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Review
. 2022 Jul 7;14(14):3321.
doi: 10.3390/cancers14143321.

Cancer-Associated Fibroblasts in the Hypoxic Tumor Microenvironment

Iljin Kim  1 , Sanga Choi  1 , Seongkyeong Yoo  1 , Mingyu Lee  2 , In-San Kim  3   4
Affiliations
Review

Cancer-Associated Fibroblasts in the Hypoxic Tumor Microenvironment

Iljin Kim et al. Cancers (Basel). .

Abstract

Solid cancers are composed of malignant cells and their surrounding matrix components. Hypoxia plays a critical role in shaping the tumor microenvironment that contributes to cancer progression and treatment failure. Cancer-associated fibroblasts (CAFs) are one of the most prominent components of the tumor microenvironment. CAFs are highly sensitive to hypoxia and participates in the crosstalk with cancer cells. Hypoxic CAFs modulate several mechanisms that induce cancer malignancy, such as extracellular matrix (ECM) remodeling, immune evasion, metabolic reprogramming, angiogenesis, metastasis, and drug resistance. Key signaling molecules regulating CAFs in hypoxia include transforming growth factor (TGF-β) and hypoxia-inducible factors (HIFs). In this article, we summarize the mechanisms underlying the hypoxic regulation of CAFs and how hypoxic CAFs affect cancer development and progression. We also discuss the potential therapeutic strategies focused on targeting CAFs in the hypoxic tumor microenvironment.

Keywords: cancer; cancer-associated fibroblast; hypoxia; tumor microenvironment.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
CAF-mediated cancer progression in hypoxia. Several mechanisms are involved in CAF-mediated cancer progression under hypoxia. HIF and TGF-β pathways play a major role in CAF activation and function. A number of genes have been demonstrated as direct transcriptional targets of HIF in either CAFs or cancer cells. Crosstalk between CAFs and cancer cells may alter ECM structure, immune responses, cell metabolism, angiogenesis, and metastasis through various signaling molecules (created with BioRender.com on June 2022).
Figure 2
Figure 2
CAF-mediated ECM remodeling in hypoxia. Hypoxia regulates extracellular environment via several mechanisms: post-translational modification of ECM proteins; ECM cross-linking; increasing ECM stiffness; collagen synthesis; collagen degradation; altering ECM-cell interactions. Abbreviations: HIF, hypoxia-inducible factor; TIMP1, TIMP metallopeptidase inhibitor 1; MMP, matrix metallopeptidase; P4HA, collagen prolyl hydroxylase; PLOD, lysyl hydroxylases; LOXL2, lysyl oxidase-like 2; TGF-β, transforming growth factor beta; PI3K, phosphoinositide 3-kinase; AKT, AKT serine/threonine kinase; FBLN5, fibulin (created with BioRender.com on June 2022).
Figure 3
Figure 3
CAF-mediated metabolic reprogramming in hypoxia. Hypoxia regulates cell metabolism via several mechanisms: switching of glucose metabolism; increasing glucose uptake; lactate production; lactate shuttling; autophagic activation; exosome release. Abbreviations: HIF, hypoxia-inducible factor; PDK1, pyruvate dehydrogenase kinase 1; PKM2, pyruvate kinase M1/2; MCT4, monocarboxylic acid transporter 4; NDUFA4L2, NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 4-like 2; GLUT1, glucose transporter 1; BNIP3, BCL2 interacting protein 3; ATP6V1G1, ATPase H+ transporting V1 subunit G1; TGF-β, transforming growth factor beta; CTGF, connective tissue growth factor (created with BioRender.com on June 2022).
See this image and copyright information in PMC

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