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      Angiogenesis in pancreatic ductal adenocarcinoma: A controversial issue

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          Abstract

          Pancreatic ductal adenocarcinoma (PDAC) occurs in the majority of cases with early loco-regional spread and distant metastases at diagnosis, leading to dismal prognosis with a 5-year overall survival rate moderately over than 5%. This malignancy is largely resistant to chemotherapy and radiation, but the reasons of the refractoriness to the therapies is still unknown. Evidence is accumulating to indicate that the PDAC microenvironment and vascularity strongly contribute to the clinical features of this disease. In particular, PDAC is characterized by excessive dense extracellular matrix deposition associated to vasculature collapse and hypoxia with low drug delivery, explaining at least partly the low efficacy of antiangiogenic drugs in this cancer. Strategies aimed to modulate tumor stroma favoring vasculature perfusion and chemotherapeutics delivery are under investigation.

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          Genetics and biology of pancreatic ductal adenocarcinoma.

          Aram Hezel, Alec C Kimmelman, Ben Z. Stanger … (2006)
          Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in the United States with a median survival of <6 mo and a dismal 5-yr survival rate of 3%-5%. The cancer's lethal nature stems from its propensity to rapidly disseminate to the lymphatic system and distant organs. This aggressive biology and resistance to conventional and targeted therapeutic agents leads to a typical clinical presentation of incurable disease at the time of diagnosis. The well-defined serial histopathologic picture and accompanying molecular profiles of PDAC and its precursor lesions have provided the framework for emerging basic and translational research. Recent advances include insights into the cancer's cellular origins, high-resolution genomic profiles pointing to potential new therapeutic targets, and refined mouse models reflecting both the genetics and histopathologic evolution of human PDAC. This confluence of developments offers the opportunity for accelerated discovery and the future promise of improved treatment.
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            Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: phase III trial of the Cancer and Leukemia Group B (CALGB 80303).

            Hedy Lee Kindler, Donna Niedzwiecki, Donna Hollis … (2010)
            The combination of gemcitabine plus bevacizumab produced a 21% response rate and a median survival of 8.8 months in a multicenter phase II trial in patients with metastatic pancreatic cancer. These encouraging data led Cancer and Leukemia Group B (CALGB) to conduct a double-blind, placebo-controlled, randomized phase III trial of gemcitabine/bevacizumab versus gemcitabine/placebo in advanced pancreatic cancer patients. Eligible patients had no prior therapy for advanced disease, Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2, no tumor invasion of adjacent organs, and no increased bleeding risk. The primary end point was overall survival. Patients were stratified by performance status, extent of disease, and prior radiotherapy. Patients received gemcitabine at 1,000 mg/m(2) over 30 minutes on days 1, 8, and 15 every 28 days and bevacizumab at 10 mg/kg or placebo on days 1 and 15 every 28 days. Between June 2004 and April 2006, 602 patients were enrolled onto the study and 535 were treated. Median overall survival was 5.8 months for gemcitabine/bevacizumab and 5.9 months for gemcitabine/placebo (P = .95). Median progression-free survival was 3.8 and 2.9 months, respectively (P = .07). Overall response rates were 13% and 10%, respectively. Patients with a performance status of 0, 1, and 2 survived a median of 7.9, 4.8, and 2.4 months, respectively. The only statistically significant differences in grades 3 and 4 toxicity occurred for hypertension (10% v 3%; P or = 3 was equivalent in both arms (14% and 15%, respectively). The addition of bevacizumab to gemcitabine does not improve survival in advanced pancreatic cancer patients.
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              Tumor-stroma interactions in pancreatic ductal adenocarcinoma.

              Daruka Mahadevan, Daniel Von Hoff (2007)
              The host stromal response to an invasive epithelial carcinoma is frequently called a desmoplastic reaction (DR) and is a universal feature of pancreatic ductal adenocarcinoma (PDA). This DR is characterized by a complex interplay between the normal host epithelial cells, invading tumor cells, stromal fibroblasts, inflammatory cells, proliferating endothelial cells, an altered extracellular matrix, and growth factors activating oncogenic signaling pathways by autocrine and paracrine mechanisms. Hence, the tumor microenvironment is a dynamic process promoting tumor growth and invasion through mechanisms likely to include anoikis resistance, genomic instability, and drug resistance. Cell coculture models, murine models (xenograft and genetic), and gene expression profiling studies on human PDA biopsies have identified several key molecules, such as collagen type I, fibronectin, laminin, matrix metalloproteinases (MMP) and their inhibitors (tissue inhibitors of MMP), growth factors (transforming growth factor beta, platelet-derived growth factor, connective tissue growth factor, and hepatocyte growth factor), chemokines, and integrins as constituents of the DR. Despite these findings, it is unclear which molecular-cellular events initiate and drive desmoplasia in PDA. Accumulating evidence indicates that pancreatic stellate cells when activated switch to a myofibroblast phenotype that produces components of the extracellular matrix, MMPs, and tissue inhibitors of MMPs by activating the mitogen-activated protein kinase (extracellular signal-regulated kinase 1/2) pathway. Based on current evidence, several therapeutic strategies are been evaluated on identified potential therapeutic targets. This review summarizes our current understanding of the mechanisms that potentially drive the DR in PDA and future possibilities for therapeutic targeting of this critical process.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Oncotarget
                Journal ID (iso-abbrev): Oncotarget
                Journal ID (publisher-id): Oncotarget
                Journal ID (publisher-id): ImpactJ
                Title: Oncotarget
                Publisher: Impact Journals LLC
                ISSN (Electronic): 1949-2553
                Publication date Collection: 6 September 2016
                Publication date (Electronic): 21 July 2016
                Volume: 7
                Issue: 36
                Pages: 58649-58658
                Affiliations
                1 Department of Medical Oncology, Hospital of Taranto, Taranto, Italy
                2 Medical Oncology Unit, Cancer Institute “Giovanni Paolo II”, Bari, Italy
                3 Department of Medical Oncology, Hospital “Vito Fazi” of Lecce, Lecce, Italy
                4 Medical Oncology Unit, University of Modena, Modena, Italy
                5 Scientific Direction, Cancer Institute “Giovanni Paolo II”, Bari, Italy
                6 Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy
                7 National Cancer Institute “Giovanni Paolo II”, Bari, Italy
                Author notes
                Correspondence to: Nicola Silvestris, n.silvestris@ 123456oncologico.bari.it
                Article
                Publisher ID: 10765
                DOI: 10.18632/oncotarget.10765
                PMC ID: 5295459
                PubMed ID: 27462915
                SO-VID: ada1f736-38a6-4eb9-93f9-906932eec916
                Copyright © Copyright: © 2016 Longo et al.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 27 May 2016
                Date accepted : 13 July 2016
                Categories
                Subject: Review

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: angiogenesis,pancreatic ductal adenocarcinoma,hypoxia,desmoplastic reaction
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: angiogenesis, pancreatic ductal adenocarcinoma, hypoxia, desmoplastic reaction

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