Transcriptional network governing the angiogenic switch in human pancreatic cancer.
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.
Abdollahi
Amir
A
Department of Radiation Oncology, German Cancer Research Center (DKFZ) and University of Heidelberg Medical School, Heidelberg 69120, Germany.
Schwager
Christian
C
Kleeff
Jörg
J
Esposito
Irene
I
Domhan
Sophie
S
Peschke
Peter
P
Hauser
Kai
K
Hahnfeldt
Philip
P
Hlatky
Lynn
L
Debus
Jürgen
J
Peters
Jeffrey M
JM
Friess
Helmut
H
Folkman
Judah
J
Huber
Peter E
PE
D000818:Animals; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks / Q000235:genetics*; D006801:Humans; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D047494:PPAR delta / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000098:blood supply* / Q000235:genetics* / Q000473:pathology; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D047494:PPAR delta