Oncogenic mutations regulate tumor microenvironment through induction of growth factors and angiogenic mediators

S. E. Wang, Y. Yu, T. L. Criswell, L. M. Debusk, P. C. Lin, R. Zent, D. H. Johnson, X. Ren, C. L. Arteaga

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Activating mutations in the tyrosine kinase domain of HER2 (ErbB2) have been identified in human cancers. Compared with wild-type HER2, mutant HER2 shows constitutively activate kinase activity and increased oncogenicity. Cells transformed by mutant HER2 are resistant to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and exhibit an attenuated response to the HER2 antibody trastuzumab. We investigated herein pathways through which mutant HER2 alters the extracellular environment, potentially leading to drug resistance and the effect of simultaneously targeting HER2 and the tumor cell microenvironment with a therapeutic intent. Expression of mutant HER2 in mammary epithelial cells activated autocrine transforming growth factor (TGF) Β1 signaling through a mechanism involving Rac1 and c-Jun N-terminal kinase-activating protein 1-dependent transcription. Cells transformed by an activating mutant of H-Ras (G12V) also expressed higher TGF-Β1 level through Rac1 activation. In addition, mutant HER2 induced the EGFR ligands TGF-α and amphiregulin at the mRNA and protein levels. Vascular endothelial growth factor, a target of the TGF-Β-Smad transcriptional regulation, was also induced as a result of expression of mutant HER2. Inhibition of TGF-Β signaling with the Alk5 small molecule inhibitor LY2109761 reduced growth and invasiveness of cells expressing mutant HER2. Combined inhibition of intracellular and paracrine effects of mutant HER2 by trastuzumab and the EGFR antibody cetuximab were more efficient than single-agent therapies. These data suggest that mutations in oncogenes such as HER2 and Ras not only alter intracellular signaling but also influence on other components of the tumor microenvironment by inducing several pro-invasive growth factors. In turn, these serve as extracellular targets of novel therapeutic strategies directed at both cancer-driving oncogenes and the modified tumor microenvironment.

Original languageEnglish (US)
Pages (from-to)3335-3348
Number of pages14
JournalOncogene
Volume29
Issue number23
DOIs
StatePublished - Jun 10 2010

Fingerprint

Tumor Microenvironment
Transforming Growth Factors
Intercellular Signaling Peptides and Proteins
Mutation
Epidermal Growth Factor Receptor
Oncogenes
Protein-Tyrosine Kinases
Cellular Microenvironment
Antibodies
JNK Mitogen-Activated Protein Kinases
Drug Resistance
Vascular Endothelial Growth Factor A
Neoplasms
Proteins
Breast
Phosphotransferases
Therapeutics
Epithelial Cells
Ligands
Messenger RNA

Keywords

  • EGFR ligands
  • HER2/ErbB2
  • Ras
  • TGF-β
  • Tumor microenvironment
  • VEGF

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Oncogenic mutations regulate tumor microenvironment through induction of growth factors and angiogenic mediators. / Wang, S. E.; Yu, Y.; Criswell, T. L.; Debusk, L. M.; Lin, P. C.; Zent, R.; Johnson, D. H.; Ren, X.; Arteaga, C. L.

In: Oncogene, Vol. 29, No. 23, 10.06.2010, p. 3335-3348.

Research output: Contribution to journalArticle

Wang, S. E. ; Yu, Y. ; Criswell, T. L. ; Debusk, L. M. ; Lin, P. C. ; Zent, R. ; Johnson, D. H. ; Ren, X. ; Arteaga, C. L. / Oncogenic mutations regulate tumor microenvironment through induction of growth factors and angiogenic mediators. In: Oncogene. 2010 ; Vol. 29, No. 23. pp. 3335-3348.
@article{526b6409595944d0975f0d92c4ce2376,
title = "Oncogenic mutations regulate tumor microenvironment through induction of growth factors and angiogenic mediators",
abstract = "Activating mutations in the tyrosine kinase domain of HER2 (ErbB2) have been identified in human cancers. Compared with wild-type HER2, mutant HER2 shows constitutively activate kinase activity and increased oncogenicity. Cells transformed by mutant HER2 are resistant to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and exhibit an attenuated response to the HER2 antibody trastuzumab. We investigated herein pathways through which mutant HER2 alters the extracellular environment, potentially leading to drug resistance and the effect of simultaneously targeting HER2 and the tumor cell microenvironment with a therapeutic intent. Expression of mutant HER2 in mammary epithelial cells activated autocrine transforming growth factor (TGF) Β1 signaling through a mechanism involving Rac1 and c-Jun N-terminal kinase-activating protein 1-dependent transcription. Cells transformed by an activating mutant of H-Ras (G12V) also expressed higher TGF-Β1 level through Rac1 activation. In addition, mutant HER2 induced the EGFR ligands TGF-α and amphiregulin at the mRNA and protein levels. Vascular endothelial growth factor, a target of the TGF-Β-Smad transcriptional regulation, was also induced as a result of expression of mutant HER2. Inhibition of TGF-Β signaling with the Alk5 small molecule inhibitor LY2109761 reduced growth and invasiveness of cells expressing mutant HER2. Combined inhibition of intracellular and paracrine effects of mutant HER2 by trastuzumab and the EGFR antibody cetuximab were more efficient than single-agent therapies. These data suggest that mutations in oncogenes such as HER2 and Ras not only alter intracellular signaling but also influence on other components of the tumor microenvironment by inducing several pro-invasive growth factors. In turn, these serve as extracellular targets of novel therapeutic strategies directed at both cancer-driving oncogenes and the modified tumor microenvironment.",
keywords = "EGFR ligands, HER2/ErbB2, Ras, TGF-β, Tumor microenvironment, VEGF",
author = "Wang, {S. E.} and Y. Yu and Criswell, {T. L.} and Debusk, {L. M.} and Lin, {P. C.} and R. Zent and Johnson, {D. H.} and X. Ren and Arteaga, {C. L.}",
year = "2010",
month = "6",
day = "10",
doi = "10.1038/onc.2010.112",
language = "English (US)",
volume = "29",
pages = "3335--3348",
journal = "Oncogene",
issn = "0950-9232",
publisher = "Nature Publishing Group",
number = "23",

