Purchase this article with an account.
Ioana Fugaru, Julie Bérubé, Narjes Babchia, Cédric Coulouarn, Frédéric Mouriaux, Solange Landreville; Uncovering the Mechanisms Behind Hepatic Microenvironment Remodeling in Metastatic Uveal Melanoma. Invest. Ophthalmol. Vis. Sci. 2017;58(8):3968.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
50% of uveal melanoma (UM) patients develop liver metastases by 10 years after the diagnosis of the primary tumor. Powerful prognostic tools help determine the likelihood of metastatic progression, however, no cure is currently available for patients with metastatic disease. Activated hepatic stellate cells (HSCs) are involved in hepatic fibrosis during the metastatic progression of colorectal and pancreatic cancers; yet their role in the metastatic progression of UM remains elusive. We postulate that HSCs enable metastatic UM cells (UMCs) to exit dormancy and enter a proliferative state by secreting cytokines and growth factors and by remodeling the hepatic extracellular matrix (ECM). Our research project aims to develop both 2D and 3D models to investigate ECM remodeling processes and bilateral interactions between HSCs and UMCs.
Matrix sheets were synthetized by HSCs using the self-assembly approach of tissue engineering. UMCs were embedded into the 3D hepatic stromas and matrix proteins were analyzed by confocal microscopy. In addition, migration tests, cytokine proteome profiling, and gene profiling were performed in order to study the bilateral interactions between HSCs and primary or metastatic UMCs.
We demonstrated that UMCs altered the ECM architecture of reconstructed HSC stromas. We observed a significant increase of transcripts/proteins associated to matrix remodeling such as fibronectin, lysyl oxidase like 4, chitinase 3 like 1 and plasminogen activator urokinase receptor in samples derived from HSCs co-cultured with metastatic UMCs. In HSCs/UMCs co-cultures, cell migration was faster and the secretome showed an increase of pro-tumoral cytokines, such as VEGF and GDF-15.
Co-culturing HSCs with metastatic UMCs resulted in ECM remodeling and increased secretion of pro-inflammatory, pro-angiogenic and pro-invasive cytokines. Our project aims to identify molecules involved in the development of a permissive metastatic microenvironment in the liver. By targeting components of the stromal response of HSCs, we might maintain liver micrometastases in permanent dormancy and have a major impact on patient survival.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
This PDF is available to Subscribers Only