The role of hypoxia in pancreatic cancer: a potential therapeutic target?

ABSTRACT

One of the key factors that correlates with poor survival of patients with pancreatic cancer is the extent of hypoxic areas within the tumor tissue. The adaptation of pancreatic cancer cells to limited oxygen delivery promotes the induction of an invasive and treatment-resistant phenotype, triggering metastases at an early stage of tumor development, which resist in most cases adjuvant therapies following tumor resection. In this article, the authors summarize the evidence demonstrating the significance of hypoxia in pancreatic cancer pathogenesis and discuss the possible hypoxia-induced mechanisms underlying its aggressive nature. We then conclude with promising strategies that target hypoxia-adapted pancreatic cancer cells.

KEYWORDS:

• Pancreatic cancer
• hypoxia
• desmoplasia
• metabolism
• TH-302
• PEGPH20
• epithelial-to-mesenchymal transition
• cancer stem cell

Financial & competing interests disclosure

M Erkan and J Kleeff are members of the Expert Tumour Hypoxia Steering Committee and have acted as consultants for Merck-Serono, Merck KGaA, Darmstadt, Germany. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• Pancreatic cancer is significantly more hypoxic when compared to other solid tumors. However, while there are several methods to measure the extent of hypoxia in pancreatic cancer tissues in vivo, their sensitivity and specificity differ significantly compromising the assessment of the amount and localization of hypoxic areas.

• When oxygen is limited, hypoxia-inducible pathways become activated, which in turn initiate a cascade of events that reinforces the aggressiveness of pancreatic cancer.

• Among hypoxia-activated pathways, the most studied is hypoxia-inducible factor-1 (HIF-1), which governs metabolism, apoptosis, and invasion-related mechanisms. Thus, the outcome of high HIF-1 is poor survival of pancreatic cancer patients; however, it should be noted that its expression can be up-regulated also by oxygen-independent pathways.

• Adaptation of hypoxia forces pancreatic cancer cells to acquire metabolic alterations that allow them to utilize various types of nutrients. On the other hand, these metabolic alterations may also be vulnerable for targeting, and agents for this purpose are under development.

• A key feature of hypoxia adaptation is epithelial-to-mesenchymal transition, which is one of the initiating factors of the metastatic cascade. Several signaling pathways have been implicated in epithelial-to-mesenchymal transition; however, the exact mechanisms remain elusive.

• While HIF-1 is responsible for several of the hypoxia-related features of pancreatic cancer that underlie its fatal clinical course, currently there is no promising clinical agent that can effectively target this transcription factor.

• A unique feature of pancreatic cancer histology is the extensive desmoplasia that surrounds the tumor tissue. There is a highly complex relationship between fibrosis and hypoxia amplifying each other and thereby reinforcing the metastatic and treatment-resistant phenotype of pancreatic cancer.

• There are contradictory reports regarding the role of components of oncogenic pathways, extracellular matrix, and the tumor microenvironment in pancreatic cancer progression and therefore clinical application of any promising target requires extensive preclinical investigation to avoid unexpected outcomes. The failure of the Hedgehog signaling inhibitor trial is a good example regarding this issue.

• There are several strategies to target the hypoxic portions of pancreatic cancer that are under preclinical and clinical development.