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

Abstract

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.

Paracrine Regulation and Immune System Pathways in the Inflammatory Tumor Microenvironment of Lung Cancer: Insights into Oncogenesis and Immunotherapeutic Strategies

“…This EMT is also potentially subject to crosstalk with TNF-α, which enhances the EMT by causing cancer cells to switch to a cytokine- and chemokine-secreting phenotype, increasing the capacity for invasion [ 52 ]. Moreover, CAFs also play an integral role in this process through their secretion of IL-6 under TGF-β-mediated fibrosis [ 53 , 54 ].…”

Cell Proteomic Footprinting: Advances in the Quality of Cellular and Cell-Derived Cancer Vaccines

“…In addition human cancer cells, endothelial cells (human microvascular endothelial cells, HMECs), and fibroblasts of various origins are represented. These cell types, like cancer cells themselves, are also considered targets for immunotherapy, as they are part of the tumor microenvironment and are required to ensure its functioning [ 75 , 76 , 77 , 78 , 79 ].…”

“…CAFs actively participate in the regulation of different biological cancer behaviors such as carcinogenesis [ 82 ], metastasis [ 83 ], and therapy resistance [ 84 ]. Therefore, fibroblast subpopulations represent promising targets for cancer immunotherapy [ 76 , 77 , 78 , 85 ]. Footprints for three different subpopulations of human fibroblasts from the previously published studies [ 46 ] were compared: primary cultures of dermal papilla fibroblasts ( n = 17), adipose-derived fibroblasts ( n = 4), and skin fibroblasts ( n = 4).…”

AI‐guided histopathology predicts brain metastasis in lung cancer patients

“…However, innate and acquired resistance to therapies and disease progression to distant metastatic sites remain a significant cause of morbidity. An increased understanding of tumor biology has suggested that the tumor microenvironment of primary NSCLC may dictate future metastatic behavior [2][3][4]. Brain metastases, in particular, are a common cause of morbidity and mortality in NSCLC [5].…”