}

TY - JOUR

T1 - Oncogenic mutations regulate tumor microenvironment through induction of growth factors and angiogenic mediators

AU - Wang, S. E.

AU - Yu, Y.

AU - Criswell, T. L.

AU - Debusk, L. M.

AU - Lin, P. C.

AU - Zent, R.

AU - Johnson, D. H.

AU - Ren, X.

AU - Arteaga, C. L.

PY - 2010/6/10

Y1 - 2010/6/10

N2 - Activating mutations in the tyrosine kinase domain of HER2 (ErbB2) have been identified in human cancers. Compared with wild-type HER2, mutant HER2 shows constitutively activate kinase activity and increased oncogenicity. Cells transformed by mutant HER2 are resistant to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and exhibit an attenuated response to the HER2 antibody trastuzumab. We investigated herein pathways through which mutant HER2 alters the extracellular environment, potentially leading to drug resistance and the effect of simultaneously targeting HER2 and the tumor cell microenvironment with a therapeutic intent. Expression of mutant HER2 in mammary epithelial cells activated autocrine transforming growth factor (TGF) Β1 signaling through a mechanism involving Rac1 and c-Jun N-terminal kinase-activating protein 1-dependent transcription. Cells transformed by an activating mutant of H-Ras (G12V) also expressed higher TGF-Β1 level through Rac1 activation. In addition, mutant HER2 induced the EGFR ligands TGF-α and amphiregulin at the mRNA and protein levels. Vascular endothelial growth factor, a target of the TGF-Β-Smad transcriptional regulation, was also induced as a result of expression of mutant HER2. Inhibition of TGF-Β signaling with the Alk5 small molecule inhibitor LY2109761 reduced growth and invasiveness of cells expressing mutant HER2. Combined inhibition of intracellular and paracrine effects of mutant HER2 by trastuzumab and the EGFR antibody cetuximab were more efficient than single-agent therapies. These data suggest that mutations in oncogenes such as HER2 and Ras not only alter intracellular signaling but also influence on other components of the tumor microenvironment by inducing several pro-invasive growth factors. In turn, these serve as extracellular targets of novel therapeutic strategies directed at both cancer-driving oncogenes and the modified tumor microenvironment.

AB - Activating mutations in the tyrosine kinase domain of HER2 (ErbB2) have been identified in human cancers. Compared with wild-type HER2, mutant HER2 shows constitutively activate kinase activity and increased oncogenicity. Cells transformed by mutant HER2 are resistant to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and exhibit an attenuated response to the HER2 antibody trastuzumab. We investigated herein pathways through which mutant HER2 alters the extracellular environment, potentially leading to drug resistance and the effect of simultaneously targeting HER2 and the tumor cell microenvironment with a therapeutic intent. Expression of mutant HER2 in mammary epithelial cells activated autocrine transforming growth factor (TGF) Β1 signaling through a mechanism involving Rac1 and c-Jun N-terminal kinase-activating protein 1-dependent transcription. Cells transformed by an activating mutant of H-Ras (G12V) also expressed higher TGF-Β1 level through Rac1 activation. In addition, mutant HER2 induced the EGFR ligands TGF-α and amphiregulin at the mRNA and protein levels. Vascular endothelial growth factor, a target of the TGF-Β-Smad transcriptional regulation, was also induced as a result of expression of mutant HER2. Inhibition of TGF-Β signaling with the Alk5 small molecule inhibitor LY2109761 reduced growth and invasiveness of cells expressing mutant HER2. Combined inhibition of intracellular and paracrine effects of mutant HER2 by trastuzumab and the EGFR antibody cetuximab were more efficient than single-agent therapies. These data suggest that mutations in oncogenes such as HER2 and Ras not only alter intracellular signaling but also influence on other components of the tumor microenvironment by inducing several pro-invasive growth factors. In turn, these serve as extracellular targets of novel therapeutic strategies directed at both cancer-driving oncogenes and the modified tumor microenvironment.

KW - EGFR ligands

KW - HER2/ErbB2

KW - Ras

KW - TGF-β

KW - Tumor microenvironment

KW - VEGF

UR - http://www.scopus.com/inward/record.url?scp=77953479867&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77953479867&partnerID=8YFLogxK

U2 - 10.1038/onc.2010.112

DO - 10.1038/onc.2010.112

M3 - Article

VL - 29

SP - 3335

EP - 3348

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 23

ER -