Transcriptional network governing the angiogenic switch in human pancreatic cancer.

Abstract

A shift of the angiogenic balance to the proangiogenic state, termed the "angiogenic switch," is a hallmark of cancer progression. Here we devise a strategy for identifying genetic participants of the angiogenic switch based on inverse regulation of genes in human endothelial cells in response to key endogenous pro- and antiangiogenic proteins. This approach reveals a global network pattern for vascular homeostasis connecting known angiogenesis-related genes with previously unknown signaling components. We also demonstrate that the angiogenic switch is governed by simultaneous regulations of multiple genes organized as transcriptional circuitries. In pancreatic cancer patients, we validate the transcriptome-derived switch of the identified "angiogenic network:" The angiogenic state in chronic pancreatitis specimens is intermediate between the normal (angiogenesis off) and neoplastic (angiogenesis on) condition, suggesting that aberrant proangiogenic environment contributes to the increased cancer risk in patients with chronic pancreatitis. In knockout experiments in mice, we show that the targeted removal of a hub node (peroxisome proliferative-activated receptor delta) of the angiogenic network markedly impairs angiogenesis and tumor growth. Further, in tumor patients, we show that peroxisome proliferative-activated receptor delta expression levels are correlated with advanced pathological tumor stage, increased risk for tumor recurrence, and distant metastasis. Our results therefore also may contribute to the rational design of antiangiogenic cancer agents; whereas "narrow" targeted cancer drugs may fail to shift the robust angiogenic regulatory network toward antiangiogenesis, the network may be more vulnerable to multiple or broad-spectrum inhibitors or to the targeted removal of the identified angiogenic "hub" nodes.

• Authors: Amir Abdollahi, Christian Schwager, Jörg Kleeff, Irene Esposito, Sophie Domhan, Peter Peschke, Kai Hauser, Philip Hahnfeldt, Lynn Hlatky, Jürgen Debus, Jeffrey M Peters, Helmut Friess, Judah Folkman, Peter E Huber
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 104 Issue 31 Pg. 12890-5 (Jul 31 2007) ISSN: 0027-8424 [Print] United States
• PMID: 17652168 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• PPAR delta

Topics

• Animals
• Gene Expression Regulation, Neoplastic
• Gene Regulatory Networks (genetics)
• Humans
• Mice
• Oligonucleotide Array Sequence Analysis
• PPAR delta (genetics)
• Pancreatic Neoplasms (blood supply, genetics, pathology)
• Signal Transduction
• Tumor Cells, Cultured