Hypoxia triggers hedgehog-mediated tumor-stromal interactions in pancreatic cancer.

Pancreatic cancer is characterized by a desmoplastic reaction that creates a dense fibroinflammatory microenvironment, promoting hypoxia and limiting cancer drug delivery due to decreased blood perfusion. Here, we describe a novel tumor-stroma interaction that may help explain the prevalence of desmoplasia in this cancer. Specifically, we found that activation of hypoxia-inducible factor-1α (HIF-1α) by tumor hypoxia strongly activates secretion of the sonic hedgehog (SHH) ligand by cancer cells, which in turn causes stromal fibroblasts to increase fibrous tissue deposition.

HIF-1alpha and cancer therapy.

Most solid tumors develop regions of hypoxia as they grow and outstrip their blood supply. In order to survive in the stressful hypoxic environment, tumor cells have developed a coordinated set of responses orchestrating their adaptation to hypoxia. The outcomes of the cellular responses to hypoxia are aggressive disease, resistance to therapy, and decreased patient survival.

Inhibiting the hypoxia response for cancer therapy: the new kid on the block.

The hypoxia-inducible transcription factor (HIF)-1alpha inhibitor KC7F2 described in this issue of Clinical Cancer Research is the newest addition to an emerging class of antitumor agents targeting the hypoxia response. Here, we discuss the proposed mechanism of action of KC7F2 and its potential strengths and limitations in comparison with other promising HIF-1alpha inhibitors.

HIF-1 regulation: not so easy come, easy go.

The hypoxia-inducible factor-1 (HIF-1) is the master regulator of the cellular response to hypoxia and its expression levels are tightly controlled through synthesis and degradation. It is widely accepted that HIF-1alpha protein accumulation during hypoxia results from inhibition of its oxygen-dependent degradation by the von Hippel Lindau protein (pVHL) pathway. However, recent data describe new pVHL- or oxygen-independent mechanisms for HIF-1alpha degradation.

TRAIL-induced cleavage and inactivation of SPAK sensitizes cells to apoptosis.

Ste20-related proline-alanine-rich kinase (SPAK) has been linked to various cellular processes, including proliferation, differentiation, and ion transport regulation. Recently, we showed that SPAK mediates signaling by the TNF receptor, RELT. The presence of a caspase cleavage site in SPAK prompted us to study its involvement in apoptotic signaling induced by another TNF member, TRAIL.