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Tumor cell integrin β4 and tumor stroma E-/P-selectin cooperatively regulate tumor growth in vivo

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Tumor cell integrin β4 and tumor stroma E-/P-selectin cooperatively regulate tumor growth in vivo. / Genduso, Sandra; Freytag, Vera; Schetler, Daniela; Kirchner, Lennart; Schiecke, Alina; Maar, Hanna; Wicklein, Daniel; Gebauer, Florian; Bröker, Katharina; Stürken, Christine; Milde-Langosch, Karin; Oliveira-Ferrer, Leticia; Ricklefs, Franz L; Ewald, Florian; Wolters-Eisfeld, Gerrit; Riecken, Kristoffer; Unrau, Ludmilla; Krause, Linda; Bohnenberger, Hanibal; Offermann, Anne; Perner, Sven; Sebens, Susanne; Lamszus, Katrin; Diehl, Linda; Linder, Stefan; Jücker, Manfred; Schumacher, Udo; Lange, Tobias.

In: J HEMATOL ONCOL, Vol. 16, No. 1, 23, 17.03.2023.

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

Harvard

Genduso, S, Freytag, V, Schetler, D, Kirchner, L, Schiecke, A, Maar, H, Wicklein, D, Gebauer, F, Bröker, K, Stürken, C, Milde-Langosch, K, Oliveira-Ferrer, L, Ricklefs, FL, Ewald, F, Wolters-Eisfeld, G, Riecken, K, Unrau, L, Krause, L, Bohnenberger, H, Offermann, A, Perner, S, Sebens, S, Lamszus, K, Diehl, L, Linder, S, Jücker, M, Schumacher, U & Lange, T 2023, 'Tumor cell integrin β4 and tumor stroma E-/P-selectin cooperatively regulate tumor growth in vivo', J HEMATOL ONCOL, vol. 16, no. 1, 23. https://doi.org/10.1186/s13045-023-01413-9

APA

Genduso, S., Freytag, V., Schetler, D., Kirchner, L., Schiecke, A., Maar, H., Wicklein, D., Gebauer, F., Bröker, K., Stürken, C., Milde-Langosch, K., Oliveira-Ferrer, L., Ricklefs, F. L., Ewald, F., Wolters-Eisfeld, G., Riecken, K., Unrau, L., Krause, L., Bohnenberger, H., ... Lange, T. (2023). Tumor cell integrin β4 and tumor stroma E-/P-selectin cooperatively regulate tumor growth in vivo. J HEMATOL ONCOL, 16(1), [23]. https://doi.org/10.1186/s13045-023-01413-9

Vancouver

Genduso S, Freytag V, Schetler D, Kirchner L, Schiecke A, Maar H et al. Tumor cell integrin β4 and tumor stroma E-/P-selectin cooperatively regulate tumor growth in vivo. J HEMATOL ONCOL. 2023 Mar 17;16(1). 23. https://doi.org/10.1186/s13045-023-01413-9

Bibtex

@article{1906a1bdeda5471b97f5295689bbbe10,
title = "Tumor cell integrin β4 and tumor stroma E-/P-selectin cooperatively regulate tumor growth in vivo",
abstract = "BACKGROUND: The immunological composition of the tumor microenvironment has a decisive influence on the biological course of cancer and is therefore of profound clinical relevance. In this study, we analyzed the cooperative effects of integrin β4 (ITGB4) on tumor cells and E-/P-selectin on endothelial cells within the tumor stroma for regulating tumor growth by shaping the local and systemic immune environment.METHODS: We used several preclinical mouse models for different solid human cancer types (xenograft and syngeneic) to explore the role of ITGB4 (shRNA-mediated knockdown in tumor cells) and E-/P-selectins (knockout in mice) for tumor growth; effects on apoptosis, proliferation and intratumoral signaling pathways were determined by histological and biochemical methods and 3D in vitro experiments; changes in the intratumoral and systemic immune cell composition were determined by flow cytometry and immunohistochemistry; chemokine levels and their attracting potential were measured by ELISA and 3D invasion assays.RESULTS: We observed a very robust synergism between ITGB4 and E-/P-selectin for the regulation of tumor growth, accompanied by an increased recruitment of CD11b+ Gr-1Hi cells with low granularity (i.e., myeloid-derived suppressor cells, MDSCs) specifically into ITGB4-depleted tumors. ITGB4-depleted tumors undergo apoptosis and actively attract MDSCs, well-known to promote tumor growth in several cancers, via increased secretion of different chemokines. MDSC trafficking into tumors crucially depends on E-/P-selectin expression. Analyses of clinical samples confirmed an inverse relationship between ITGB4 expression in tumors and number of tumor-infiltrating leukocytes.CONCLUSIONS: These findings suggest a distinct vulnerability of ITGB4Lo tumors for MDSC-directed immunotherapies.",
author = "Sandra Genduso and Vera Freytag and Daniela Schetler and Lennart Kirchner and Alina Schiecke and Hanna Maar and Daniel Wicklein and Florian Gebauer and Katharina Br{\"o}ker and Christine St{\"u}rken and Karin Milde-Langosch and Leticia Oliveira-Ferrer and Ricklefs, {Franz L} and Florian Ewald and Gerrit Wolters-Eisfeld and Kristoffer Riecken and Ludmilla Unrau and Linda Krause and Hanibal Bohnenberger and Anne Offermann and Sven Perner and Susanne Sebens and Katrin Lamszus and Linda Diehl and Stefan Linder and Manfred J{\"u}cker and Udo Schumacher and Tobias Lange",
note = "{\textcopyright} 2023. The Author(s).",
year = "2023",
month = mar,
day = "17",
doi = "10.1186/s13045-023-01413-9",
language = "English",
volume = "16",
journal = "J HEMATOL ONCOL",
issn = "1756-8722",
publisher = "BioMed Central Ltd.",
number = "1",

