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

The aim of this study was to explore the possible involvement of the angiopoietin (Ang)-1, -2/Tie-2 system in the development, growth, and metastases evolution of gastroenteropancreatic-neuroendocrine tumors (GEP-NETs). We prospectively examined the serum levels of Tie-2, Ang-1, and Ang-2 by ELISA in 42 patients with proven GEP-NETs and 27 controls. We also determined the expression of the Ang/Tie-2 system in freshly isolated peripheral blood monocytes and in tumor cells from malignant primary tumors and/or liver metastases samples from GEP-NET patients by flow cytometry and/or RT-PCR. Furthermore, the function of the Ang/Tie-2 system in monocytes from controls and patients was assessed by a chemotaxis assay. GEP-NET patients showed enhanced serum levels of soluble form of Tie-2 (sTie-2), Ang-1, and Ang-2 (P<0.05 in all cases), compared to controls. sTie-2 and Ang-2 levels were significantly higher in GEP-NETs with metastases compared to those with no metastases. In addition, a significant correlation was detected between Ang-2 levels and chromogranin A or sTie-2 concentrations or 5-hydroxy-indole acetic acid excretion (r=0.71, r=0.60, and r=0.81 respectively, P<0.01 in all cases). Furthermore, we observed an enhanced expression of Ang-1, Ang-2, and Tie-2 in freshly isolated tumor cells from GEP-NET both by immunohistochemistry and by RT-PCR. Interestingly, an enhanced expression and function of Tie-2 was detected in monocytes from GEP-NET patients. Our data suggest that the Ang/Tie-2 system is involved in the growth and development of metastases of GEP-NETs, and that favors the recruitment of Tie-2+ monocytes to the tumor site, where they can promote inflammation and angiogenesis.

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Sexual dimorphism in small-intestinal neuroendocrine tumors: lower prevalence of mesenteric disease in premenopausal women

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgac001 ◽

2022 ◽

Author(s):

Anela Blažević ◽

Anand M Iyer ◽

Marie-Louise F van Velthuysen ◽

Johannes Hofland ◽

Lindsey Oudijk ◽

...

Keyword(s):

Estrogen Receptor ◽

Sexual Dimorphism ◽

Tumor Cells ◽

Neuroendocrine Tumors ◽

Estrogen Receptor Alpha ◽

Premenopausal Women ◽

Primary Tumors ◽

Tertiary Center ◽

Male Patients ◽

Small Intestinal

Abstract Context Small intestinal neuroendocrine tumors (SI-NETs) have a modest but significantly higher prevalence and worse prognosis in male patients. Objective This work aims to increase understanding of this sexual dimorphism in SI-NETs. Patients and Methods Retrospectively, SI-NET patients treated in a single tertiary center were included and analyzed for disease characteristics. Estrogen receptor 1 (ESR1) and 2 (ESR2), progesterone receptor (PGR) and androgen receptor (AR) mRNA expression was assessed in primary tumors and healthy intestine. Estrogen receptor alpha (ERα) and AR protein expression was analyzed by immunohistochemistry in primary tumors and mesenteric metastases. Results Of the 559 patients, 47% were female. Mesenteric metastasis/fibrosis was more prevalent in men (71/46%) than women (58/37%, P=0.001 and P = 0.027). In women, prevalence of mesenteric metastases increased gradually with age from 41.1% in women <50 years to 71.7% in women >70 years. Increased expression of ESR1 and AR mRNA was observed in primary tumors compared to healthy intestine (both P < 0.001). ERα staining was observed in tumor cells and stroma with a strong correlation between tumor cells of primary tumors and mesenteric metastases (rho=0.831, P=0.02), but not in stroma (rho=-0.037, P=0.91). AR expression was only found in stroma. Conclusion Sexual dimorphism in SI-NETs was most pronounced in mesenteric disease and the risk of mesenteric metastasis in women increased around menopause. The combination of increased ERα and AR expression in the SI-NET microenvironment suggests a modulating role of sex steroids in the development of the characteristic SI-NET mesenteric metastasis and associated fibrosis.

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Localization of Neuroendrocrine Tumors Using Somatostatin Receptor Imaging with Indium-111-Pentetreotide (OctreoScan)

Cancer Control ◽

10.1177/107327489700400105 ◽

1997 ◽

Vol 4 (1) ◽

pp. 1-3 ◽

Cited By ~ 7

Author(s):

E. Christopher Ellison ◽

William J. Schirmer ◽

John O. Olsen ◽

Rodney V. Pozderac ◽

George Hinkle ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Imaging Techniques ◽

