Abstract
BackgroundThe tumor microenvironment has been described as a critical milieu determining tumor growth and metastases. A pivotal role of metastasis-inducing S100A4 in the development of tumor stroma has been proven in animal models and verified in human breast cancer biopsies. Expression and release of S100A4 has been shown in various types of stroma composing cells, including fibroblasts and immune cells. However, the events implicated in upstream and downstream pathways regulating the activity of the extracellular S100A4 protein in the tumor milieu remain unsolved.Methodology/Principal FindingsWe studied the interplay between the tumor cell-derived cytokine regulated-upon-activation, normal T-cell expressed and secreted (RANTES; CCL5) and S100A4 which were shown to be critical factors in tumor progression. We found that RANTES stimulates the externalization of S100A4 via microparticle shedding from the plasma membrane of tumor and stroma cells. Conversely, the released S100A4 protein induces the upregulation of fibronectin (FN) in fibroblasts and a number of cytokines, including RANTES in tumor cells as well as stimulates cell motility in a wound healing assay. Importantly, using wild type and S100A4-deficient mouse models, we demonstrated a substantial influence of tumor cell-derived RANTES on S100A4 release into blood circulation which ultimately increases the metastatic burden in mice.Conclusions/SignificanceAltogether, the data presented strongly validate the pro-metastatic function of S100A4 in the tumor microenvironment and define how the tumor cell-derived cytokine RANTES acts as a critical regulator of S100A4-dependent tumor cell dissemination. Additionally, for the first time we demonstrated the mechanism of S100A4 release associated with plasma membrane microparticle shedding from various cells types.
Highlights
Over the past decade, the intriguing model of tumor development emerged based on the concept that throughout the entire process of cancer etiology, progression, and metastasis, the tumor microenvironment could be an active participant
Identification of cytokines specific for metastatic vs nonmetastatic tumor cells We previously suggested the existence of soluble tumor cellderived factor(s) which induces the stimulation of S100A4 externalization from different tumor stroma cells [7]
We found RANTES/CCL5, MIP-1c/CCL9, VEGF, p-Selectin, IGFBP3, IGFBP-5, sTNFR1, G-CSF, and CXCL-16 as the most prominently expressed VMR-specific cytokines (Fig. 1A), whereas MIP-2/CXCL-2 appeared to be the only cytokine differentially expressed in CSML0 and was not detected in VMR-conditioned media (CM) (Fig. 1A)
Summary
The intriguing model of tumor development emerged based on the concept that throughout the entire process of cancer etiology, progression, and metastasis, the tumor microenvironment could be an active participant. The production and release of these factors implicate both tumor and various types of physiologically altered stroma cells, such as fibroblasts and immune and vasculature composing cells [1,2,3]. A pivotal role of metastasis-inducing S100A4 in the development of tumor stroma has been proven in animal models and verified in human breast cancer biopsies. Expression and release of S100A4 has been shown in various types of stroma composing cells, including fibroblasts and immune cells. The events implicated in upstream and downstream pathways regulating the activity of the extracellular S100A4 protein in the tumor milieu remain unsolved
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