S100A4-neutralizing antibody suppresses spontaneous tumor progression, pre-metastatic niche formation and alters T-cell polarization balance

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

S100A4-neutralizing antibody suppresses spontaneous tumor progression, pre-metastatic niche formation and alters T-cell polarization balance. / Grum-Schwensen, Birgitte; Klingelhöfer, Jörg; Beck, Mette; Bonefeld, Charlotte Menné; Hamerlik, Petra; Guldberg, Per; Grigorian, Mariam; Lukanidin, Eugene; Ambartsumian, Noona.

In: B M C Cancer, Vol. 15, 44, 2015, p. 1-14.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Grum-Schwensen, B, Klingelhöfer, J, Beck, M, Bonefeld, CM, Hamerlik, P, Guldberg, P, Grigorian, M, Lukanidin, E & Ambartsumian, N 2015, 'S100A4-neutralizing antibody suppresses spontaneous tumor progression, pre-metastatic niche formation and alters T-cell polarization balance', B M C Cancer, vol. 15, 44, pp. 1-14. https://doi.org/10.1186/s12885-015-1034-2

APA

Grum-Schwensen, B., Klingelhöfer, J., Beck, M., Bonefeld, C. M., Hamerlik, P., Guldberg, P., Grigorian, M., Lukanidin, E., & Ambartsumian, N. (2015). S100A4-neutralizing antibody suppresses spontaneous tumor progression, pre-metastatic niche formation and alters T-cell polarization balance. B M C Cancer, 15, 1-14. [44]. https://doi.org/10.1186/s12885-015-1034-2

Vancouver

Grum-Schwensen B, Klingelhöfer J, Beck M, Bonefeld CM, Hamerlik P, Guldberg P et al. S100A4-neutralizing antibody suppresses spontaneous tumor progression, pre-metastatic niche formation and alters T-cell polarization balance. B M C Cancer. 2015;15:1-14. 44. https://doi.org/10.1186/s12885-015-1034-2

Author

Grum-Schwensen, Birgitte ; Klingelhöfer, Jörg ; Beck, Mette ; Bonefeld, Charlotte Menné ; Hamerlik, Petra ; Guldberg, Per ; Grigorian, Mariam ; Lukanidin, Eugene ; Ambartsumian, Noona. / S100A4-neutralizing antibody suppresses spontaneous tumor progression, pre-metastatic niche formation and alters T-cell polarization balance. In: B M C Cancer. 2015 ; Vol. 15. pp. 1-14.

Bibtex

@article{e117b01a9bae45c58f2cdd436cf50493,
title = "S100A4-neutralizing antibody suppresses spontaneous tumor progression, pre-metastatic niche formation and alters T-cell polarization balance",
abstract = "BACKGROUND: The tumor microenvironment plays a determinative role in stimulating tumor progression and metastasis. Notably, tumor-stroma signals affect the pattern of infiltrated immune cells and the profile of tumor-released cytokines. Among the known molecules that are engaged in stimulating the metastatic spread of tumor cells is the S100A4 protein. S100A4 is known as an inducer of inflammatory processes and has been shown to attract T-cells to the primary tumor and to the pre-metastatic niche. The present study aims to examine the immunomodulatory role of S100A4 in vivo and in vitro and assess the mode of action of 6B12, a S100A4 neutralizing antibody.METHODS: The therapeutic effect of the 6B12 antibody was evaluated in two different mouse models. First, in a model of spontaneous breast cancer we assessed the dynamics of tumor growth and metastasis. Second, in a model of metastatic niche formation we determined the expression of metastatic niche markers. The levels of cytokine expression were assessed using antibody as well as PCR arrays and the results confirmed by qRT-PCR and ELISA. T-cell phenotyping and in vitro differentiation analyses were performed by flow cytometry.RESULTS: We show that the S100A4 protein alters the expression of transcription factor and signal transduction pathway genes involved in the T-cell lineage differentiation. T-cells challenged with S100A4 demonstrated reduced proportion of Th1-polarized cells shifting the Th1/Th2 balance towards the Th2 pro-tumorigenic phenotype. The 6B12 antibody restored the Th1/Th2 balance. Furthermore, we provide evidence that the 6B12 antibody deploys its anti-metastatic effect, by suppressing the attraction of T-cells to the site of primary tumor and pre-metastatic niche. This was associated with delayed primary tumor growth, decreased vessel density and inhibition of metastases.CONCLUSION: The S100A4 blocking antibody (6B12) reduces tumor growth and metastasis in a model of spontaneous breast cancer. The 6B12 antibody treatment inhibits T cell accumulation at the primary and pre-metastatic tumor sites. The 6B12 antibody acts as an immunomodulatory agent and thus supports the view that the 6B12 antibody is a promising therapeutic candidate to fight cancer.",
keywords = "Animals, Antibodies, Monoclonal, Antibodies, Neutralizing, Cell Differentiation, Cell Line, Tumor, Cytokines, Disease Models, Animal, Disease Progression, Female, Lymphocyte Activation, Lymphocyte Count, Mice, Mice, Knockout, Neoplasm Metastasis, Neoplasms, S100 Proteins, Signal Transduction, Spleen, T-Lymphocyte Subsets, T-Lymphocytes, Tumor Microenvironment",
author = "Birgitte Grum-Schwensen and J{\"o}rg Klingelh{\"o}fer and Mette Beck and Bonefeld, {Charlotte Menn{\'e}} and Petra Hamerlik and Per Guldberg and Mariam Grigorian and Eugene Lukanidin and Noona Ambartsumian",
year = "2015",
doi = "10.1186/s12885-015-1034-2",
language = "English",
volume = "15",
pages = "1--14",
journal = "B M C Cancer",
issn = "1471-2407",
publisher = "BioMed Central Ltd.",

