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 angiogenesisrelated 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 ␦) of the angiogenic network markedly impairs angiogenesis and tumor growth. Further, in tumor patients, we show that peroxisome proliferative-activated receptor ␦ 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.angiogenesis ͉ cancer therapy ͉ homeostatic balance ͉ systems biology ͉ pancreatic carcinoma

A Roundabout Way to Cancer

“…In contrast, only one study has reported detection of Slit1 in the vasculature (Abdollahi et al, 2007), suggesting that it may not play a key role in developmental and tumor angiogenesis, although future studies may change this view. As for Slit receptors, Robo4 appears to be expressed by all endothelial cells, whereas Robo1 may only be expressed on some types of blood vessels (Huminiecki et al, 2002; Legg et al, 2008; Mura et al, 2011; Park et al, 2003; Sheldon et al, 2009; Verissimo et al, 2009).…”

“…Elevated levels of Robo1 are seen in several pathological animal models, such as retinopathy of prematurity and neovascularized corneas (Han and Zhang, 2010; Huang et al, 2009a). Robo1 was also identified as a putative pro-angiogenic gene in assays to elucidate human genes whose expression correlates with either increased or decreased angiogenesis (Abdollahi et al, 2007). Taken together these data suggest that Robo1 functions to restrict angiogenesis, either on its own or in a complex with Robo4, but additional studies are required to fully elucidate its role during developmental and pathological angiogenesis.…”

PPARδ promotes oncogenic redirection of TGF-β1 signaling through the activation of the ABCA1-Cav1 pathway

“…15 In colorectal cancer cells, loss of APC upregulates PPARδ through the β-catenin/TCF-4 cascade, and targeted deletion of PPARδ attenuates intestinal adenoma growth in Apc Min/+ mice. 16,17 However, other studies show that PPARδ deletion enhances polyp growth in Apc Min/+ mice, and PPARδ activation attenuates colon carcinogenesis.…”

Epithelial NEMO/IKKγ limits fibrosis and promotes regeneration during pancreatitis

“…(D) Published microarray data (ArrayExpress, accession number E-European Molecular Biology Laboratory (E-EMBL)-6) were reanalysed for a correlation between the expression of CXCR4 and the profibrogenic genes COL1A2 and FN1 (encoding fibronectin). Shown are the Affymetrix intensities 23. (E) Expression of CXCR4 in human chronic pancreatitis visualised by immunohistochemistry.…”