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Metastasis-promoting S100A4 and RANTES interplay in tumor microenvironment

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The local microenvironment around tumor cells can be an active participant of tumor progression and metastasis.

An active role of metastasis-promoting S100A4, a small Ca2+-binding protein of the S100 protein family, in tumor and stroma cells interplay has been convincingly demonstrated in vitro and invivo models. Up- regulation of S100A4 expression in stroma cells (fibroblasts, immune and vascular cells) has been shown in mouse tumor models and human breast cancer biopsies. Moreover, we found that certain metastatic versus to non-metastatic tumor cells produce factors which stimulate release of S100A4 from the fibroblasts and immune cells in culture. In turn the extracellular S100A4 is able to confer pro-metastatic features on tumor cells (activation of MMPs, remodelling of cytoskeleton, modulation of transcription factors). Aim.

To identify and characterize tumor-derived factor(s) stimulating metastasis-inducing S100A4 in tumor microenvironment. Results.

Using cytokine antibody microarray we compared cytokine patterns in the conditioned medium from VMR (metastatic) and CSLM-0 (non-metastatic) cells. A Number of cytokines were found differentially produced in these cell lines. Studies on selected cytokines revealed effect of CC chemokine RANTES (CCL5) on increase of S100A4 level release from cultured fibroblasts. Moreover, using Quantitative real time RT-PCR (qPCR) we found transcriptional activation (15 times) of S100A4 in VMR cells, but not in CSML-0. We observed that antibodies against RANTES added to the condition medium of VMR cells abolish activation of S100A4 secretion.

We investigated the mechanisms of S100A4 secretion and found thatS100A4 is released from the cells not via conventional, Golgi-associated pathway but rather by membrane blebbing.

Additionally, we demonstrated that there are reciprocal effects between S100A4 and RANTES. Thus, we found transcriptional activation of RANTES in VMR cells in response to the recombinant S100A4 protein (150 times) by qPCR.

We will discuss the role of S100A4/RANTES circuit in tumor microenvironment and its significance for tumor progression and metastases.
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Document Type: Abstract

Affiliations: 1: Biomedicinsk Institut, Panum, Blegdamsvej 3, 2200 Kbh N 2: Afdeling for Molekylær Kræftbiologi, Kræftens Bekæmpelse, Strandboulevarden 49, 2100 København Ø

Publication date: May 1, 2008

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