}

RIS

TY - JOUR

T1 - S100A4-neutralizing antibody suppresses spontaneous tumor progression, pre-metastatic niche formation and alters T-cell polarization balance

AU - Grum-Schwensen, Birgitte

AU - Klingelhöfer, Jörg

AU - Beck, Mette

AU - Bonefeld, Charlotte Menné

AU - Hamerlik, Petra

AU - Guldberg, Per

AU - Grigorian, Mariam

AU - Lukanidin, Eugene

AU - Ambartsumian, Noona

PY - 2015

Y1 - 2015

N2 - BACKGROUND: The tumor microenvironment plays a determinative role in stimulating tumor progression and metastasis. Notably, tumor-stroma signals affect the pattern of infiltrated immune cells and the profile of tumor-released cytokines. Among the known molecules that are engaged in stimulating the metastatic spread of tumor cells is the S100A4 protein. S100A4 is known as an inducer of inflammatory processes and has been shown to attract T-cells to the primary tumor and to the pre-metastatic niche. The present study aims to examine the immunomodulatory role of S100A4 in vivo and in vitro and assess the mode of action of 6B12, a S100A4 neutralizing antibody.METHODS: The therapeutic effect of the 6B12 antibody was evaluated in two different mouse models. First, in a model of spontaneous breast cancer we assessed the dynamics of tumor growth and metastasis. Second, in a model of metastatic niche formation we determined the expression of metastatic niche markers. The levels of cytokine expression were assessed using antibody as well as PCR arrays and the results confirmed by qRT-PCR and ELISA. T-cell phenotyping and in vitro differentiation analyses were performed by flow cytometry.RESULTS: We show that the S100A4 protein alters the expression of transcription factor and signal transduction pathway genes involved in the T-cell lineage differentiation. T-cells challenged with S100A4 demonstrated reduced proportion of Th1-polarized cells shifting the Th1/Th2 balance towards the Th2 pro-tumorigenic phenotype. The 6B12 antibody restored the Th1/Th2 balance. Furthermore, we provide evidence that the 6B12 antibody deploys its anti-metastatic effect, by suppressing the attraction of T-cells to the site of primary tumor and pre-metastatic niche. This was associated with delayed primary tumor growth, decreased vessel density and inhibition of metastases.CONCLUSION: The S100A4 blocking antibody (6B12) reduces tumor growth and metastasis in a model of spontaneous breast cancer. The 6B12 antibody treatment inhibits T cell accumulation at the primary and pre-metastatic tumor sites. The 6B12 antibody acts as an immunomodulatory agent and thus supports the view that the 6B12 antibody is a promising therapeutic candidate to fight cancer.

AB - BACKGROUND: The tumor microenvironment plays a determinative role in stimulating tumor progression and metastasis. Notably, tumor-stroma signals affect the pattern of infiltrated immune cells and the profile of tumor-released cytokines. Among the known molecules that are engaged in stimulating the metastatic spread of tumor cells is the S100A4 protein. S100A4 is known as an inducer of inflammatory processes and has been shown to attract T-cells to the primary tumor and to the pre-metastatic niche. The present study aims to examine the immunomodulatory role of S100A4 in vivo and in vitro and assess the mode of action of 6B12, a S100A4 neutralizing antibody.METHODS: The therapeutic effect of the 6B12 antibody was evaluated in two different mouse models. First, in a model of spontaneous breast cancer we assessed the dynamics of tumor growth and metastasis. Second, in a model of metastatic niche formation we determined the expression of metastatic niche markers. The levels of cytokine expression were assessed using antibody as well as PCR arrays and the results confirmed by qRT-PCR and ELISA. T-cell phenotyping and in vitro differentiation analyses were performed by flow cytometry.RESULTS: We show that the S100A4 protein alters the expression of transcription factor and signal transduction pathway genes involved in the T-cell lineage differentiation. T-cells challenged with S100A4 demonstrated reduced proportion of Th1-polarized cells shifting the Th1/Th2 balance towards the Th2 pro-tumorigenic phenotype. The 6B12 antibody restored the Th1/Th2 balance. Furthermore, we provide evidence that the 6B12 antibody deploys its anti-metastatic effect, by suppressing the attraction of T-cells to the site of primary tumor and pre-metastatic niche. This was associated with delayed primary tumor growth, decreased vessel density and inhibition of metastases.CONCLUSION: The S100A4 blocking antibody (6B12) reduces tumor growth and metastasis in a model of spontaneous breast cancer. The 6B12 antibody treatment inhibits T cell accumulation at the primary and pre-metastatic tumor sites. The 6B12 antibody acts as an immunomodulatory agent and thus supports the view that the 6B12 antibody is a promising therapeutic candidate to fight cancer.

KW - Animals

KW - Antibodies, Monoclonal

KW - Antibodies, Neutralizing

KW - Cell Differentiation

KW - Cell Line, Tumor

KW - Cytokines

KW - Disease Models, Animal

KW - Disease Progression

KW - Female

KW - Lymphocyte Activation

KW - Lymphocyte Count

KW - Mice

KW - Mice, Knockout

KW - Neoplasm Metastasis

KW - Neoplasms

KW - S100 Proteins

KW - Signal Transduction

KW - Spleen

KW - T-Lymphocyte Subsets

KW - T-Lymphocytes

KW - Tumor Microenvironment

U2 - 10.1186/s12885-015-1034-2

DO - 10.1186/s12885-015-1034-2

M3 - Journal article

C2 - 25884510

VL - 15

SP - 1

EP - 14

JO - B M C Cancer

JF - B M C Cancer

SN - 1471-2407

M1 - 44

ER -

ID: 160920857