Fight the Cancer, Hit the CAF!

Abstract

The tumor microenvironment (TME) is comprised of different cellular components, such as immune and stromal cells, which co-operate in unison to promote tumor progression and metastasis. In the last decade, there has been an increasing focus on one specific component of the TME, the stromal component, often referred to as Cancer-Associated Fibroblasts (CAF). CAF modulate the immune response and alter the composition of the extracellular matrix with a decisive impact on the response to immunotherapies and conventional chemotherapy. The most recent publications based on single-cell analysis have underlined CAF heterogeneity and the unique plasticity that strongly impact the TME. In this review, we focus not only on the characterization of CAF based on the most recent findings, but also on their impact on the immune system. We also discuss clinical trials and preclinical studies where targeting CAF revealed controversial results. Therefore, future efforts should focus on understanding the functional properties of individual subtypes of CAF, taking into consideration the peculiarities of each pathological context.

DDIT4 promotes malignancy of head and neck squamous cell carcinoma

“…CAFs are an important TME component and play crucial roles in tumor progression, angiogenesis, metastasis, and extracellular matrix remodeling. CAFs are also critical regulators of tumor immunity, and can release a specific set of immunomodulatory proteins that potentially regulate both adaptive and innate immunity against tumor 29,38 . Importantly, hypoxia, particularly via hypoxic induction of ROS, could induce the TGF‐b and PDGF secretions in tumor cells, potentially contributing to the precursor‐to‐CAF differentiation 38,49 .…”

“…Hypoxia also leads to significant remodeling of CAF proteome, inducing angiogenic sprouting. In turn, CAFs can also trigger metabolism‐related pathways to regulate the tumor cell‐produced metabolites (potentially toxic, such as lactate) to sustain tumor development 29,50 . For instance, ovarian cancer cell‐secreted LPA could regulate HIF‐1a transcription by binding to the LPA receptor of activated fibroblasts, inducing them to gradually upregulate glycolysis via metabolic pathways 29,51 .…”

“…In turn, CAFs can also trigger metabolism‐related pathways to regulate the tumor cell‐produced metabolites (potentially toxic, such as lactate) to sustain tumor development 29,50 . For instance, ovarian cancer cell‐secreted LPA could regulate HIF‐1a transcription by binding to the LPA receptor of activated fibroblasts, inducing them to gradually upregulate glycolysis via metabolic pathways 29,51 . The lactate released during the process intensified the oxidative stress in the TME, resulting in concurrent activation of autophagy 29,52 .…”

“…Besides, fibroblast activation, which results into cancer‐associated fibroblasts (CAFs), has been shown to have regulatory effect on tumor progression. Differentiation of CAFs in the TME occurs in a TGF‐β dependent manner 29 . CAFs contribute critical roles in angiogenesis, extracellular matrix remodeling, tumor growth, metastasis, and immune regulation, either through direct interaction with tumor cells or by releasing matrix metalloproteinases, extracellular matrix components, chemokines, angiogenesis‐inducing molecules, or other cytokines 29,30 .…”

“…Differentiation of CAFs in the TME occurs in a TGF-β dependent manner. 29 CAFs contribute critical roles in angiogenesis, extracellular matrix remodeling, tumor growth, metastasis, and immune regulation, either through direct interaction with tumor cells or by releasing matrix metalloproteinases, extracellular matrix components, chemokines, angiogenesis-inducing molecules, or other cytokines. 29,30 A better understanding of TME may improve the overall effectiveness of immunotherapy in HNSCC treatment.…”