Metastasis of aggressive amoeboid sarcoma cells is dependent on Rho/ROCK/MLC signaling
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RESEARCH
Open Access
Metastasis of aggressive amoeboid sarcoma cells is dependent on Rho/ROCK/MLC signaling Jan Kosla2†, Daniela Paňková1†, Jiří Plachý2, Ondřej Tolde1, Kristýna Bicanová1, Michal Dvořák2, Daniel Rösel1 and Jan Brábek1*
Abstract Background: Although there is extensive evidence for the amoeboid invasiveness of cancer cells in vitro, much less is known about the role of amoeboid invasiveness in metastasis and the importance of Rho/ROCK/MLC signaling in this process. Results: We analyzed the dependence of amoeboid invasiveness of rat and chicken sarcoma cells and the metastatic activity of chicken cells on individual elements of the Rho/ROCK/MLC pathway. In both animal models, inhibition of Rho, ROCK or MLC resulted in greatly decreased cell invasiveness in vitro, while inhibition of extracellular proteases using a broad spectrum inhibitor did not have a significant effect. The inhibition of both Rho activity and MLC phosphorylation by dominant negative mutants led to a decreased capability of chicken sarcoma cells to metastasize. Moreover, the overexpression of RhoA in non-metastatic chicken cells resulted in the rescue of both invasiveness and metastatic capability. Rho and ROCK, unlike MLC, appeared to be directly involved in the maintenance of the amoeboid phenotype, as their inhibition resulted in the amoeboid-mesenchymal transition in analyzed cell lines. Conclusion: Taken together, these results suggest that protease-independent invasion controlled by elements of the Rho/ROCK/MLC pathway can be frequently exploited by metastatic sarcoma cells. Keywords: Metastasis, Sarcoma, RhoA, ROCK, MLC, Amoeboid invasiveness, 3D environment, Chicken model
Background Cancer metastasis is a multistage process composed of series of phenotypic and biochemical changes, including altered gene expression, angiogenesis, lymphangiogenesis, motility and cell shape [1]. During the first step of metastatic spreading, the malignant tumor cells initiate separation from the primary tumor mass and break contacts with neighboring cells. Then, the tumor cells degrade and penetrate the extracellular matrix and enter the bloodstream or lymphatic system, from where they can exit at a new site and proliferate in secondary organs [2]. The most critical steps in metastasis are the cell migration and cell invasion that are responsible for the malignancy of tumor cells invading the surrounding tissues [3-5]. This is represented by dynamic filamentous * Correspondence: [email protected] † Equal contributors 1 Department of Cell Biology, Faculty of Science, Charles University in Prague, Viničná 7, 12843 Prague 2, Czech Republic Full list of author information is available at the end of the article
actin cytoskeletal remodeling, which enables tumor cells to adhere to the extracellular matrix and generate intracellular forces for cell movement [3-5]. Actin remodeling and the whole process of cell movement are regulated by small GTPases of the Rho family, mainly RhoA, RhoC, cdc42 and Rac [6,7]. Nevertheless the capacity of tumor c
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