Targeting hypoxic tumor microenvironment in pancreatic cancer

Abstract

Attributable to its late diagnosis, early metastasis, and poor prognosis, pancreatic cancer remains one of the most lethal diseases worldwide. Unlike other solid tumors, pancreatic cancer harbors ample stromal cells and abundant extracellular matrix but lacks vascularization, resulting in persistent and severe hypoxia within the tumor. Hypoxic microenvironment has extensive effects on biological behaviors or malignant phenotypes of pancreatic cancer, including metabolic reprogramming, cancer stemness, invasion and metastasis, and pathological angiogenesis, which synergistically contribute to development and therapeutic resistance of pancreatic cancer. Through various mechanisms including but not confined to maintenance of redox homeostasis, activation of autophagy, epigenetic regulation, and those induced by hypoxia-inducible factors, intratumoral hypoxia drives the above biological processes in pancreatic cancer. Recognizing the pivotal roles of hypoxia in pancreatic cancer progression and therapies, hypoxia-based antitumoral strategies have been continuously developed over the recent years, some of which have been applied in clinical trials to evaluate their efficacy and safety in combinatory therapies for patients with pancreatic cancer. In this review, we discuss the molecular mechanisms underlying hypoxia-induced aggressive and therapeutically resistant phenotypes in both pancreatic cancerous and stromal cells. Additionally, we focus more on innovative therapies targeting the tumor hypoxic microenvironment itself, which hold great potential to overcome the resistance to chemotherapy and radiotherapy and to enhance antitumor efficacy and reduce toxicity to normal tissues.

Keywords: Angiogenesis; Autophagy; EMT and metastasis; Hypoxia; Innovative therapies; Metabolic reprogramming; Pancreatic cancer; Redox homeostasis; Stemness; Therapeutic resistance.

Fig. 1

Oxygen-dependent transcriptional regulation of HIFs. Under normoxic conditions, HIF-α protein is continually transcribed and rapidly degraded owing to the posttranslational hydroxylation of highly conserved proline residues by PHDs. Oxygen, Fe²⁺, and α-KG are substrates in this reaction. HIF-α, with hydroxyl group tags, subsequently interacts with the Von Hippel-Lindau protein (pVHL) E3 ubiquitin ligase complex for degradation via the ubiquitin–proteasome pathway. Under hypoxia, the activities of factor inhibiting HIFs (FIHs) and PHDs are suppressed, and thus HIF-α is stabilized and translocated into the nucleus to bind with HIF-β. Inhibition of PHDs and activation of p38 MAPK mediated by ROS are involved in HIF-α stabilization. With the help of transcriptional coactivators such as cyclic adenosine monophosphate response element-binding protein (CBP) and acetyltransferase (p300), the resultant heterodimeric HIF-α/β dimer binds to HREs and transcriptionally activates the targeted genes involved in malignant phenotypes and protumor mechanisms of PC. Abbreviations: Asn, asparagine; Pro, proline

Fig. 2

Molecular crosstalk among hypoxia-induced malignant phenotypes in PC. Hexagons represent phenotypes. Arrows indicate positive modulations, while blunt ends indicate negative modulations. Abbreviations: Gem, gemcitabine; QSOX1, quiescin sulfhydryl oxidase 1; LASP-1, LIM and SH3 protein 1

Fig. 3

Effects of microenvironmental remodeling on PC progression under hypoxia. Hypoxia-driven ROS production activates PSCs to secrete various soluble factors, favoring the malignant phenotypes of PC. Hypoxia-stimulated TGF-α signaling induces Fbln5 expression through a PI3K/AKT-dependent mechanism in A-PSC, and Fbln5 competes with fibronectin for integrin binding and reduces ROS production. Upward arrows indicate upregulation of expression, and other arrows indicate positive modulations or release of molecules. Abbreviations: A-PSC, activated pancreatic stellate cells; Gem, gemcitabine; Q-PSC, quiescent pancreatic stellate cells

Fig. 4

Summary of hypoxia-based therapeutic strategies for PC. Arrows indicate positive modulations or transitions, while blunt ends indicate negative modulations. Abbreviations: HAPs, hypoxia-activated prodrugs; NIR, near-infrared radiation; PDT, photodynamic therapy; SDT, sonodynamic therapy; UV, ultraviolet