10 research outputs found
Remodeling of extracellular matrix by normal and tumor-associated fibroblasts promotes cervical cancer progression
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-
β
1 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
α
6
β
4 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