}

RIS

TY - JOUR

T1 - Tumor cell integrin β4 and tumor stroma E-/P-selectin cooperatively regulate tumor growth in vivo

AU - Genduso, Sandra

AU - Freytag, Vera

AU - Schetler, Daniela

AU - Kirchner, Lennart

AU - Schiecke, Alina

AU - Maar, Hanna

AU - Wicklein, Daniel

AU - Gebauer, Florian

AU - Bröker, Katharina

AU - Stürken, Christine

AU - Milde-Langosch, Karin

AU - Oliveira-Ferrer, Leticia

AU - Ricklefs, Franz L

AU - Ewald, Florian

AU - Wolters-Eisfeld, Gerrit

AU - Riecken, Kristoffer

AU - Unrau, Ludmilla

AU - Krause, Linda

AU - Bohnenberger, Hanibal

AU - Offermann, Anne

AU - Perner, Sven

AU - Sebens, Susanne

AU - Lamszus, Katrin

AU - Diehl, Linda

AU - Linder, Stefan

AU - Jücker, Manfred

AU - Schumacher, Udo

AU - Lange, Tobias

N1 - © 2023. The Author(s).

PY - 2023/3/17

Y1 - 2023/3/17

N2 - BACKGROUND: The immunological composition of the tumor microenvironment has a decisive influence on the biological course of cancer and is therefore of profound clinical relevance. In this study, we analyzed the cooperative effects of integrin β4 (ITGB4) on tumor cells and E-/P-selectin on endothelial cells within the tumor stroma for regulating tumor growth by shaping the local and systemic immune environment.METHODS: We used several preclinical mouse models for different solid human cancer types (xenograft and syngeneic) to explore the role of ITGB4 (shRNA-mediated knockdown in tumor cells) and E-/P-selectins (knockout in mice) for tumor growth; effects on apoptosis, proliferation and intratumoral signaling pathways were determined by histological and biochemical methods and 3D in vitro experiments; changes in the intratumoral and systemic immune cell composition were determined by flow cytometry and immunohistochemistry; chemokine levels and their attracting potential were measured by ELISA and 3D invasion assays.RESULTS: We observed a very robust synergism between ITGB4 and E-/P-selectin for the regulation of tumor growth, accompanied by an increased recruitment of CD11b+ Gr-1Hi cells with low granularity (i.e., myeloid-derived suppressor cells, MDSCs) specifically into ITGB4-depleted tumors. ITGB4-depleted tumors undergo apoptosis and actively attract MDSCs, well-known to promote tumor growth in several cancers, via increased secretion of different chemokines. MDSC trafficking into tumors crucially depends on E-/P-selectin expression. Analyses of clinical samples confirmed an inverse relationship between ITGB4 expression in tumors and number of tumor-infiltrating leukocytes.CONCLUSIONS: These findings suggest a distinct vulnerability of ITGB4Lo tumors for MDSC-directed immunotherapies.

AB - BACKGROUND: The immunological composition of the tumor microenvironment has a decisive influence on the biological course of cancer and is therefore of profound clinical relevance. In this study, we analyzed the cooperative effects of integrin β4 (ITGB4) on tumor cells and E-/P-selectin on endothelial cells within the tumor stroma for regulating tumor growth by shaping the local and systemic immune environment.METHODS: We used several preclinical mouse models for different solid human cancer types (xenograft and syngeneic) to explore the role of ITGB4 (shRNA-mediated knockdown in tumor cells) and E-/P-selectins (knockout in mice) for tumor growth; effects on apoptosis, proliferation and intratumoral signaling pathways were determined by histological and biochemical methods and 3D in vitro experiments; changes in the intratumoral and systemic immune cell composition were determined by flow cytometry and immunohistochemistry; chemokine levels and their attracting potential were measured by ELISA and 3D invasion assays.RESULTS: We observed a very robust synergism between ITGB4 and E-/P-selectin for the regulation of tumor growth, accompanied by an increased recruitment of CD11b+ Gr-1Hi cells with low granularity (i.e., myeloid-derived suppressor cells, MDSCs) specifically into ITGB4-depleted tumors. ITGB4-depleted tumors undergo apoptosis and actively attract MDSCs, well-known to promote tumor growth in several cancers, via increased secretion of different chemokines. MDSC trafficking into tumors crucially depends on E-/P-selectin expression. Analyses of clinical samples confirmed an inverse relationship between ITGB4 expression in tumors and number of tumor-infiltrating leukocytes.CONCLUSIONS: These findings suggest a distinct vulnerability of ITGB4Lo tumors for MDSC-directed immunotherapies.

U2 - 10.1186/s13045-023-01413-9

DO - 10.1186/s13045-023-01413-9

M3 - SCORING: Journal article

C2 - 36932441

VL - 16

JO - J HEMATOL ONCOL

JF - J HEMATOL ONCOL

SN - 1756-8722

IS - 1

M1 - 23

ER -