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Cancer associated fibroblasts induce proliferation and therapeutic resistance to everolimus in neuroendocrine tumors through STAT3 activation

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Cancer associated fibroblasts induce proliferation and therapeutic resistance to everolimus in neuroendocrine tumors through STAT3 activation. / Amin, Tania; Viol, Fabrice; Krause, Jenny; Fahl, Martina; Eggers, Corinna; Awwad, Fayez; Schmidt, Benjamin; Benten, Daniel; Ungefroren, Hendrik; Fraune, Christoph; Clauditz, Till S; Sauter, Guido; Izbicki, Jakob R; Lohse, Ansgar W; Huber, Samuel; Schrader, Jörg.

In: NEUROENDOCRINOLOGY, Vol. 113, No. 5, 2023, p. 501-518.

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

Harvard

Amin, T, Viol, F, Krause, J, Fahl, M, Eggers, C, Awwad, F, Schmidt, B, Benten, D, Ungefroren, H, Fraune, C, Clauditz, TS, Sauter, G, Izbicki, JR, Lohse, AW, Huber, S & Schrader, J 2023, 'Cancer associated fibroblasts induce proliferation and therapeutic resistance to everolimus in neuroendocrine tumors through STAT3 activation', NEUROENDOCRINOLOGY, vol. 113, no. 5, pp. 501-518. https://doi.org/10.1159/000528539

APA

Amin, T., Viol, F., Krause, J., Fahl, M., Eggers, C., Awwad, F., Schmidt, B., Benten, D., Ungefroren, H., Fraune, C., Clauditz, T. S., Sauter, G., Izbicki, J. R., Lohse, A. W., Huber, S., & Schrader, J. (2023). Cancer associated fibroblasts induce proliferation and therapeutic resistance to everolimus in neuroendocrine tumors through STAT3 activation. NEUROENDOCRINOLOGY, 113(5), 501-518. https://doi.org/10.1159/000528539

Vancouver

Amin T, Viol F, Krause J, Fahl M, Eggers C, Awwad F et al. Cancer associated fibroblasts induce proliferation and therapeutic resistance to everolimus in neuroendocrine tumors through STAT3 activation. NEUROENDOCRINOLOGY. 2023;113(5):501-518. https://doi.org/10.1159/000528539

Bibtex

@article{2c7dba6a024e4bc3bd2f361c304ef9e3,
title = "Cancer associated fibroblasts induce proliferation and therapeutic resistance to everolimus in neuroendocrine tumors through STAT3 activation",
abstract = "INTRODUCTION: Cancer-associated fibroblasts (CAF) have been identified as relevant contributors to cancer progression and drug resistance in many tumors. Although neuroendocrine tumors (NET) are often associated with a strong stromal reaction, no study has addressed whether CAF are involved in progression and therapeutic resistance in NET. The aim of this study was to characterize the role of CAF in NET.METHODS: We established primary CAF cultures derived from NET liver metastases to study the effect on NET cell lines NT-3 and BON. Immunohistochemistry was performed on tissue sections of primary and metastatic NET tissue.RESULTS: Immunohistochemistry identified CAF dispersed in between tumor cells and within fibrotic bands separating tumor cell clusters in NET. Stimulating NET cells with CAF decreased expression of SSTR2 and chromogranin A and induced expression of CXCR4. CAF induced a 2.3-fold increase in proliferation and completely reversed the response to everolimus in NT-3 cells. We identified STAT3 as the main signaling pathway induced by CAF. STAT3 targeting by small interfering RNA knockdown and inhibitors prevented CAF-induced proliferation and restored everolimus responsiveness. STAT3 activation in NET tissue was associated with decreased chromogranin A expression, increased Ki-67 index, and decreased 5-year overall and progression-free survival. CAF directly influence proliferation and therapeutic response in NET cells.CONCLUSION: Identifying STAT3 as the contributing pathway of this so far neglected tumor-stroma interaction has the potential to become a new therapeutic target to halt tumor growth and to restore therapeutic responsiveness in NET.",
author = "Tania Amin and Fabrice Viol and Jenny Krause and Martina Fahl and Corinna Eggers and Fayez Awwad and Benjamin Schmidt and Daniel Benten and Hendrik Ungefroren and Christoph Fraune and Clauditz, {Till S} and Guido Sauter and Izbicki, {Jakob R} and Lohse, {Ansgar W} and Samuel Huber and J{\"o}rg Schrader",
note = "S. Karger AG, Basel.",
year = "2023",
doi = "10.1159/000528539",
language = "English",
volume = "113",
pages = "501--518",
journal = "NEUROENDOCRINOLOGY",
issn = "0028-3835",
publisher = "S. Karger AG",
number = "5",

