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.
Highlights
Pancreatic cancer (PC) remains a highly fatal malignancy and is the fourth leading cause of cancer-related mortality in both sexes in the US [1], while it is the sixth leading cause of cancer-related mortality in China [2]
We summarized the molecular mechanisms underlying hypoxia-mediated malignant
Another study demonstrated that KRAS/MEK/ERK signaling exacerbates hypoxia-driven Hypoxia-inducible factors (HIF)-1α and HIF-2α protein stability in pancreatic ductal adenocarcinoma (PDAC) cells that express activated KRAS, followed by upregulation of downstream HIF-1α-induced effectors such as Carbonic anhydrase IX (CA9) and monocarboxylate transporter (MCT) 4, leading to perturbation of pH regulation and metabolic rewiring toward a glycolytic phenotype [41]
Summary
Pancreatic cancer (PC) remains a highly fatal malignancy and is the fourth leading cause of cancer-related mortality in both sexes in the US [1], while it is the sixth leading cause of cancer-related mortality in China [2]. Another study demonstrated that KRAS/MEK/ERK signaling exacerbates hypoxia-driven HIF-1α and HIF-2α protein stability in PDAC cells that express activated KRAS, followed by upregulation of downstream HIF-1α-induced effectors such as CA9 and monocarboxylate transporter (MCT) 4, leading to perturbation of pH regulation and metabolic rewiring toward a glycolytic phenotype [41].
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