Interaction of extracellular S100A4 with RAGE prompts prometastatic activation of A375 melanoma cells

Abstract

S100A4, a member of the S100 protein family of EF‐hand calcium‐binding proteins, is overexpressed in various tumour entities, including melanoma, and plays an important role in tumour progression. Several studies in epithelial and mesenchymal tumours revealed a correlation between extracellular S100A4 and metastasis. However, exact mechanisms how S100A4 stimulates metastasis in melanoma are still unknown. From a pilot experiment on baseline synthesis and secretion of S100A4 in human melanoma cell lines, which are in broad laboratory use, A375 wild‐type cells and, additionally, newly generated A375 cell lines stably transfected with human S100A4 (A375‐hS100A4) or human receptor for advanced glycation endproducts (A375‐hRAGE), were selected to investigate the influence of extracellular S100A4 on cell motility, adhesion, migration and invasion in more detail. We demonstrated that A375 cells actively secrete S100A4 in the extracellular space via an endoplasmic reticulum‐Golgi‐dependent pathway. S100A4 overexpression and secretion resulted in prometastatic activation of A375 cells. Moreover, we determined the influence of S100A4‐RAGE interaction and its blockade on A375, A375‐hS100A4, A375‐hRAGE cells, and showed that interaction of RAGE with extracellular S100A4 contributes to the observed activation of A375 cells. This investigation reveals additional molecular targets for therapeutic approaches aiming at blockade of ligand binding to RAGE or RAGE signalling to inhibit melanoma metastasis.

Melanoma Brain Metastasis: Mechanisms, Models, and Medicine

“…Recently, Herwig et al demonstrated a role for high levels of extracellular S100A4, a member of the S100 calcium-binding protein family, in decreasing inter-endothelial tight junction integrity by using A375 human melanoma cells and an in vitro BBB model [ 54 , 55 ]. Paracrine-mediated signaling of S100A4 secreted from melanoma cells with its cognate receptor, receptor for advanced glycation end-products (RAGE), on endothelial cells enabled transmigration.…”

Biomarkers in Malignant Melanoma: Recent Trends and Critical Perspective

“…S100A4, also called metastasis-associated protein, is universally overexpressed in a variety of tumor entities and is an independent marker for tumor progression, invasion, metastasis, poor survival, and prognosis (1). S100A4 influences cell motility, inflammation, angiogenesis, and apoptosis due to interaction between tumor cells and their microenvironment (59)(60)(61)(62)(63)(64). However, extracellular S100A4 seems to be of major importance in this context and, therefore, may possibly serve as a blood marker.…”

“…Because of the RAGE expression in melanocytes and melanoma cells, calprotectin seems to be an activator in these cells and it is a potential target for intervention in melanomagenesis (69). The latter should also be considered regarding interaction of S100A4 with RAGE (61,62). Another study presented evidence for S100A8/A9 as a novel predictive marker for ipilimumab treatment of metastatic Stage IV melanoma patients.…”

A melanoma és az agyi áttétképződés molekuláris háttere

“…Az extracelluláris S100A4 (S100 kalciumkötő protein A4) molekula emelkedett szintje csökkenti a tight junction integritását humán melanomasejtekben [51]. A melanomasejtek S100A4 fehérjét választanak ki, amely parakrin módon kötődik receptorához.…”