Article

Targeting angiogenesis in pancreatic cancer: rationale and pitfalls

Department of Medicine, Dartmouth Hitchcock Medical Center and Dartmouth Medical School, Hanover, NH, USA.
Langenbeck s Archives of Surgery (Impact Factor: 2.16). 02/2008; 393(6):901-10. DOI: 10.1007/s00423-008-0280-z
Source: PubMed

ABSTRACT INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer responsible for over 20% of deaths due to gastrointestinal malignancies. PDAC is usually diagnosed at an advanced stage which, in part, helps to explain its high resistance to chemotherapy and radiotherapy. In addition, the cancer cells in PDAC have a high propensity to metastasize and to aberrantly express several key regulators of angiogenesis and invasion. Chemotherapy has only provided a modest impact on mean survival and often induces side effects. Targeting angiogenesis alone or in combination with other modalities should be investigated to determine if it may provide for increased survival. MATERIALS AND METHODS: This review summarizes the alterations in PDAC that play a critical role in angiogenesis and provides an overview of current and therapeutic strategies that may be useful for targeting angiogenesis in this malignancy.

Download full-text

Full-text

Available from: Chery A Whipple, Sep 26, 2014
1 Follower
 · 
69 Views
 · 
24 Downloads
  • Source
    • "Unlike other cancers, PDAC has been considered a non-vascular cancer9. Nevertheless, multiple studies have provided ample evidence in support of a positive correlation between vascular density and PDAC progression8940. Moreover, studies find pancreatic cancer cells directly involved in modulation of tumor angiogenesis in vivo through paracrine-autocrine loops, and VEGF signaling has been considered a prime promoting factor9. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The complex signaling networks between cancer cells and adjacent endothelial cells make it challenging to unravel how cancer cells send extracellular messages to promote aberrant vascularization or tumor angiogenesis. Here, in vitro and in vivo models show that pancreatic cancer cell generated unique microenvironments can underlie endothelial cell migration and tumor angiogenesis. Mechanistically, we find that pancreatic cancer cell secreted CCN1/Cyr61 matricellular protein rewires the microenvironment to promote endothelial cell migration and tumor angiogenesis. This event can be overcome by Sonic Hedgehog (SHh) antibody treatment. Collectively, these studies identify a novel CCN1 signaling program in pancreatic cancer cells which activates SHh through autocrine-paracrine circuits to promote endothelial cell migration and tumor angiogenesis and suggests that CCN1 signaling of pancreatic cancer cells is vital for the regulation of tumor angiogenesis. Thus CCN1 signaling could be an ideal target for tumor vascular disruption in pancreatic cancer.
    Scientific Reports 05/2014; 4:4995. DOI:10.1038/srep04995 · 5.58 Impact Factor
  • Source
    • "chemotherapy (Verma et al, 2006; Whipple and Korc, 2008), and poor prognosis in PDAC patients (Hiraoka et al, 2010). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Hypoxia is a driving force in pancreatic-ductal-adenocarcinoma (PDAC) growth, metastasis and chemoresistance. The muscle-isoform of lactate dehydrogenase (LDH-A) constitutes a major checkpoint for the switch to anaerobic glycolysis, ensuring supply of energy and anabolites in hypoxic-environments. Therefore, we investigated the molecular mechanisms underlying the pharmacological interaction of novel LDH-A inhibitors in combination with gemcitabine in PDAC cells. Methods: Lactate dehydrogenase A levels were studied by quantitative RT–PCR, western blot, immunofluorescence and activity assays in 14 PDAC cells, including primary-cell-cultures and spheroids, in normoxic and hypoxic conditions. Cell proliferation, migration and key determinants of drug activity were evaluated by sulforhodamine-B-assay, wound-healing assay, PCR and LC-MS/MS. Results: Lactate dehydrogenase A was significantly increased under hypoxic conditions (1% O2), where the novel LDH-A inhibitors proved to be particularly effective (e.g., with IC50 values of 0.9 vs 16.3 μM for NHI-1 in LPC006 in hypoxia vs normoxia, respectively). These compounds induced apoptosis, affected invasiveness and spheroid-growth, reducing expression of metalloproteinases and cancer-stem-like-cells markers (CD133+). Their synergistic interaction with gemcitabine, with combination index values <0.4 in hypoxia, might also be attributed to modulation of gemcitabine metabolism, overcoming the reduced synthesis of phosphorylated metabolites. Conclusion: Lactate dehydrogenase A is a viable target in PDAC, and novel LDH-A inhibitors display synergistic cytotoxic activity with gemcitabine, offering an innovative tool in hypoxic tumours.
    British Journal of Cancer 10/2013; 110(1). DOI:10.1038/bjc.2013.681 · 4.82 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Mithramycin (MIT) and tolfenamic acid (TA) inhibit the activity of the transcription factor Sp1. In the present study, we investigated whether pancreatic cancer treatment with a combination of these compounds has a synergistic effect on Sp1 activity, tumor growth, and their underlying response mechanisms. Treatment of pancreatic tumor xenografts with MIT and TA produced dose-dependent antitumor activity, and significant antitumor activity of either compound alone was directly associated with systemic side effects. Combination treatment with nontoxic doses of both compounds produced synergistic antitumor activity, whereas treatment with a nontoxic dose of either compound alone lacked a discernible antitumor effect. Synergistic therapeutic effects correlated directly with synergistic antiproliferation and antiangiogenesis in vitro. Moreover, combination treatment resulted in Sp1 protein degradation, drastically downregulating expression of Sp1 and vascular endothelial growth factor. Our findings established that Sp1 is a critical target of TA and MIT in human pancreatic cancer therapy, rationalizing clinical studies to determine the effect of existing pancreatic cancer therapy regimens on Sp1 signaling in tumors and normal pancreatic tissue, and the ability of Sp1-targeting strategies to modify cancer responses.
    Cancer Research 02/2010; 70(3):1111-9. DOI:10.1158/0008-5472.CAN-09-3282 · 9.28 Impact Factor
Show more