Prognostic impact of Notch ligands and receptors in nonsmall cell lung cancer

Coexpression of Notch-1 and vascular endothelial growth factor-A predicts poor survival

Authors

  • Tom Donnem MD, PhD,

    Corresponding author
    1. Institute of Clinical Medicine, University of Tromso, Tromso, Norway
    2. Department of Oncology, University Hospital of North Norway, Tromso, Norway
    • Department of Oncology, University Hospital of North Norway, 9038 Tromso, Norway
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    • Fax: (011) 47 77626779

  • Sigve Andersen MD,

    1. Institute of Clinical Medicine, University of Tromso, Tromso, Norway
    2. Department of Oncology, University Hospital of North Norway, Tromso, Norway
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  • Khalid Al-Shibli MD, PhD,

    1. Institute of Medical Biology, University of Tromso, Tromso, Norway
    2. Department of Pathology, Nordland Central Hospital, Bodo, Norway
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  • Samer Al-Saad MD, PhD,

    1. Institute of Medical Biology, University of Tromso, Tromso, Norway
    2. Department of Pathology, University Hospital of North Norway, Tromso, Norway
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  • Lill-Tove Busund MD, PhD,

    1. Institute of Medical Biology, University of Tromso, Tromso, Norway
    2. Department of Pathology, University Hospital of North Norway, Tromso, Norway
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  • Roy M. Bremnes MD, PhD

    1. Institute of Clinical Medicine, University of Tromso, Tromso, Norway
    2. Department of Oncology, University Hospital of North Norway, Tromso, Norway
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Abstract

BACKGROUND:

Notch signaling plays a key role in embryonic vascular development and angiogenesis. The authors aimed to study the prognostic role of the angiogenesis-related Notch ligands and receptors and investigate the prognostic impact of the coexpression of vascular endothelial growth factor-A (VEGF-A) and Notch signaling.

METHODS:

Tumor tissue samples from 335 resected patients with stage I to IIIA nonsmall cell lung cancer (NSCLC) were obtained, and tissue microarrays were constructed from duplicate cores of tumor cells and tumor-related stroma from each specimen. Immunohistochemistry was used to evaluate the expression of the molecular markers Notch-1, Notch-4, Delta-like ligand 4 (DLL4), and Jagged-1.

RESULTS:

There were 191 squamous cell carcinomas (SCCs), 113 adenocarcinomas (ACs), and 31 large cell carcinomas. In AC, low tumor cell Delta-like ligand 4 expression was an independent negative prognostic factor (hazard ratio [HR], 2.9; 95% confidence interval [CI], 1.4-6.3 [P = .006]), whereas high tumor cell Notch-1 expression was an independent negative prognostic factor (HR, 2.2; 95% CI, 1.2-4.1 [P<.001]). In SCC, low stromal Delta-like ligand 4 expression was an independent indicator of poor prognosis (HR, 3.3; 95% CI, 1.8-6.1 [P<.001]). The coexpression of Notch-1 and VEGF-A had a significant prognostic impact (P<.001). For Notch-1 and VEGF-A, low/low (n = 142) versus high/high (n = 35) expression resulted in 5-year survival rates of 69% and 32%, respectively.

CONCLUSIONS:

Delta-like ligand 4 and Notch-1 are independent prognostic factors in NSCLC, but have diverse impacts in SCC and AC. The coexpression of tumor cell Notch-1/VEGF-A has a major impact on survival. Cancer 2010. © 2010 American Cancer Society.

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