Mechanical Forces in IPF and Lung Cancer: A New Therapeutic Target?

Abnormal mechanical tissue stiffness and mechanical stretch, which are both generated in the lung with idiopathic pulmonary fibrosis (IPF), may contribute to the onset and progression of IPF-related lung cancer, according to a research review and analysis published recently in the European Journal of Cell Biology.

Compared with the general population, patients with IPF run a higher risk of lung cancer (the leading cause of cancer-related death worldwide), said review authors. Among patients with IPF, the morbidity of lung cancer is high and life-expectancy is further reduced. Although previous literature reviews have shown the common molecular connections shared by IFP and lung cancer, the mechanisms by which IPF increases lung cancer morbidity and mortality has remained an open question.

To address this question, review authors analyzed more than 100 research articles published between 2006 and 2022 on IPF and lung cancer, carefully analyzing the pathological features of both diseases. Based on this analysis, the reviewers postulated “the possible effects of mechanical forces that are generated in IPF on the initiation and progression of lung cancer from the perspective of the hallmarks of cancer, including proliferation, metastasis, angiogenesis, cancer stem cells, immunology, epigenetics, and metabolism,” said the authors, “so as to advance our understanding of the pathogenesis of IPF-related lung cancer and to harness these concepts for lung cancer mechanotherapies.”

The review authors’ analysis found lung carcinomas and the typical scar tissue build-up from IPF are most common in the outer area of the lungs, and that these honeycomb areas in IPF are the most common location for lung cancers to develop. The carcinomas and scar tissue build-up both cause a high-stretch force to be exerted in these peripheral areas. In addition, the condensed fibrous tissue in the IPF-scarred honeycomb areas is subject to increased stiffness.

These abnormal mechanical forces of increased tissue stiffness and stretch are pathological characteristics present in the development of IPF, said the researchers. Moreover, these same unusual mechanical forces in the lung generated with IPF support the development of cancer and initiate the commencement of pre-tumorous signals, they added.

The clinical implication of these findings is that mechanomedicine may represent a novel opportunity for treating IPF-related lung cancer, said review. Given the limitations of chemotherapy and radiotherapy — the current mainstays of lung cancer therapy — novel targets are “urgently needed,” they noted. Therefore, “modulating the remodeling of ECM [extracellular matrix] components or targeting mechanical transduction might be an appealing target for therapeutic intervention” in patients with IPF-related lung cancer.

Notably, pirfenidone, which targets collagen synthesis, has already proven effective in reducing IPF-lung cancer morbidity. Other promising therapies may be lysyl oxidase (LOX) enzymes, which are vital to maintaining tissue stiffness, and mechanosensors such as yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) cofactors, said review authors.

The review authors concluded that “the aberrant mechanical forces that are generated in the lung with IPF may contribute to the onset and progression of lung cancer,” and that “targeting mechanical transduction may present a novel and promising strategy for lung cancer therapy.”

Reference

Wang C, Yang J. Mechanical forces: The missing link between idiopathic pulmonary fibrosis and lung cancer. Eur J Cell Biol. Published online May 10, 2022. doi:10.1016/j.ejcb.2022.151234