Cancer-Associated Fibroblasts in the Hypoxic Tumor Microenvironment

SIMPLE SUMMARY: Cancers have regions of low oxygen concentration where hypoxia-related signaling pathways are activated. The hypoxic tumor microenvironment has been widely accepted as a hallmark of cancer and shown to be a critical factor in the crosstalk between cancer and stromal cells. Fibroblasts are one of the most abundant cellular components in the tumor stroma and are also significantly affected by oxygen deprivation. In this case, we discuss the molecular and cellular mechanisms that regulate fibroblasts under hypoxic conditions and their effect on cancer development and progression. Unraveling these regulatory mechanisms could be exploited in developing potential fibroblast-specific therapeutics for cancer. 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.