RhoA knockout fibroblasts lose tumor-inhibitory capacity in vitro and promote tumor growth in vivo

Show full item record



Permalink

http://hdl.handle.net/10138/179114

Citation

Alkasalias , T , Alexeyenko , A , Hennig , K , Danielsson , F , Lebbink , R J , Fielden , M , Turunen , S P , Lehti , K , Kashuba , V , Madapura , H S , Bozoky , B , Lundberg , E , Balland , M , Guven , H , Klein , G , Gad , A K B & Pavlova , T 2017 , ' RhoA knockout fibroblasts lose tumor-inhibitory capacity in vitro and promote tumor growth in vivo ' , Proceedings of the National Academy of Sciences of the United States of America , vol. 114 , no. 8 , pp. E1413-E1421 . https://doi.org/10.1073/pnas.1621161114

Title: RhoA knockout fibroblasts lose tumor-inhibitory capacity in vitro and promote tumor growth in vivo
Author: Alkasalias, Twana; Alexeyenko, Andrey; Hennig, Katharina; Danielsson, Frida; Lebbink, Robert Jan; Fielden, Matthew; Turunen, S. Pauliina; Lehti, Kaisa; Kashuba, Vladimir; Madapura, Harsha S.; Bozoky, Benedek; Lundberg, Emma; Balland, Martial; Guven, Hayrettin; Klein, George; Gad, Annica K. B.; Pavlova, Tatiana
Contributor: University of Helsinki, Research Programs Unit
Date: 2017-02-21
Language: eng
Number of pages: 9
Belongs to series: Proceedings of the National Academy of Sciences of the United States of America
ISSN: 0027-8424
URI: http://hdl.handle.net/10138/179114
Abstract: Fibroblasts are a main player in the tumor-inhibitory microenvironment. Upon tumor initiation and progression, fibroblasts can lose their tumor-inhibitory capacity and promote tumor growth. The molecular mechanisms that underlie this switch have not been defined completely. Previously, we identified four proteins over-expressed in cancer-associated fibroblasts and linked to Rho GTPase signaling. Here, we show that knocking out the Ras homolog family member A (RhoA) gene in normal fibroblasts decreased their tumor-inhibitory capacity, as judged by neighbor suppression in vitro and accompanied by promotion of tumor growth in vivo. This also induced PC3 cancer cell motility and increased colony size in 2D cultures. RhoA knockout in fibroblasts induced vimentin intermediate filament reorganization, accompanied by reduced contractile force and increased stiffness of cells. There was also loss of wide F-actin stress fibers and large focal adhesions. In addition, we observed a significant loss of a-smooth muscle actin, which indicates a difference between RhoA knockout fibroblasts and classic cancer-associated fibroblasts. In 3D collagen matrix, RhoA knockout reduced fibroblast branching and meshwork formation and resulted in more compactly clustered tumor-cell colonies in coculture with PC3 cells, which might boost tumor stem-like properties. Coculturing RhoA knockout fibroblasts and PC3 cells induced expression of proinflammatory genes in both. Inflammatory mediators may induce tumor cell stemness. Network enrichment analysis of transcriptomic changes, however, revealed that the Rho signaling pathway per se was significantly triggered only after coculturing with tumor cells. Taken together, our findings in vivo and in vitro indicate that Rho signaling governs the inhibitory effects by fibroblasts on tumor-cell growth.
Subject: Rho GTPases
RhoA
cancer-associated fibroblasts
tumor-inhibitory capacity
cytoskeleton
CANCER-ASSOCIATED FIBROBLASTS
GENE-SET
CELL
FORCE
PROGRESSION
METASTASIS
MECHANOTRANSDUCTION
MYOFIBROBLASTS
EXPRESSION
ADHESIONS
3111 Biomedicine
Rights:


Files in this item

Total number of downloads: Loading...

Files Size Format View
RhoA_knockout_fibroblasts.pdf 1.653Mb PDF View/Open

This item appears in the following Collection(s)

Show full item record