Hypoxia and Neuroblastoma Tumorigenesis

Neuroblastoma is the most common pediatric solid tumor that arises from the sympathetic nervous system. Neuroblastoma tumors exhibit clinical and biological heterogeneity associated with certain genetic aberrations. Advanced stage neuroblastoma is refractory to all conventional therapeutic modalities and is associated with a dismal prognosis. The cure rate of children with high-risk stage IV neuroblastoma remains low, providing a compelling reason to better understand the molecular mechanisms that can be targeted to treat this disease.

Neuroblastoma tumors present hypoxic areas and metastasize to sites such as bone and bone marrow. Hypoxia induces a multitude of biological responses in cells and also alters neuronal characteristics of human neuroblastoma cells. Hypoxia-inducible factors (HIFs) are transcriptional regulators that mediate the cellular response to low oxygen. Although HIF-1α is usually considered as the principal mediator of hypoxic adaptation, several tissues and different cell types express both HIF-1α and HIF-2α isoforms under hypoxia. HIFs are also implicated in the progression of several cancer forms including neuroblastoma.

Transient hypoxia and subsequent reoxygenation is a common phenomenon occurring within most solid tumors. Intermittent hypoxic tumor cells have the potential to influence the in tumor response to therapy. In our laboratory, we study the effects of intermittent hypoxia/HIFs on tumor cell clonogenicity, differentiation and tumorigenicity using in vitro and in vivo approaches. These studies should generate major insights into the pathogenesis of intermittent hypoxia-induced alterations in neuroblastoma tumors and in turn should suggest novel targets for therapeutic interventions.