Molecular interactions of ErbB1 (EGFR) and integrin-β1 in astrocytoma frozen sections predict clinical outcome and correlate with Akt-mediated in vitro radioresistance

Miklós Petrás, Tamás Lajtos, Elza Friedländer, A. Klekner, Éva Pintye, Burt G. Feuerstein, János Szöllsi, G. Vereb

Research output: Contribution to journalArticle

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Abstract

IntroductionTreatment of astrocytoma is frequently hampered by radioresistance of the tumor. In addition to overexpression of ErbB1/EGFR, functional crosstalk between receptor tyrosine kinases and cell adhesion molecules may also contribute to therapy resistance.MethodsAcceptor photobleaching FRET was implemented on frozen sections of clinical astrocytoma to check the role of ErbB1-integrin-β1 interaction. U251 glioma subclones were obtained by introducing extra CHR7 material or the ErbB1 gene to test the relevance and mechanism of this interaction in vitro.ResultsGrade IV tumors showed higher ErbB1 and integrin-β1 expression and greater ErbB1-integrin-β1 heteroassociation than did grade II tumors. Of these, the extent of molecular association was a single determinant of tumor grade and prognosis in stepwise logistic regression. In vitro, integrin-β1 was upregulated, and radiosensitivity was diminished by ectopic ErbB1 expression. Great excess of ErbB1 provided colony forming advantage over medium excess but did not yield better radiation resistance or faster proliferation and decreased to medium level over time, whereas integrin-β1 levels remained elevated and defined the extent of radioresistance. Increased expression of ErbB1 and integrin-β1 was paralleled by decreasing ErbB1 homoassociation and increasing ErbB1-integrin-β1 heteroassociation. Microscopic two-sided FRET revealed that pixels with higher ErbB1-integrin-β1 heteroassociation exhibited lowed ErbB1 homoassociation, indicating competition for association partners among these molecules. Boosted Akt phosphorylation response to EGF accompanied this shift toward heteroassociation, and the consequentially increased radioresistance could be reverted by inhibiting PI3K.ConclusionThe clinically relevant ErbB1-integrin-β1 heteroassociation may be used as a target of both predictive diagnostics and molecular therapy.

Original languageEnglish
Pages (from-to)1027-1040
Number of pages14
JournalNeuro-Oncology
Volume15
Issue number8
DOIs
Publication statusPublished - Aug 2013

Fingerprint

Astrocytoma
Frozen Sections
Integrins
Neoplasms
Photobleaching
erbB-1 Genes
In Vitro Techniques
Molecular Pathology
Radiation Tolerance
Cell Adhesion Molecules
Receptor Protein-Tyrosine Kinases
Phosphatidylinositol 3-Kinases
Epidermal Growth Factor
Glioma
Logistic Models
Phosphorylation
Radiation
Therapeutics

Keywords

  • Akt-dependent radioresistance
  • astrocytoma fresh frozen sections
  • ErbB1 (EGFR)
  • integrin-β1
  • molecular interaction predicting prognosis

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Clinical Neurology

Cite this

Molecular interactions of ErbB1 (EGFR) and integrin-β1 in astrocytoma frozen sections predict clinical outcome and correlate with Akt-mediated in vitro radioresistance. / Petrás, Miklós; Lajtos, Tamás; Friedländer, Elza; Klekner, A.; Pintye, Éva; Feuerstein, Burt G.; Szöllsi, János; Vereb, G.

In: Neuro-Oncology, Vol. 15, No. 8, 08.2013, p. 1027-1040.

Research output: Contribution to journalArticle

Petrás, Miklós ; Lajtos, Tamás ; Friedländer, Elza ; Klekner, A. ; Pintye, Éva ; Feuerstein, Burt G. ; Szöllsi, János ; Vereb, G. / Molecular interactions of ErbB1 (EGFR) and integrin-β1 in astrocytoma frozen sections predict clinical outcome and correlate with Akt-mediated in vitro radioresistance. In: Neuro-Oncology. 2013 ; Vol. 15, No. 8. pp. 1027-1040.
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T1 - Molecular interactions of ErbB1 (EGFR) and integrin-β1 in astrocytoma frozen sections predict clinical outcome and correlate with Akt-mediated in vitro radioresistance

AU - Petrás, Miklós

AU - Lajtos, Tamás

AU - Friedländer, Elza

AU - Klekner, A.

