Hypoxia-Induced Signaling Promotes Prostate Cancer Progression: Exosomes Role as Messenger of Hypoxic Response in Tumor Microenvironment

Abstract

Prostate cancer (PCA) is the leading malignancy in men and the second leading cause of cancer-related deaths. Hypoxia (low O2 condition) is considered an early event in prostate carcinogenesis associated with an aggressive phenotype. In fact, clinically, hypoxia and hypoxia-related biomarkers are associated with treatment failure and disease progression. Hypoxia-inducible factor 1 (HIF-1) is the key factor that is activated under hypoxia, and mediates adaptation of cells to hypoxic conditions through regulating the expression of genes associated with angiogenesis, epithelial-to-mesenchymal transition (EMT), metastasis, survival, proliferation, metabolism, sternness, hormone-refractory progression, and therapeutic resistance. Besides HIF-1, several other signaling pathways including PI3K/Akt/mTOR, NADPH oxidase (NOX), Wnt/b-catenin, and Hedgehog are activated in cancer cells under hypoxic conditions, and also contribute in hypoxia-induced biological effects in HIF-1-dependent and -independent manners. Hypoxic cancer cells cause extensive changes in the tumor microenvironment both local and distant, and recent studies have provided ample evidence supporting the crucial role of nanosized vesicles "exosomes" in mediating hypoxia-induced tumor microenvironment remodeling. Exosomes' role has been reported in hypoxia-induced angiogenesis, sternness, activation of cancer-associated fibroblasts (CAFs), and EMT. Together, existing literature suggests that hypoxia plays a predominant role in PCA growth and progression, and PCA could be effectively prevented and treated via targeting hypoxia/hypoxia-related signaling pathways.

FIG. 1

Activation of signaling pathways in hypoxic cancer cells. In hypoxic cancer cells, several signaling pathways are activated including HIF-1α, PI3K/Akt/mTOR, Wnt/β-catenin, NOX, and Hedgehog. These signaling pathways have significant cross talk, and together they contribute to hypoxia-induced cancer cells survival, proliferation, angiogenesis, stemness, EMT, metastasis, and androgen-independent growth.

FIG 2

Exosomes act as messenger of hypoxic response in cancer cells. Biogenesis of exosomes is increased in hypoxic cancer cells dependent on HIF-1α and cellular lipid level, and in turn hypoxic cancer cells secrete higher amounts of exosomes loaded with unique cargo (miRNAs, proteins, and bioactive lipids). Hypoxic cancer cells exosomes uptake by receipt cells in the tumor microenvironment results in higher angiogenesis, EMT, CAF activation, and increased stemness.