The oncogenic landscape of the idiopathic pulmonary fibrosis: a narrative review

Abstract

Background and objective: Translational research is a source of continuous innovation in medicine, more particularly for clinical research on new treatment modalities in idiopathic pulmonary fibrosis (IPF) patients. However, the heterogeneity of the disease is well recognized, and different pathological and molecular settings have been identified. The molecular mechanisms by which IPF proceeds in time and space remains poorly understood. Although some IPF features are reminiscent of cancer, the dynamics of malignant divergent clonal selective pressure and heterogeneity clearly differ from those occurring in IPF. This is reflected in the absence of patient proper selection and stratification to biological agents (pirfenidone, nintedanib) which limit therapeutic efficacy. Consequently, increased costs are related to the clinical management of advanced IPF patients. Steady collaboration and fluid communication between pneumo-oncologists, radiologists and molecular biologists is a clear priority for the correct interpretation of tests and the definition of effective personalized strategies against this orphan disease. The present work aims at providing the most relevant hints shared by cancer and IPF.

Methods: A systematic literature review was performed to identify all relevant data. The examined databases were Scopus, Web of Science, Cochrane, Google Scholar, and PubMed. The last search was run on January 5, 2022. We have primarily conducted separated research for lung cancer, IPF, genetics, epigenetics, surgery in IPF and cancer.

Key content and findings: The data here presented mainly focus on gene mutations, epigenetics and novel therapeutic approaches. Moreover, epidemiology, prognostic variables and in new treatment strategies adopted in patients with IPF and lung cancer are discussed as well.

Conclusions: Overall, the findings of this narrative review will be of help in defining the key molecular features that could applied in IPF setting with promising rationale to improve therapy and to better manage those cases carrying IPF and cancer concomitantly.

Keywords: Idiopathic pulmonary fibrosis (IPF); cancer; genetics; immunotherapy; personalized medicine.

Figure 1

IPF and cancer. The two diseases share common pathogenic pathways that should be exploited for novel therapeutic approaches. The oncogenic gain behaves as main driver of proliferative and invasive phenotypes. Heterogeneity which characterizes both diseases, refers to clonal selection (cancer) and histology (IPF). The specific IPF context impacts on the therapeutic exploitation of targeting oncogenes. IPF, idiopathic pulmonary fibrosis. IPF, idiopathic pulmonary fibrosis.

Figure 2

Functional annotation of the MET oncogene as an actionable target of IPF. MET-mediated events in IPF rely on qualitative differences among physiological signals. No driver genetic lesions, causally implicated in the disease can be clearly demonstrated (“Fibrogenic Expedience”). The MET blockage falls among those therapeutic strategies aimed at impairing the “aberrant recapitulation of developmental programs”. The hypoxia-induced MET up-regulation might cooperate in triggering IPF regenerative/reparative processes. HGF, hepatocyte growth factor; IPF, idiopathic pulmonary fibrosis.

Figure 3

Stem cells and their application in lung fibrosis. Stem cells can be classified into embryonal stem cells (ESC), adult stem cells (ASC) and induced pluripotent stem cells (IPSC) according to their origin. ESCs derive from embryo blastocysts, ASC can be isolated from various tissues, such as bone marrow, lung, adipose tissue, umbilical cord blood, umbilical cord tissue and amniotic fluid. IPSC are obtained from somatic cells using reprogramming factors (OCT3/4, SOX2, C-MYC, KLF4), responsible for re-programming to pluripotency. Stem cells can be administrated intravenously, intratracheally or intraperitoneally. They migrate to the injured sites of the lungs where they differentiate in alveolar type II cells and exert anti-inflammatory, antifibrotic and immunomodulant actions. IPF, idiopathic pulmonary fibrosis.

Figure 4

Stem cells and secretoma. Lung spheroid cells are round aggregates composed by stem cells and stromal cells. They produce a complex of proteins and growth factors, complexify named as secretoma, also including exosomes. Lung spheroid cell-secretome (LSC-Sec) and exosomes (LSC-Exo) reproduce a regenerative microenvironment and promote differentiation of stem cells towards epithelial phenotypes. EMT, epithelial mesenchymal transition.