Influence of hypoxia and neoangiogenesis on the growth of pancreatic cancer

Abstract

As with other solid tumors, the growth and metastasis of pancreatic cancer is critically dependent on tumor angiogenesis. A major stimulus for a tumor's recruitment of additional blood vessels is cellular hypoxia, a condition which is especially pronounced in this neoplasm. Hypoxia induces transcriptional activation of genes that alter cellular metabolism and promote neoangiogenesis. Pancreatic cancer cells have demonstrated activation of such adaptive pathways even in the absence of hypoxia. A highly-angiogenic response in this neoplasm correlates with increased tumor growth, increased metastasis, and decreased survival. Pancreatic cancers expressing high levels of vascular endothelial growth factor, a potent pro-angiogenic cytokine, also have a higher incidence of metastasis and poorer prognosis. Pancreatic cancer cells uniquely express receptors for vascular endothelial growth factor, indicating a role for an autocrine loop in tumor proliferation and invasion. Multiple experimental anti-angiogenic strategies, many of which target vascular endothelial growth factor, reduce pancreatic cancer growth, spread, and angiogenesis. Anti-angiogenic treatments for pancreatic cancer will likely be most effective when used as an integral part of a combination chemotherapeutic regimen.

Figure 1

Structure of the HIF-1 Complex. The hypoxia inducible factor 1 complex (HIF-1) is a dimer composed of two proteins involved in hypoxic gene transactivation, HIF-1α and HIF-1β (ARNT). Dimerization between these two factors is mediated by the helix-loop-helix (HLH) and Per-ARNT-SIM domains, and DNA binding involves the basic (b-) region of the b-HLH domains. HIF-1 modulates transcription through its transactivation domains (TAD). Between amino acids 401 and 603, HIF-1α contains an oxygen-dependent degradation domain (ODD) which controls its degradation under normoxia [24]. Fig. 1

Figure 2

Molecular mechanisms of hypoxia-induced angiogenesis. Under normoxic conditions (panel A), HIF-1α is hydroxylated by the active prolyl-4-hydroxylase enzyme, which facilitates the binding of VHL protein and leads to rapid HIF-1α degradation by the ubiquitin proteasome system. In the face of hypoxia (panel B), the hydroxylase enzyme is inactive and HIF-1α is stabilized in its de-hydroxylated state. The stable HIF-1α translocates to the nucleus, where it accumulates and dimerizes with the constitutively expressed HIF-1β, forming the intact HIF-1 complex. This complex binds hypoxia response elements (HREs) in selective genes to alter transcriptional activity. A notable hypoxia-induced gene is that coding for vascular endothelial growth factor (VEGF), a cytokine which potently stimulates neoangiogenesis [24].