead to the inhibition of its upstream growth factor signalling. Activation of the growth factor receptors is triggered by the binding of their cognate ligands in the extracellular space. However, whether secreted proteins contribute to the mTORC1-dependent feedback loops remains unclear. We found that cells with hyperactive mTORC1 secrete a protein that potently inhibits the function of IGF-1...
March 2016: Nature Cell Biology
Elizabete Bagordakis, Iris Sawazaki-Calone, Carolina Carneiro Soares Macedo, Carolina M Carnielli, Carine Ervolino de Oliveira, Priscila Campioni Rodrigues, Ana Lucia C A Rangel, Jean Nunes Dos Santos, Juha Risteli, Edgard Graner, Tuula Salo, Adriana Franco Paes Leme, Ricardo D Coletta
An important role has been attributed to cancer-associated fibroblasts (CAFs) in the tumorigenesis of oral squamous cell carcinoma (OSCC), the most common tumor of the oral cavity. Previous studies demonstrated that CAF-secreted molecules promote the proliferation and invasion of OSCC cells, inducing a more aggressive phenotype. In this study, we searched for differences in the secretome of CAFs and normal oral fibroblasts (NOF) using mass spectrometry-based proteomics and biological network analysis. Comparison of the secretome profiles revealed that upregulated proteins involved mainly in extracellular matrix organization and disassembly and collagen metabolism...
July 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
M M Koczorowska, S Tholen, F Bucher, L Lutz, J N Kizhakkedathu, O De Wever, U F Wellner, M L Biniossek, A Stahl, S Lassmann, O Schilling
Cancer associated fibroblasts (CAFs) constitute an abundant stromal component of most solid tumors. Fibroblast activation protein (FAP) α is a cell surface protease that is expressed by CAFs. We corroborate this expression profile by immunohistochemical analysis of colorectal cancer specimens. To better understand the tumor-contextual role of FAPα, we investigate how FAPα shapes functional and proteomic features of CAFs using loss- and gain-of function cellular model systems. FAPα activity has a strong impact on the secreted CAF proteome ("secretome"), including reduced levels of anti-angiogenic factors, elevated levels of transforming growth factor (TGF) β, and an impact on matrix processing enzymes...
January 2016: Molecular Oncology
Sun-Xia Chen, Xiao-En Xu, Xiao-Qing Wang, Shu-Jian Cui, Lei-Lei Xu, Ying-Hua Jiang, Yang Zhang, Hai-Bo Yan, Qian Zhang, Jie Qiao, Peng-Yuan Yang, Feng Liu
The tumor cell proliferation, migration and invasion were influenced by the interaction between the cancer cells and their microenvironment. In current study, we established two pairs of the primary fibroblast cultures from colorectal adenocarcinoma tissues and the normal counterparts and identified 227 proteins in the colonic fibroblast secretomes; half of these proteins were novel. The mass spectrometry data and analyzed results presented here provide novel insights into the molecular characteristics and modulatory role of colon cancer associated fibroblasts...
December 2014: Data in Brief
Camille Duluc, Siham Moatassim-Billah, Mounira Chalabi-Dchar, Aurélie Perraud, Rémi Samain, Florence Breibach, Marion Gayral, Pierre Cordelier, Marie-Bernadette Delisle, Marie-Pierre Bousquet-Dubouch, Richard Tomasini, Herbert Schmid, Muriel Mathonnet, Stéphane Pyronnet, Yvan Martineau, Corinne Bousquet
Pancreatic ductal adenocarcinoma (PDAC) is extremely stroma-rich. Cancer-associated fibroblasts (CAFs) secrete proteins that activate survival and promote chemoresistance of cancer cells. Our results demonstrate that CAF secretome-triggered chemoresistance is abolished upon inhibition of the protein synthesis mTOR/4E-BP1 regulatory pathway which we found highly activated in primary cultures of α-SMA-positive CAFs, isolated from human PDAC resections. CAFs selectively express the sst1 somatostatin receptor...
June 2015: EMBO Molecular Medicine
Ridwana Chowdhury, Jason P Webber, Mark Gurney, Malcolm D Mason, Zsuzsanna Tabi, Aled Clayton
Stromal fibroblasts become altered in response to solid cancers, to exhibit myofibroblastic characteristics, with disease promoting influence. Infiltrating mesenchymal stem cells (MSC) may contribute towards these changes, but the factors secreted by cancer cells that impact MSC differentiation are poorly understood. We investigated the role of nano-metre sized vesicles (exosomes), secreted by prostate cancer cells, on the differentiation of bone-marrow MSC (BM-MSC), and the subsequent functional consequences of such changes...
January 20, 2015: Oncotarget
Mieke Van Bockstal, Kathleen Lambein, Mireille Van Gele, Elly De Vlieghere, Ridha Limame, Geert Braems, Rudy Van den Broecke, Veronique Cocquyt, Hannelore Denys, Marc Bracke, Louis Libbrecht, Olivier De Wever
Cancer progression is characterized by a complex reciprocity between neoplastic epithelium and adjacent stromal cells. In ductal carcinoma in situ (DCIS) of the breast, both reduced stromal decorin expression and myxoid stroma are correlated with increased recurrence risk. In this study, we aimed to investigate paracrine regulation of expression of decorin and related extracellular matrix (ECM) proteins in cancer-associated fibroblasts (CAFs). Transforming growth factor-β1 (TGF-β1) was identified as a competent ECM modulator, as it reduced decorin and strongly enhanced versican, biglycan and type I collagen expression...
2014: Oncoscience
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