Idiopathic Pulmonary Fibrosis and Lung Cancer: Mechanisms and Molecular Targets

Abstract

Idiopathic pulmonary fibrosis (IPF) is the most common idiopathic interstitial pulmonary disease with a median survival of 2–4 years after diagnosis. A significant number of IPF patients have risk factors, such as a history of smoking or concomitant emphysema, both of which can predispose the patient to lung cancer (LC) (mostly non-small cell lung cancer (NSCLC)). In fact, IPF itself increases the risk of LC development by 7% to 20%. In this regard, there are multiple common genetic, molecular, and cellular processes that connect lung fibrosis with LC, such as myofibroblast/mesenchymal transition, myofibroblast activation and uncontrolled proliferation, endoplasmic reticulum stress, alterations of growth factors expression, oxidative stress, and large genetic and epigenetic variations that can predispose the patient to develop IPF and LC. The current approved IPF therapies, pirfenidone and nintedanib, are also active in LC. In fact, nintedanib is approved as a second line treatment in NSCLC, and pirfenidone has shown anti-neoplastic effects in preclinical studies. In this review, we focus on the current knowledge on the mechanisms implicated in the development of LC in patients with IPF as well as in current IPF and LC-IPF candidate therapies based on novel molecular advances.

Worse lung cancer outcome in patients with lower respiratory tract infection confirmed at time of diagnosis

“…The incidence of pulmonary malignancy in patients with IPF (4.8% to 48%) is significantly higher than in patients without IPF (2.0% to 6.4%) . The mechanism of increased cancer development in IPF might be associated with increased inflammatory reaction, cell damage, abnormal fibroblast production and the activation of specific signaling pathways (e.g., Wnt/β‐catein) . In our data set, about half of the patients had a significant underlying lung disease (COPD/IPF); however, this was not associated with differences in patients' characteristics of histology in the presence of LRTI.…”

Association of common genetic variants in theCPSF7andSDHAF2genes with Canine Idiopathic Pulmonary Fibrosis in the West Highland White Terrier

“…We ran the GWAS accounting for relatedness and population stratification using the linear mixed model as implemented in the GEMMA software [26]. Age and sex were not included as covariates in the model because these factors did not differ significantly between the AF and UF animals.…”

“…The genetic-association reported in our study might reveal the importance of CPSF7 in CIPF perhaps through the same pathologic mechanism as in lung cancer. IPF in humans is a risk factor for lung cancer, increasing the chance of development from 7% to 10% [26]. Additionally, there are several genetic, molecular and cellular mechanisms shared between lung fibrosis and lung cancer such as myofibroblast activation, endoplasmatic reticulum stress, alteration of growth factor expression, and genetic and epigenetic variations [26].…”

“…IPF in humans is a risk factor for lung cancer, increasing the chance of development from 7% to 10% [26]. Additionally, there are several genetic, molecular and cellular mechanisms shared between lung fibrosis and lung cancer such as myofibroblast activation, endoplasmatic reticulum stress, alteration of growth factor expression, and genetic and epigenetic variations [26]. CPFS7 has also associated with liver cancer [27].…”

Novel Pyrimidines as Multitarget Protein Tyrosine Kinase Inhibitors for the Treatment of Idiopathic Pulmonary Fibrosis (IPF)

“…As a progressive, severely debilitating disease, the median survival time of this fatal lung disease is only between 3 and 5 years from diagnosis. Unfortunately, the etiology and pathology of IPF have not been elucidated to date . Generally, IPF is thought to result from epithelial cell injury and the subsequent unconstrained fibrotic process.…”