Cancer-associated fibroblasts in nonsmall cell lung cancer: From molecular mechanisms to clinical implications

Abstract

Lung cancer is the common and leading cause of cancer death worldwide. The tumor microenvironment has been recognized to be instrumental in tumorigenesis. To have a deep understanding of the molecular mechanism of nonsmall cell lung carcinoma (NSCLC), cancer-associated fibroblasts (CAFs) have gained increasing research interests. CAFs belong to the crucial and dominant cell population in the tumor microenvironment to support the cancer cells. The interplay and partnership between cancer cells and CAFs contribute to each stage of tumorigenesis. CAFs exhibit prominent heterogeneity and secrete different kinds of cytokines and chemokines, growth factors and extracellular matrix proteins involved in cancer cell proliferation, invasion, metastasis and chemoresistance. Many studies focused on the protumorigenic functions of CAFs, yet many challenges about the heterogeneity of CAFS remain unresolved. This review comprehensively summarized the tumor-promoting role and molecular mechanisms of CAFs in NSCLC, including their origin, phenotypic changes and heterogeneity and their functional roles in carcinogenesis. Meanwhile, we also highlighted the updated molecular classifications based on the molecular features and functional roles of CAFs. With the development of cutting-edge platforms and further investigations of CAFs, novel therapeutic strategies for accurately targeting CAFs in NSCLC may be developed based on the increased understanding of the relevant molecular mechanisms.

Keywords: cancer-associated fibroblast; heterogeneity; nonsmall-cell lung cancer; tumor microenvironment.

FIGURE 1

The origin, activating factors and subpopulations of cancer‐associated fibroblasts (CAFs) in nonsmall‐cell lung cancer (NSCLC) are diverse and heterogeneous. (A) Multiple activating factors promote the transition from normal fibroblasts to CAFs in the tumor microenvironment. (B) The diversity of CAF sources. CAFs are not only derived from resident fibroblasts, but also from other cell types, including stellate cell, mesenchymal stem cell, epithelial cell, pericyte and even adipocyte. (C) Various classification systems for lung cancer CAFs to define subpopulations based on molecular features and functional roles (created with BioRender.com) [Color figure can be viewed at wileyonlinelibrary.com]

FIGURE 2

The expression and clinical significance of cancer‐associated fibroblasts (CAFs)‐related biomarkers in lung cancer. The expression level of multiple CAF biomarkers is based on (A) AJCC stages, (B) T stages and (C) M stages. The high expression of related CAF markers is associated with advanced AJCC stage, tumor invasion and distant metastasis. (D) High expression of several CAF markers is associated with unfavorable clinical outcomes in nonsmall‐cell lung cancer (NSCLC) (TCGA cohort), suggesting the promoting role of CAFs in lung cancer progression [Color figure can be viewed at wileyonlinelibrary.com]

FIGURE 3

The protumorigenic roles of cancer‐associated fibroblasts (CAFs) in nonsmall‐cell lung cancer (NSCLC). CAFs secrete multiple cytokines, chemokines and growth factors to directly stimulate (A) cancer cell proliferation, (B) invasion and metastasis, (C) angiogenesis, (D) immune evasion and (E) resistance to treatment. Meanwhile, the CAFs also shape the tumor microenvironment through remodeling the extracellular matrix (ECM) to provide a chemoresistance mechanism (created with BioRender.com) [Color figure can be viewed at wileyonlinelibrary.com]