Hypoxia inducible factor (HIF) in the tumor microenvironment: friend or foe?

Abstract

Hypoxia acts as an important regulator of physiological and pathological processes. Hypoxia inducible factors (HIFs) are the central players involved in the cellular adaptation to hypoxia and are regulated by oxygen sensing EGLN prolyl hydroxylases. Hypoxia affects many aspects of cellular growth through both redox effects and through the stabilization of HIFs. The HIF isoforms likely have differential effects on tumor growth via alteration of metabolism, growth, and self-renewal and are likely highly context-dependent. In some tumors such as renal cell carcinoma, the EGLN/HIF axis appears to drive tumorigenesis, while in many others HIF1 and HIF2 may actually have a tumor suppressive role. An emerging role of HIF biology is its effects on the tumor microenvironment. The EGLN/HIF axis plays a key role in regulating the function of the various components of the tumor microenvironment, which include cancer-associated fibroblasts, endothelial cells, immune cells, and the extracellular matrix (ECM). Here, we discuss hypoxia and the diverse roles of HIFs in the setting of tumorigenesis and the maintenance of the tumor microenvironment as well as possible future directions of the field.

Keywords: HIF; cellular homeostasis; hypoxia; mouse model; tumor microenvironment.

Figure 1

The diverse physiological roles of HIF protein

Figure 2

Components of Human HIF heterodimer.

Figure 3

Oxygen-dependent regulation of HIFα protein.

Figure 4

The oncogenic and tumor suppressive activity of HIF in tumor and stromal cells.

Figure 5

Dual recombinase system for pancreatic cancer. Flp recombinase directs tumorigenesis in the target tissue by a tissue-specific Flp (in this case, Pdx1-FlpO), which activates Kras and knocks out Trp53. This leaves stromal components available to be regulated by the Cre/lox system.