The association of the angiopoietin/Tie-2 system with the development of metastasis and leukocyte migration in neuroendocrine tumors

Figueroa-Vega, Nicté; Díaz, Ángel; Adrados, Magdalena; Álvarez-Escolá, Cristina; Paniagua, Amalia; Aragonés, Julián; Martín-Pérez, Elena; Leskelä, Susanna; Moreno–Otero, Ricardo; González‐Amaro, Roberto; Marazuela, Mónica

doi:10.1677/erc-10-0020

Cited by 26 publications

(23 citation statements)

References 42 publications

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“…Ang-2 concentrations above the 75th percentile predicted shorter survival (p = 0.0003). These findings are supported by other studies of patients with NET [36,37]. Significantly elevated levels of serum Ang-2 levels (p = 0.01) were found in patients with NET (n = 47; 17 with pancreatic NET), compared with healthy controls (n = 44), and the time to disease progression was shorter in those patients with serum Ang-2 levels above 4,756 pg/ml (p = 0.04) [37].…”

Section: Molecular Targets In Pancreatic Netsupporting

confidence: 91%

From Targets to Treatments: A Review of Molecular Targets in Pancreatic Neuroendocrine Tumors

2011

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Pancreatic neuroendocrine tumors (pancreatic NET) are relatively rare, slowly growing tumors, although their incidence is increasing, and patients may survive for several years with metastatic disease. Apart from symptomatic relief, there have been few treatment options for these tumors in the past. More recently, investigators have explored the potential of molecularly targeted agents in treating pancreatic NET, with some success. In this review, we consider the data supporting exploitation of different targets in pancreatic NET, including peptide receptors, receptor tyrosine kinases (involved in tumor angiogenesis and more directly supporting tumor growth), and intracellular targets, such as the mammalian target of rapamycin (mTOR), which has a central role in regulating cell growth, metabolism, and apoptosis. Probably due to the paucity of pancreatic NET, many clinical trials to date have included heterogeneous NET populations, and there are few randomized studies of this specific patient population. Very recently, promising results have been achieved in placebo-controlled, phase III trials with the multitargeted tyrosine kinase inhibitor, sunitinib, and the mTOR inhibitor, everolimus. These agents have been approved or are currently being reviewed by authorities for use in patients with pancreatic NET. Here we review potential molecular targets in pancreatic NET and summarize the available data for targeted agents from phase II and III trials open to patients with this tumor.

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Section: Molecular Targets In Pancreatic Netsupporting

confidence: 91%

From Targets to Treatments: A Review of Molecular Targets in Pancreatic Neuroendocrine Tumors

2011

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“…This supports the possible administration of anti-Ang2 therapy for NSCLC in a postoperative adjuvant setting[33]. Therefore, if we want to control the growth of tumors, targeting Angiopoietins-Tie2 signaling, especially Ang-1, Ang-2, Tie-2, in esophageal cancer cells seems to be a promising and important mechanism for cancer treatment[34]. …”

Section: Discussionmentioning

confidence: 82%

All-trans retinoic acid suppresses the angiopoietin-Tie2 pathway and inhibits angiogenesis and metastasis in esophageal squamous cell carcinoma

et al. 2017

PLoS ONE

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Esophageal squamous cell carcinoma (ESCC) is the second common cancer in Henan province and is well-known for aggressiveness and dismal prognosis. Adjuvant therapies, chemotherapy, radiotherapy and endoscopic treatment have not improved survival rates in patients with late stage esophageal carcinoma. All-trans retinoic acid (ATRA) is the active ingredient of Vitamin A and affects a wide spectrum of biological processes including development, growth, neural function, immune function, reproduction, and vision. It is one of the most potent therapeutic agents used for treating cancers, especially lung adenocarcinomas. ATRA inhibits metastatic potential and angiogenesis in several tumor models. We investigated the effects of ATRA on the expression of angiopoietin 1 (Ang-1), angiopoietin 2 (Ang-2) and receptor Tie-2 in EC1 cells in vitro. We also assessed the growth and migration of EC1 cells in vitro. ATRA treatment caused 29.5% and 40.3% reduction of the growth of EC1 cells after 24 hours and 48 hours, relative to the control. ATRA plus fluorouracil treatment reduced the viability more strongly than either drug alone, indicating an additive effect. Moreover, ATRA decreased EC1 migration by 87%. Furthermore, ATRA treatment led to a marked decrease of the transcript levels of Ang-1, Ang-2, Tie-2, VEGF, and VEGF receptors, as assessed by real-time RT-PCR. Importantly, the protein levels of Ang-1, Ang-2 and Tie-2 were reduced by ATRA treatment. In vivo, we found ATRA treatment suppressed the tumor growth and improved the cachexia of mice. Importantly, ATRA treatment decreased the expression of CD31, Ang-1, Ang-2 and Tie-2 in subcutaneous tumors of EC1 cells. Collectively, our findings demonstrate that ATRA exhibits a dose- and temporal-dependent effect on the metastatic behavior, suppresses the angiopoietin-Tie2 pathway and inhibits angiogenesis and the progression of xenograft tumors of EC1 cells.

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“…Serum angiopoietin 2 (ANG2) and TIE2 levels are significantly elevated in patients with NETs compared with controls, and in patients with distant metastases compared with those without metastasis. Time to disease progression is shorter in patients with higher serum ANG2 levels (Srirajaskanthan et al 2009, Detjen et al 2010, Figueroa-Vega et al 2010. Inhibitors of the TIE2 pathway are being evaluated in other solid tumours and may be worth exploring for NETs.…”

Section: Inducing Angiogenesismentioning

confidence: 99%

Hallmarks of gastrointestinal neuroendocrine tumours: implications for treatment

Walenkamp¹,

Crespo²,

Maya³

et al. 2014

Endocrine-Related Cancer

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In the past few years, there have been advances in the treatment of neuroendocrine tumours (NETs) and improvements in our understanding of NET biology. However, the benefits to patients have been relatively modest and much remains yet to be done. The 'Hallmarks of Cancer', as defined by Hanahan and Weinberg, provide a conceptual framework for understanding the aberrations that underlie tumourigenesis and to help identify potential targets for therapy. In this study, our objective is to review the major molecular characteristics of NETs, based on the recently modified 'Hallmarks of Cancer', and highlight areas that require further research.

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The association of the angiopoietin/Tie-2 system with the development of metastasis and leukocyte migration in neuroendocrine tumors

Cited by 26 publications

References 42 publications

From Targets to Treatments: A Review of Molecular Targets in Pancreatic Neuroendocrine Tumors

From Targets to Treatments: A Review of Molecular Targets in Pancreatic Neuroendocrine Tumors

All-trans retinoic acid suppresses the angiopoietin-Tie2 pathway and inhibits angiogenesis and metastasis in esophageal squamous cell carcinoma

Hallmarks of gastrointestinal neuroendocrine tumours: implications for treatment

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