Therapeutic Targeting of Cancer-Associated Fibroblasts in the Non-Small Cell Lung Cancer Tumor Microenvironment

Simple Summary In the tumor microenvironment, cancer-associated fibroblasts (CAFs) have multiple tumor-promoting functions in drug resistance, regulation of the niche of cancer stem cells and formation of the immunosuppressive network. Multiple mechanisms are involved, including production of growth factors, cytokines, and chemokines, as well as extracellular matrix remodeling. While cancer treatment generally targets cancer cells, elucidation of the tumor microenvironment has allowed for successful targeting of cells other than cancer cells involved in the construction of the tumor microenvironment. Cancer cells are prone to develop drug resistance, whereas resistance to treatments targeting the tumor microenvironment may be less likely to develop. Therefore, various treatment strategies against CAFs have attracted attention as possible novel cancer treatments. Lung cancer is the most frequently diagnosed cancer and the leading cause of cancer death worldwide. The most common lung cancer is non-small cell lung cancer (NSCLC), with an overall 5-year survival rate of around 20% because NSCLC is a metastatic disease. A better understanding of the mechanism underlying lung cancer metastasis is therefore urgently needed. The tumor microenvironment involves different types of stromal cells and functions as key components in the progression of NSCLC. Through epithelial-mesenchymal transition (EMT), in which epithelial cells lose their polarity and acquire mesenchymal potential, cancer cells acquire metastatic abilities, as well as cancer stem-cell-like potential. We previously reported that cancer-associated fibroblasts (CAFs) interact with lung cancer cells to allow for the acquisition of malignancy and treatment resistance by paracrine loops via EMT signals in the tumor microenvironment. Furthermore, CAFs regulate the cytotoxic activity of immune cells via various cytokines and chemokines, creating a microenvironment of immune tolerance. Regulation of CAFs can therefore affect immune responses. Recent research has shown several roles of CAFs in NSCLC tumorigenesis, owing to their heterogeneity, so molecular markers of CAFs should be elucidated to better classify tumor-promoting subtypes and facilitate the establishment of CAF-specific targeted therapies. CAF-targeted cancer treatments may suppress EMT and regulate the niche of cancer stem cells and the immunosuppressive network and thus may prove useful for NSCLC treatment through multiple mechanisms.