IGFBP3 inhibits tumour growth and invasion of H1299 lung cancer cells and leads to improved survival in patients with lung cancer

Introduction: The insulin-like growth factor (IGF)-pathway is involved in tumour cell proliferation, metastasis, and survival. We aimed to find out what effects IGF binding protein 3 (IGFBP3) exerted on H1299 lung cancer (LC) cells in terms of tumour growth and invasion and whether IGFBP3 was associated with clinical and pathological parameters in a prospective cohort of LC patients. Methods: H1299 cells were transfected with an IGFBP3-expressing vector. Its influence on apoptosis induction via flow cytometry annexin V FITC assay, cell proliferation in 2D and 3D cell culture, and invasion were examined. Expression of several matrix metalloproteinases (MMPs) and inhibitors (TIMP-1) were further investigated in IGFBP3-transfected LC cells. Data on LC patients (n=131), tumour characteristics, and survival were prospectively collected. Statistics included group comparisons, correlation, and survival. Results: IGFBP3 did not influence apoptosis induction and 2D cell proliferation. However, both spheroid growth (3D proliferation) and invasion of IGFBP3-transfected cells planted in an extracellular matrix-based gel were significantly inhibited. IGFBP3 inhibited MMP-1 release and the total MMP activity. In LC patients, higher IGFBP3 plasma levels correlated with both lower clinical tumour stage, grading, Ki-67 staining and the absence of necrosis (p<0.05, respectively). Increased IGFBP3 plasma levels were associated with improved overall survival (hazard ratio 0.37, P = 0.01). Conclusions: Overexpressed IGFBP3 in a LC cell line inhibited tumour growth and invasion. Increased IGFBP3 plasma levels in LC patients were associated with improved patient survival.