AU - Pintye, Éva

AU - Feuerstein, Burt G.

AU - Szöllsi, János

AU - Vereb, G.

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N2 - IntroductionTreatment of astrocytoma is frequently hampered by radioresistance of the tumor. In addition to overexpression of ErbB1/EGFR, functional crosstalk between receptor tyrosine kinases and cell adhesion molecules may also contribute to therapy resistance.MethodsAcceptor photobleaching FRET was implemented on frozen sections of clinical astrocytoma to check the role of ErbB1-integrin-β1 interaction. U251 glioma subclones were obtained by introducing extra CHR7 material or the ErbB1 gene to test the relevance and mechanism of this interaction in vitro.ResultsGrade IV tumors showed higher ErbB1 and integrin-β1 expression and greater ErbB1-integrin-β1 heteroassociation than did grade II tumors. Of these, the extent of molecular association was a single determinant of tumor grade and prognosis in stepwise logistic regression. In vitro, integrin-β1 was upregulated, and radiosensitivity was diminished by ectopic ErbB1 expression. Great excess of ErbB1 provided colony forming advantage over medium excess but did not yield better radiation resistance or faster proliferation and decreased to medium level over time, whereas integrin-β1 levels remained elevated and defined the extent of radioresistance. Increased expression of ErbB1 and integrin-β1 was paralleled by decreasing ErbB1 homoassociation and increasing ErbB1-integrin-β1 heteroassociation. Microscopic two-sided FRET revealed that pixels with higher ErbB1-integrin-β1 heteroassociation exhibited lowed ErbB1 homoassociation, indicating competition for association partners among these molecules. Boosted Akt phosphorylation response to EGF accompanied this shift toward heteroassociation, and the consequentially increased radioresistance could be reverted by inhibiting PI3K.ConclusionThe clinically relevant ErbB1-integrin-β1 heteroassociation may be used as a target of both predictive diagnostics and molecular therapy.

AB - IntroductionTreatment of astrocytoma is frequently hampered by radioresistance of the tumor. In addition to overexpression of ErbB1/EGFR, functional crosstalk between receptor tyrosine kinases and cell adhesion molecules may also contribute to therapy resistance.MethodsAcceptor photobleaching FRET was implemented on frozen sections of clinical astrocytoma to check the role of ErbB1-integrin-β1 interaction. U251 glioma subclones were obtained by introducing extra CHR7 material or the ErbB1 gene to test the relevance and mechanism of this interaction in vitro.ResultsGrade IV tumors showed higher ErbB1 and integrin-β1 expression and greater ErbB1-integrin-β1 heteroassociation than did grade II tumors. Of these, the extent of molecular association was a single determinant of tumor grade and prognosis in stepwise logistic regression. In vitro, integrin-β1 was upregulated, and radiosensitivity was diminished by ectopic ErbB1 expression. Great excess of ErbB1 provided colony forming advantage over medium excess but did not yield better radiation resistance or faster proliferation and decreased to medium level over time, whereas integrin-β1 levels remained elevated and defined the extent of radioresistance. Increased expression of ErbB1 and integrin-β1 was paralleled by decreasing ErbB1 homoassociation and increasing ErbB1-integrin-β1 heteroassociation. Microscopic two-sided FRET revealed that pixels with higher ErbB1-integrin-β1 heteroassociation exhibited lowed ErbB1 homoassociation, indicating competition for association partners among these molecules. Boosted Akt phosphorylation response to EGF accompanied this shift toward heteroassociation, and the consequentially increased radioresistance could be reverted by inhibiting PI3K.ConclusionThe clinically relevant ErbB1-integrin-β1 heteroassociation may be used as a target of both predictive diagnostics and molecular therapy.

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