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: 2.19). 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.

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Available from: Chery A Whipple, Sep 26, 2014
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    • "Although PDAC is generally a hypovascular tumor, there was significant interest in using anti-VEGF agents in PDAC in the early 2000s because VEGF expression was thought to protect the tumor endothelium and tumor cells from cytotoxic agents and radiation [12]. Indeed, angiogenesis is a fundamental phenomenon associated with the development and progression of almost every type of cancer including pancreatic cancer13141516 . Neovascularization promotes the growth of tumor cells by nourishing them with oxygen and nutrients. "
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    ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) has a high mortality rate and outcomes have not improved substantially for decades. Significant attention has focused on the biological drivers of the disease, and preclinical work has pointed to multiple biomarker candidates and therapeutic avenues. However, translation of these promising biomarkers and treatment strategies to patients has not been overwhelmingly successful. New strategies to account for the significant heterogeneity of the disease are needed so that rational treatments can be administered. Here, we focus on how physical sciences-based approaches may play a role in stratifying patients for clinical trials, and how this view of PDAC may reinvigorate treatment strategies that have been abandoned after "failing" to fulfill their potential in unselected patient populations. By complementing biological approaches, the development of physical biomarkers of PDAC may help deliver on the promise of personalized medicine for this devastating disease.
    Full-text · Article · Jan 2016 · Cancer letters
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    • "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. "
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    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.
    Full-text · Article · May 2014 · Scientific Reports
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    • "chemotherapy (Verma et al, 2006; Whipple and Korc, 2008), and poor prognosis in PDAC patients (Hiraoka et al, 2010). "
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    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.
    Full-text · Article · Oct 2013 · British Journal of Cancer
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