}

RIS

TY - JOUR

T1 - Cancer associated fibroblasts induce proliferation and therapeutic resistance to everolimus in neuroendocrine tumors through STAT3 activation

AU - Amin, Tania

AU - Viol, Fabrice

AU - Krause, Jenny

AU - Fahl, Martina

AU - Eggers, Corinna

AU - Awwad, Fayez

AU - Schmidt, Benjamin

AU - Benten, Daniel

AU - Ungefroren, Hendrik

AU - Fraune, Christoph

AU - Clauditz, Till S

AU - Sauter, Guido

AU - Izbicki, Jakob R

AU - Lohse, Ansgar W

AU - Huber, Samuel

AU - Schrader, Jörg

N1 - S. Karger AG, Basel.

PY - 2023

Y1 - 2023

N2 - INTRODUCTION: Cancer-associated fibroblasts (CAF) have been identified as relevant contributors to cancer progression and drug resistance in many tumors. Although neuroendocrine tumors (NET) are often associated with a strong stromal reaction, no study has addressed whether CAF are involved in progression and therapeutic resistance in NET. The aim of this study was to characterize the role of CAF in NET.METHODS: We established primary CAF cultures derived from NET liver metastases to study the effect on NET cell lines NT-3 and BON. Immunohistochemistry was performed on tissue sections of primary and metastatic NET tissue.RESULTS: Immunohistochemistry identified CAF dispersed in between tumor cells and within fibrotic bands separating tumor cell clusters in NET. Stimulating NET cells with CAF decreased expression of SSTR2 and chromogranin A and induced expression of CXCR4. CAF induced a 2.3-fold increase in proliferation and completely reversed the response to everolimus in NT-3 cells. We identified STAT3 as the main signaling pathway induced by CAF. STAT3 targeting by small interfering RNA knockdown and inhibitors prevented CAF-induced proliferation and restored everolimus responsiveness. STAT3 activation in NET tissue was associated with decreased chromogranin A expression, increased Ki-67 index, and decreased 5-year overall and progression-free survival. CAF directly influence proliferation and therapeutic response in NET cells.CONCLUSION: Identifying STAT3 as the contributing pathway of this so far neglected tumor-stroma interaction has the potential to become a new therapeutic target to halt tumor growth and to restore therapeutic responsiveness in NET.

AB - INTRODUCTION: Cancer-associated fibroblasts (CAF) have been identified as relevant contributors to cancer progression and drug resistance in many tumors. Although neuroendocrine tumors (NET) are often associated with a strong stromal reaction, no study has addressed whether CAF are involved in progression and therapeutic resistance in NET. The aim of this study was to characterize the role of CAF in NET.METHODS: We established primary CAF cultures derived from NET liver metastases to study the effect on NET cell lines NT-3 and BON. Immunohistochemistry was performed on tissue sections of primary and metastatic NET tissue.RESULTS: Immunohistochemistry identified CAF dispersed in between tumor cells and within fibrotic bands separating tumor cell clusters in NET. Stimulating NET cells with CAF decreased expression of SSTR2 and chromogranin A and induced expression of CXCR4. CAF induced a 2.3-fold increase in proliferation and completely reversed the response to everolimus in NT-3 cells. We identified STAT3 as the main signaling pathway induced by CAF. STAT3 targeting by small interfering RNA knockdown and inhibitors prevented CAF-induced proliferation and restored everolimus responsiveness. STAT3 activation in NET tissue was associated with decreased chromogranin A expression, increased Ki-67 index, and decreased 5-year overall and progression-free survival. CAF directly influence proliferation and therapeutic response in NET cells.CONCLUSION: Identifying STAT3 as the contributing pathway of this so far neglected tumor-stroma interaction has the potential to become a new therapeutic target to halt tumor growth and to restore therapeutic responsiveness in NET.

U2 - 10.1159/000528539

DO - 10.1159/000528539

M3 - SCORING: Journal article

C2 - 36473454

VL - 113

SP - 501

EP - 518

JO - NEUROENDOCRINOLOGY

JF - NEUROENDOCRINOLOGY

SN - 0028-3835

IS - 5

ER -