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


RESULTS
We 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
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.
Forst
Birgitte
B
Department for Molecular Cancer Biology, Danish Cancer Society, Copenhagen, Denmark.
Hansen
Matilde Thye
MT
Klingelhöfer
Jörg
J
Møller
Henrik Devitt
HD
Nielsen
Gitte Helle
GH
Grum-Schwensen
Birgitte
B
Ambartsumian
Noona
N
Lukanidin
Eugene
E
Grigorian
Mariam
M
D000818:Animals; D045744:Cell Line, Tumor; D055252:Cell-Derived Microparticles; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000502:physiology*; D018450:Disease Progression; D005347:Fibroblasts; D008264:Macrophages; D051379:Mice; D018345:Mice, Knockout; D009362:Neoplasm Metastasis / Q000473:pathology*; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000502:physiology*
C503460:Ccl5 protein, mouse; D018946:Chemokine CCL5; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C470944:S100a4 protein, mouse