Abstract
Non-small cell lung cancer (NSCLC) patients with idiopathic pulmonary fibrosis (IPF) show poor prognosis. Periostin is an extracellular matrix protein highly expressed in the lung tissues of IPF. This study aimed to investigate the possibility that periostin secreted by fibroblasts derived from IPF lung might affect proliferation of NSCLC cells. Periostin was more highly expressed and secreted by fibroblasts from diseased human lung with IPF (DIPF) than by normal human lung fibroblasts (NHLF). Cocultivation of NSCLC cells with conditioned media (CM) from DIPF increased proliferation of NSCLC cells through pErk signaling, with this proliferation attenuated by periostin-neutralizing antibodies. Knockdown of integrin β3, a subunit of the periostin receptor, in NSCLC cells suppressed proliferation of NSCLC cells promoted by recombinant human periostin and CM of DIPF. On in vivo examination, DIPF promoted tumor progression more than NHLF, and knockdown of integrin β3 in NSCLC cells suppressed tumor progression promoted by DIPF. Fibroblasts derived from surgical specimens from IPF patients also increased secretion of periostin compared to those from non-IPF patients. Periostin secreted from IPF-activated fibroblasts plays critical roles in the proliferation of NSCLC cells. The present study provides a solid basis for considering periostin-targeted therapy for NSCLC patients with IPF.
Highlights
Non-small cell lung cancer (NSCLC) patients with idiopathic pulmonary fibrosis (IPF) show poor prognosis
Western blot (WB) for pErk expression was performed using frozen specimens obtained from patients, which showed a high level of pErk expression in LC-IPF as compared to LC-non-IPF samples (n = 3 each), suggesting that cell proliferation signaling is more highly activated in tumors with IPF (Supplementary Fig. 1a, Supplementary Table 2)
We showed that patients with LC-IPF had a poor prognosis and LC-IPF had higher SUVmax in FDG-PET, indicating that LC-IPF had higher malignant potential than LC-non-IPF
Summary
Non-small cell lung cancer (NSCLC) patients with idiopathic pulmonary fibrosis (IPF) show poor prognosis. A significant number of IPF patients display risk factors associated with NSCLC, so multiple common genetic, molecular, and cellular processes appear to connect lung fibrosis with N SCLC5,7. Clinical significance of idiopathic pulmonary fibrosis (IPF) in non-small cell lung cancer (NSCLC) patients. LC-IPF, NSCLC patient with IPF; LC-non-IPF, NSCLC patient without IPF; mo, months; RNA-Seq, ribonucleic acid sequencing; WB, Western blot; NHLF, normal human lung fibroblast; DIPF, diseased human lung fibroblast-IPF; SULF1, sulfatase 1; CTHRC1, collagen triple helix repeat containing 1; LOX, lysyl oxidase; SPARC,secreted protein acidic and cysteine rich; LOXL2, lysyl oxidase-like 2; POSTN, periostin; CTGF, connective tissue growth factor, COL1A2, collagen type I alpha 2 chain; COL1A1, collagen type I alpha 1 chain; S100A4, S100 calcium-binding protein A4. Common molecule for these two pathologies and clarifying the function of the molecule on cancer could be key to overcoming LC-IPF
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