High NOTCH activity induces radiation resistance in non small cell lung cancer

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• 作者：Jan Theys ; Sanaz Yahyanejad ; Roger Habets ; Paul Span ; Ludwig Dubois ; Kim Paesmans ; Bo Kattenbeld ; Jack Cleutjens ; Arjan J. Groot ; Olga C.J. Schuurbiers ; Philippe Lambin ; Jan Bussink ; Marc Vooijs
• 关键词：NOTCH ; NSCLC ; Radiation ; Hypoxia
• 刊名：Radiotherapy and Oncology
• 出版年：September, 2013
• 年：2013
• 卷：108
• 期：3
• 页码：440-445
• 全文大小：1255 K

文摘

Background and purpose

Patients with advanced NSCLC have survival rates <15%. The NOTCH pathway plays an important role during lung development and physiology but is often deregulated in lung cancer, making it a potential therapeutic target. We investigated NOTCH signaling in NSCLC and hypothesized that high NOTCH activity contributes to radiation resistance.

Materials and methods

NOTCH signaling in NSCLC patient samples was investigated using quantitative RT-PCR. H460 NSCLC cells with either high or blocked NOTCH activity were generated and their radiation sensitivity monitored using clonogenic assays. In vivo, xenograft tumors were irradiated and response assessed using growth delay. Microenvironmental parameters were analyzed by immunohistochemistry.

Results

Patients with high NOTCH activity in tumors showed significantly worse disease-free survival. In vitro, NOTCH activity did not affect the proliferation or intrinsic radiosensitivity of NSCLC cells. In contrast, xenografts with blocked NOTCH activity grew slower than wild type tumors. Tumors with high NOTCH activity grew significantly faster, were more hypoxic and showed a radioresistant phenotype.

Conclusions

We demonstrate an important role for NOTCH in tumor growth and correlate high NOTCH activity with poor prognosis and radioresistance. Blocking NOTCH activity in NSCLC might be a promising intervention to improve outcome after radiotherapy.