Metastasis-inducing S100A4 and RANTES cooperate in promoting tumor progression in mice

TY - JOUR

T1 - Metastasis-inducing S100A4 and RANTES cooperate in promoting tumor progression in mice

AU - Forst, Birgitte

AU - Hansen, Matilde Thye

AU - Klingelhöfer, Jörg

AU - Møller, Henrik Devitt

AU - Nielsen, Gitte Helle

AU - Grum-Schwensen, Birgitte

AU - Ambartsumian, Noona

AU - Lukanidin, Eugene

AU - Grigorian, Mariam

PY - 2010

Y1 - 2010

N2 - Background: The 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 Findings: We studied the interplay between the tumor cell-derived cytokine regulated-uponactivation, 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/Significance: Altogether, 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.

AB - Background: The 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 Findings: We studied the interplay between the tumor cell-derived cytokine regulated-uponactivation, 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/Significance: Altogether, 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.

KW - Animals

KW - Cell Line, Tumor

KW - Cell-Derived Microparticles

KW - Cells, Cultured

KW - Chemokine CCL5

KW - Disease Progression

KW - Fibroblasts

KW - Macrophages

KW - Mice

KW - Mice, Knockout

KW - Neoplasm Metastasis

KW - S100 Proteins

U2 - 10.1371/journal.pone.0010374

DO - 10.1371/journal.pone.0010374

M3 - Journal article

C2 - 20442771

SN - 1932-6203

VL - 5

SP - e10374

JO - PLoS Computational Biology

JF - PLoS Computational Biology

IS - 4

ER -