Influence of hypoxia and neoangiogenesis on the growth of pancreatic cancer.
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.
Duffy
John P
JP
Section of Gastrointestinal Surgery, The David Geffen School of Medicine at UCLA, 72-215 CHS, MC 690418, Los Angeles, CA 90095-6904, USA. jpduffy@ucla.edu
Eibl
Guido
G
Reber
Howard A
HA
Hines
Oscar J
OJ
D000818:Animals; D002455:Cell Division; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology*; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008954:Models, Biological; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D009687:Nuclear Proteins / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D014157:Transcription Factors / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A