Cancer-associated fibroblasts in non-small cell lung cancer: Understanding the activation mechanism and its potential in novel therapies

Cancer cells have been the target of conventional anti-cancer therapy to date, but stromal cells (cells with a structural or connective role) involved in cancer cell infiltration and metastasis are likely to be the key to new therapies. In collaboration with Program Director Yoshihide Hayashizaki, Coordinator Masayoshi Itoh, and others at the RIKEN Preventive Medicine and Diagnosis Innovation Program (currently DNAFORM, Inc.), Professor Kazuhisa Takahashi, Associate Professor Shinsaku Togo, graduate student Moe Iwai, and colleagues at the Graduate School of Medicine at Juntendo University conducted comprehensive genetic analysis on cancer-associated fibroblasts (CAFs) in non-small cell lung cancer, which accounts for the majority of lung cancer cases. The analysis revealed that the expression of a cell adhesion molecule, integrin α11, activates the migration ability of CAFs, leading to cancer metastasis and recurrence after surgery. Associate Professor Togo said, "This is the first report on the regulator of functional activation of CAFs in the cancer stroma. Because ERK1/2 inhibitors have been successfully used to suppress the activation of the migration ability of CAFs at the cellular level, their concomitant use with molecular-targeted drugs may contribute to reducing lung cancer mortality in the future." The findings of this study were published in the online version of Molecular Oncology.

The disappearance of all cancer tissues after treatment with molecular-targeted drugs is exceedingly rare in non-small cell lung cancer. In many cases, a significantly small amount of cancer tissue that has become resistant to molecular-targeted drugs, as well as the surrounding cancer stromal tissue, remains. The survival rate decreases in proportion with the amount of this cancer stromal tissue, even if it is removed by surgery. Therefore, understanding cancer stromal tissue is necessary for curing advanced cancer.

During the removal of solid cancers, cancer cells as well as surrounding cells are removed. Therefore, the research group conducted a study using normal and cancer stromal tissue samples collected from 16 patients with non-small cell lung cancer.

First, they focused on the migration ability of CAFs clustered in the cancer stroma. CAFs are activated through their interaction with surrounding cancer cells, promoting cancer cell progression. The research group found that compared with normal lung fibroblasts, CAFs isolated from the cancer stroma have activated migration ability toward collagen type I and fibronectin, which are the major proteins in the cancer stroma.

Next, they comprehensively analyzed transcriptional promoter activity using the CAGE method developed by RIKEN to clarify the regulators involved in the activation of the CAF-specific migration ability.

It was shown that integrin α11, a receptor for type I collagen, was highly active in CAFs and that CAFs had increased expression of integrin α11 even at the protein level. Moreover, the higher the expression of integrin α11 in cancer stromal tissue, including CAFs, the more likely postoperative recurrence occurs, and its expression level is increased in the advanced disease stages, indicating a correlation between the expression of integrin α11 and the deterioration of prognosis. Furthermore, the expression of integrin α11 in the cancer stroma was correlated with the expression of collagen type XIαI, which has been reported as a specific marker of CAFs. It was also revealed that the transcriptional activity and expression of collagen type XIαI at gene and protein levels were high in CAFs.

In addition, the expression of integrin α11 and collagen type XIα was increased in the normal lung fibroblasts cultured in the lung cancer cell culture medium, which resulted in a CAF-specific phenotype and cancer cell properties. In contrast, the culture medium harvested from CAFs activated the migration of lung cancer cells.

Associate Professor Togo said, "We found that normal lung fibroblasts are educated by cancer cells to become cancer-related fibroblasts and that the cancer-related fibroblasts activate the migration ability of cancer cells."

Hypothesizing that integrin α11, which is highly expressed in CAFs, enhances the migration ability of CAFs toward type I collagen and fibronectin via the ERK1/2 signaling independently of the fibronectin receptor α5β1, the research group found that the activation of CAFs is suppressed by an ERK1/2 inhibitor. These results will hopefully lead to new therapeutic treatments for lung cancer.