Remodeling of extracellular matrix by normal and tumor-associated fibroblasts promotes cervical cancer progression

Alexandra Fullár, József Dudás, Lászlóné Oláh, Péter Hollósi, Z. Papp, G. Sobel, Katalin Karászi, S. Paku, Kornélia Baghy, I. Kovalszky

Research output: Contribution to journalArticle

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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. 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.

Original languageEnglish
Article number256
JournalBMC Cancer
Volume15
Issue number1
DOIs
Publication statusPublished - Apr 11 2015

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Uterine Cervical Neoplasms
Extracellular Matrix
Fibroblasts
Laminin
Integrins
Peptide Hydrolases
Coculture Techniques
Vitronectin Receptors
Neoplasms
Fibronectin Receptors
Laminin Receptors
Osteopontin
Cancer-Associated Fibroblasts
Fibronectins
Basement Membrane
Cervix Uteri
Glycoproteins
Collagen
Immunohistochemistry
Cell Proliferation

Keywords

  • Cancer associated fibroblasts
  • Cervical cancer
  • Extracellular matrix remodeling
  • Integrins
  • Laminin-1
  • Stromal fibroblasts

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Genetics

Cite this

Remodeling of extracellular matrix by normal and tumor-associated fibroblasts promotes cervical cancer progression. / Fullár, Alexandra; Dudás, József; Oláh, Lászlóné; Hollósi, Péter; Papp, Z.; Sobel, G.; Karászi, Katalin; Paku, S.; Baghy, Kornélia; Kovalszky, I.

In: BMC Cancer, Vol. 15, No. 1, 256, 11.04.2015.

Research output: Contribution to journalArticle

Fullár, Alexandra ; Dudás, József ; Oláh, Lászlóné ; Hollósi, Péter ; Papp, Z. ; Sobel, G. ; Karászi, Katalin ; Paku, S. ; Baghy, Kornélia ; Kovalszky, I. / Remodeling of extracellular matrix by normal and tumor-associated fibroblasts promotes cervical cancer progression. In: BMC Cancer. 2015 ; Vol. 15, No. 1.
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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. 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.",
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AU - Fullár, Alexandra

AU - Dudás, József

AU - Oláh, Lászlóné

AU - Hollósi, Péter

AU - Papp, Z.

AU - Sobel, G.

AU - Karászi, Katalin

AU - Paku, S.

AU - Baghy, Kornélia

AU - Kovalszky, I.

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AB - 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. 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.

KW - Cancer associated fibroblasts

KW - Cervical cancer

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KW - Integrins

KW - Laminin-1

KW - Stromal fibroblasts

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