title: Remodeling of extracellular matrix by normal and tumor-associated fibroblasts promotes cervical cancer progression.
abstract: BACKGROUND
  Comparison of tissue microarray results of 29 cervical cancer and 27 normal cervix tissue samples using immunohistochemistry revealed considerable reorganization of the fibrillar stroma of these tumors. Preliminary densitometry analysis of laminin-1, α-smooth muscle actin (SMA) and fibronectin immunostaining demonstrated 3.8-fold upregulation of laminin-1 and 5.2-fold increase of SMA in the interstitial stroma, indicating that these proteins and the activated fibroblasts play important role in the pathogenesis of cervical cancer. In the present work we investigated the role of normal and tumor-associated fibroblasts.
  
  
  METHODS
  In vitro models were used to throw light on the multifactorial process of tumor-stroma interaction, by means of studying the cooperation between tumor cells and fibroblasts. Fibroblasts from normal cervix and cervical cancers were grown either separately or in co-culture with CSCC7 cervical cancer cell line. Changes manifest in secreted glycoproteins, integrins and matrix metallo-proteases (MMPs) were explored.
  
  
  RESULTS
  While normal fibroblasts produced components of interstitial matrix and TGF-β1 that promoted cell proliferation, cancer-associated fibroblasts (CAFs) synthesized ample amounts of laminin-1. The following results support the significance of laminin-1 in the invasion of CSCC7 cells: 1.) Tumor-associated fibroblasts produced more laminin-1 and less components of fibrillar ECM than normal cells; 2.) The production of laminin chains was further increased when CSCC7 cells were grown in co-culture with fibroblasts; 3.) CSCC7 cells were capable of increasing their laminin production; 4.) Tumor cells predominantly expressed integrin α6β4 laminin receptors and migrated towards laminin. The integrin profile of both normal and tumor-associated fibroblasts was similar, expressing receptors for fibronectin, vitronectin and osteopontin. MMP-7 secreted by CSCC7 cells was upregulated by the presence of normal fibroblasts, whereas MMP-2 produced mainly by fibroblasts was activated in the presence of CSCC7 cells.
  
  
  CONCLUSIONS
  Our results indicate that in addition to degradation of the basement membrane, invasion of cervical cancer is accomplished by the remodeling of the interstitial stroma, which process includes decrease and partial replacement of fibronectin and collagens by a laminin-rich matrix.
authors.affiliation: 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary. fullarsz@gmail.com.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Fullár
authors.affiliation: Department of Otorhinolaryngology, Medical University Innsbruck, Innsbruck, Austria. jozsef.dudas@i-med.ac.at.
authors.forename: József
authors.initials: J
authors.lastname: Dudás
authors.affiliation: 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary. julcsi@korb1.sote.hu.
authors.forename: Lászlóné
authors.initials: L
authors.lastname: Oláh
authors.affiliation: 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary. phollosi@yahoo.com.|Tumor Progression Research Group, Hungarian Academy of Sciences, Budapest, Hungary. phollosi@yahoo.com.
authors.forename: Péter
authors.initials: P
authors.lastname: Hollósi
authors.affiliation: Maternity Private Department Kútvölgyi Clinical Block, Semmelweis University, Budapest, Hungary. maternity@maternity.hu.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Papp
authors.affiliation: 2nd Department of Obstetrics and Gynecology, Semmelweis University, Budapest, Hungary. gabor@sobel.hu.
authors.forename: Gábor
authors.initials: G
authors.lastname: Sobel
authors.affiliation: CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK. katalin.karaszi@nds.ox.ac.uk.
authors.forename: Katalin
authors.initials: K
authors.lastname: Karászi
authors.affiliation: 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary. paku@korb1.sote.hu.|Tumor Progression Research Group, Hungarian Academy of Sciences, Budapest, Hungary. paku@korb1.sote.hu.
authors.forename: Sándor
authors.initials: S
authors.lastname: Paku
authors.affiliation: 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary. kori@korb1.sote.hu.
authors.forename: Kornélia
authors.initials: K
authors.lastname: Baghy
authors.affiliation: 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary. koval@korb1.sote.hu.
authors.forename: Ilona
authors.initials: I
authors.lastname: Kovalszky
mesh_terms: D000199:Actins / Q000096:biosynthesis / Q000235:genetics; D000328:Adult; D000368:Aged; D001485:Basement Membrane / Q000378:metabolism / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics; D018920:Coculture Techniques; D005109:Extracellular Matrix / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005353:Fibronectins / Q000096:biosynthesis* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016023:Integrins / Q000096:biosynthesis / Q000235:genetics; D007797:Laminin / Q000096:biosynthesis* / Q000235:genetics; D008875:Middle Aged; D046888:Tissue Array Analysis; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis* / Q000235:genetics; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D000199:Actins; D005353:Fibronectins; D016023:Integrins; D007797:Laminin; D053773:Transforming Growth Factor beta1; C121346:laminin 1