Chemotherapy activates Notch pathway to promote repopulation of lung squamous cell carcinoma: a putative mechanism of recurrence

Monday, October 24, 2011 — Poster Session I
Noon – 2:00 p.m.	Natcher Conference Center	NCI	CANCER-13

Authors

• C Lee
• D Esposito
• C-P Day
• G Merlino

Abstract

Post-chemotherapy repopulation may drive the recurrence of cancer. It is believed that cancer cells may take advantage of wound-healing pathways to promote repopulation. Lung squamous cell carcinoma (SCC) is a major subtype of lung cancer derived from pulmonary airway epithelium. In this study, we hypothesize that lung SCC repopulates by activating the Notch pathway, which is critical for the regeneration of wounded lung epithelium. Murine and human lung SCC cell lines were treated with first-line chemotherapeutic agents, paclitaxel, cisplatin, or gemcitabine, and then allowed recovered in normal culture medium. During the recovery from each treatment, Notch pathway downstream gene HEY1 has been upregulated in lung SCC cells. γ-secretase inhibitors at the concentration that suppressed HEY1 upregulation delayed growth of lung SCC cells. Moreover, using different labeling markers to track cell growth, we found drug-treated lung SCC cells in recovery phase can stimulate the growth of healthy cells in co-culture, while medium conditioned by treated cells had no significant effect. These results implied that direct contact between surviving cells and healthy cells is required for repopulation, thus cell-surface Notch ligand such as Jagged-1 may be involved. Our results suggest that Notch inhibitor may prevent post-chemotherapy recurrence of lung SCC.

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