Abstract
The therapy of advanced renal cell carcinoma (RCC) is still a major challenge. To intervene therapeutically a deeper comprehension of the particular steps of metastasis is necessary. In this context membrane bound receptors like integrins play a decisive role. We analyzed the integrin α5 expression in 141 clear cell RCC patients by Western blot. Patients with RCC expressed a significant higher level of integrin α5 in tumor than in normal tissue. The integrin α5 expression correlated with tumor grade, the development of distant metastases within five years after tumor nephrectomy and reduced survival. The RCC cell lines Caki-1 and CCF-RC1, which highly express integrin α5, were treated with fibronectin in combination with or without an inhibiting anti-integrin α5 antibody. Afterwards the migration, adhesion, viability and prominent signaling molecules were analyzed. Both cell lines showed a significant reduced migration potential as well as a decreased adhesion potential to fibronectin after treatment with an integrin α5 blocking antibody. A contribution of the AKT and ERK1/2 signaling pathways could be demonstrated. The results indicate integrin α5 as a potent marker to discriminate patients’ tumor prognosis. Consequently the integrin subunit α5 can be considered as a target for individual therapy of advanced RCC.
Highlights
Integrins are a major family of transmembrane heterodimer glycoproteins
The 24 integrin receptors are composed of one of the 18 alpha and one of the 8 beta subunits, each subunit with an extracellular domain, a transmembrane region and a short cytoplasmic tail [3]. Most integrins bind their ligands via the arginine-glycine-aspartic acid (RDG) sequence and recruit different signaling kinases like the focal adhesion kinase (FAK) or SRC (Rous sarcoma oncogene cellular homologue) homology 2 containingprotein (SHC), activate pathways like the mitogen activated protein kinase (MAPK) signaling cascade or the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/ AKT8 virus oncogene cellular homolog (AKT) signaling cascade and as a result regulate cellular processes [4, 5]
The protein level of integrin α5 subunit was determined in renal cell carcinoma (RCC) tumors of a cohort of 141 patients with clear cell RCC
Summary
Integrins are a major family of transmembrane heterodimer glycoproteins They mediate several focal adhesion contacts between cells and extracellular matrix (ECM) components, inducing cell processes like migration, adhesion, proliferation and apoptosis [1, 2]. In colon carcinoma and basal-like breast cancer increased integrin α5 is associated with tumor progression and metastasis [6,7,8]. One explanatory approach for the effects of the invasive role of this subunit is its ability to modulate several matrix metalloproteinases (MMP) [13, 14] Another factor, angiopoetin-2, is capable to trigger the integrin α5 expression, leading to increased adhesion and migration of breast cancer cells [15]. In the presented study we analyzed the expression of integrin α5 in a cohort of RCC patients and subsequently investigated its role in important cellular processes of metastasis in vitro
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