The Notch and TGF-β Signaling Pathways Contribute to the Aggressiveness of Clear Cell Renal Cell Carcinoma

Jonas Sjölund,Anna-Karin Boström,Börje Ljungberg,Erik Fredlund,Martin Johansson,Håkan Axelson,Sugata Manna,Aristidis Moustakas,David Lindgren,Andrew Yeudall

doi:10.1371/journal.pone.0023057

Jonas Sjölund, Anna-Karin Boström + Show 8 more

Open Access

https://doi.org/10.1371/journal.pone.0023057

Copy DOI

Abstract

BackgroundDespite recent progress, therapy for metastatic clear cell renal cell carcinoma (CCRCC) is still inadequate. Dysregulated Notch signaling in CCRCC contributes to tumor growth, but the full spectrum of downstream processes regulated by Notch in this tumor form is unknown.Methodology/Principal FindingsWe show that inhibition of endogenous Notch signaling modulates TGF-β dependent gene regulation in CCRCC cells. Analysis of gene expression data representing 176 CCRCCs showed that elevated TGF-β pathway activity correlated significantly with shortened disease specific survival (log-rank test, p = 0.006) and patients with metastatic disease showed a significantly elevated TGF-β signaling activity (two-sided Student's t-test, p = 0.044). Inhibition of Notch signaling led to attenuation of both basal and TGF-β1 induced TGF-β signaling in CCRCC cells, including an extensive set of genes known to be involved in migration and invasion. Functional analyses revealed that Notch inhibition decreased the migratory and invasive capacity of CCRCC cells.ConclusionAn extensive cross-talk between the Notch and TGF-β signaling cascades is present in CCRCC and the functional properties of these two pathways are associated with the aggressiveness of this disease.

Highlights

Clear cell renal cell carcinoma (CCRCC) is the most common malignancy of the kidney [1]
An extensive cross-talk between the Notch and TGF-b signaling cascades is present in clear cell renal cell carcinoma (CCRCC) and the functional properties of these two pathways are associated with the aggressiveness of this disease
Our previous work established that active Notch signaling is an inherent property of CCRCC cells [8]

Summary

Introduction

Clear cell renal cell carcinoma (CCRCC) is the most common malignancy of the kidney [1]. About a quarter of the CCRCC patients have metastatic disease at the time of diagnosis and eventually one-third of the patients presented with localized tumors at diagnosis relapse. Despite recent advances using multikinase inhibitors, disseminated CCRCC remains inherently treatment resistant [2]. Studies leading to a better understanding of the factors that determines the metastatic phenotype of CCRCC are warranted [3]. Dysregulated Notch signaling has been implicated in a wide variety of pathological conditions, including cancer [5]. Therapy for metastatic clear cell renal cell carcinoma (CCRCC) is still inadequate. Dysregulated Notch signaling in CCRCC contributes to tumor growth, but the full spectrum of downstream processes regulated by Notch in this tumor form is unknown

Methods

Results

Conclusion