From Hypoxia to Bone: Reprogramming the Prostate Cancer Metastatic Cascade

Abstract

Bone is the most frequent site of distant metastasis in advanced prostate cancer (PCa), contributing substantially to patient morbidity and mortality. Hypoxia, a defining feature of the solid tumour microenvironment, plays a pivotal role in driving bone-tropic progression by promoting epithelial-to-mesenchymal transition (EMT), cancer stemness, extracellular matrix (ECM) remodelling, and activation of key signalling pathways such as Wingless/Integrated (Wnt) Wnt/β-catenin and PI3K/Akt. Hypoxia also enhances the secretion of extracellular vesicles (EVs), enriched with pro-metastatic cargos, and upregulates bone-homing molecules including CXCR4, integrins, and PIM kinases, fostering pre-metastatic niche formation and skeletal colonisation. In this review, we analysed current evidence on how hypoxia orchestrates PCa dissemination to bone, focusing on the molecular crosstalk between HIF signalling, Wnt activation, EV-mediated communication, and cellular plasticity. We further explore therapeutic strategies targeting hypoxia-related pathways, such as HIF inhibitors, hypoxia-activated prodrugs, and Wnt antagonists, with an emphasis on overcoming therapy resistance in castration-resistant PCa (CRPC). By examining the mechanistic underpinnings of hypoxia-driven bone metastasis, we highlight promising translational avenues for improving patient outcomes in advanced PCa.

Keywords: EMT; HIF-1α; Wnt signalling; bone metastasis; extracellular vesicles; hypoxia; prostate cancer; therapy resistance.

Figure 1

HIF the master regulator of the cellular response to low oxygen (hypoxia). Under normoxia, HIF-1α is hydroxylated by PHD enzymes. Hydroxylated HIF-1α binds to VHL protein. This complex is ubiquitinated and degraded by the proteasome. Under Hypoxia, PHD enzymes are inactive due to a lack of oxygen. HIF-1α escapes degradation, accumulates, and translocates to the nucleus where it dimerises with HIF-β (known as ARNT) and binds to hypoxia response elements in DNA. This activates transcription of hypoxia adaptive pathways.

Figure 2

HIF-1α regulated cellular functions. (A) Upregulates glucose importer (GLUT1), increases glycolytic flux (e.g., hexokinase HK & lactate dehydrogenase LD) and conversion to lactate (exported via MCT1), supporting rapid cell growth and survival in hypoxic environments (Warburg Effect). (B) Binds to hypoxia response elements in the VEGF promoter, enhancing its expression and stimulating angiogenesis. (C) Promotes EMT by activating the transcription factors—Snail, Slug, TWIST, and ZEB1/2—reducing cell–cell adhesion and polarity, and increasing motility and invasiveness. Enhances Wnt/β-catenin signalling by promoting β-catenin nuclear localisation and transcriptional activity. (D) Enhances the expression of MMPs that degrade the extracellular matrix. These changes collectively facilitate cancer cell migration, invasion, and metastasis under hypoxic conditions. (E) Enhances Notch receptor expression and activation of the Notch intracellular domain (NICD), which translocates to the nucleus to influence transcription of genes in angiogenesis, stem cell maintenance, and EMT. (F) Upregulates PD-L1 expression on tumour, which binds to PD-1 on T cells, suppressing their cytotoxic activity and promoting T cell exhaustion. Negatively regulates MHC class I expression, contributing to immune evasion in hypoxic tumour environments by less T cell receptor (TCR) binding. Up and down arrows indicate general movement of proteins in the cytoplasm and nucleus.

Figure 3

Targeted therapeutic strategies against hypoxia-induced EV signalling and bone metastasis. Hypoxia in the PCa tumour microenvironment stabilises HIF-1α, which transcriptionally upregulates pro-metastatic factors such as VEGF (angiogenesis), miR-210 (cell survival), and CAIX (pH regulation). This drives EMT, immune evasion, and release of EVs loaded with oncogenic and immunomodulatory cargo. Targeted therapies include HIF-1α inhibitors, (PX-478), hypoxia-activated prodrugs (TH-302), Wnt/β-catenin and EMT blockers (PRI-724, ICG-001, ZEB1/Snail siRNAs), and EV biogenesis inhibitors (GW4869, Rab27a blockade). The diagram illustrates how these processes promote pre-metastatic niche formation and bone colonisation. Combination approaches integrating hypoxia-targeted agents with immune checkpoint inhibitors or AR antagonists offer promising avenues for combating bone metastasis in CRPC. Red T-bar arrows indicate direct molecular inhibition of hypoxia-induced pathways and blue T-bar arrows indicate inhibition of downstream metastatic processes. Created by BioRender Science Suite Inc (Toronto, ON, Canada).