Somatostatin Receptor ◽

Somatostatin Receptors ◽

Receptor Imaging ◽

Gastroenteropancreatic Neuroendocrine Tumors ◽

Primary Tumors ◽

Duodenal Tumor ◽

Computed Tomography Scanning ◽

Indium 111

Background Many imaging methods have been used to detect neuroendocrine tumors of the gastrointestinal system. There is no gold standard for identifying the location of primary tumors and their potential metastases, and most conventional imaging techniques cannot detect tumors less than 1.0 cm in size. Methods The authors have investigated the use of 111In-pentetreotide as an imaging agent for abdominal neuroendocrine tumors. Results The agent is cleared rapidly by the kidneys and is primarily excreted intact with a biologic half-life of six hours. The largest radiation burden is to the spleen and kidneys. A nine-center study conducted in Europe involved 365 patients with gastroenteropancreatic neuroendocrine tumors that were also imaged by other methods. The results of 111In-pentetreotide were in agreement with those obtained by other methods for 79% of tumor locations. An additional 110 tumor localizations were detected that were not seen with conventional methods. The smallest gastrinoma imaged by 111In-pentetreotide was a 4-mm duodenal tumor. Conclusions Scintigraphy with 111In-pentetreotide is effective in visualizing various somatostatin receptors characteristic of neuroendocrine tumors of the gastrointestinal tract. Insulinomas, however, are not well imaged. Concurrent computed tomography scanning is advised to minimize the risk of missing liver metastases.

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Immunohistochemical localization of neuron-specific enolase in gastroenteropancreatic neuroendocrine tumors. Correlation with tissue and serum levels of neuron-specific enolase

Cancer ◽

10.1002/1097-0142(19841001)54:7<1364::aid-cncr2820540722>3.0.co;2-y ◽

1984 ◽

Vol 54 (7) ◽

pp. 1364-1369 ◽

Cited By ~ 30

Author(s):

Shannon Simpson ◽

Aaron I. Vinik ◽

Paul J. Marangos ◽

Ricardo V. Lloyd

Keyword(s):

Neuroendocrine Tumors ◽

Neuron Specific Enolase ◽

Serum Levels ◽

Immunohistochemical Localization ◽

Gastroenteropancreatic Neuroendocrine Tumors

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Histone H2B as a functionally important plasminogen receptor on macrophages

Blood ◽

10.1182/blood-2007-03-079392 ◽

2007 ◽

Vol 110 (10) ◽

pp. 3763-3772 ◽

Cited By ~ 77

Author(s):

Riku Das ◽

Tim Burke ◽

Edward F. Plow

Keyword(s):

Binding Capacity ◽

Peritoneal Macrophages ◽

Blood Monocytes ◽

Histone H2b ◽

Cell Recruitment ◽

Annexin 2 ◽

Enhanced Expression ◽

And Function ◽

Mouse Peritoneal Macrophages

AbstractPlasminogen (Plg) facilitates inflammatory cell recruitment, a function that depends upon its binding to Plg receptors (Plg-Rs). However, the Plg-Rs that are critical for cell migration are not well defined. Three previously characterized Plg-Rs (α-enolase, annexin 2, and p11) and a recently identified Plg-R (histone H2B [H2B]) were assessed for their contribution to Plg binding and function on macrophages. Two murine macrophage cell lines (RAW 264.7 and J774A.1) and mouse peritoneal macrophages induced by thioglycollate were analyzed. All 4 Plg-Rs were present on the surface of these cells and showed enhanced expression on the thioglycollate-induced macrophages compared with peripheral blood monocytes. Using blocking Fab fragments to each Plg-R, H2B supported approximately 50% of the Plg binding capacity, whereas the other Plg-Rs contributed less than 25%. Anti-H2B Fab also demonstrated a major role of this Plg-R in plasmin generation and matrix invasion. When mice were treated intravenously with anti-H2B Fab, peritoneal macrophage recruitment in response to thioglycollate was reduced by approximately 45% at 24, 48, and 72 hours, with no effect on blood monocyte levels. Taken together, these data suggest that multiple Plg-Rs do contribute to Plg binding to macrophages, and among these, H2B plays a very prominent and functionally important role.

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Metachronous double primary neuroendocrine tumors in larynx and lung: a case report

Journal of International Medical Research ◽

10.1177/0300060520962928 ◽

2020 ◽

Vol 48 (11) ◽

pp. 030006052096292

Author(s):

In Hye Song ◽

Youn Soo Lee ◽

Dong-Il Sun ◽

Yong-Kil Hong ◽

Kyo-Young Lee

Keyword(s):

Tumor Cells ◽

Carcinoid Tumor ◽

Neuroendocrine Tumors ◽

Lower Lobe ◽

Proliferation Index ◽

Atypical Carcinoid ◽

Voice Change ◽

Large Tumor ◽

Ki 67 ◽

Primary Tumors

When a patient harbors two or more neuroendocrine tumors (NETs), it can be difficult to determine whether they are double primary tumors or metastases. A 60-year-old man complained of voice change lasting 1 month. On physical examination and imaging, a 1.8-cm mass was observed in his epiglottis, and a laser epiglottectomy was performed. Upon microscopic examination, the tumor consisted of medium-sized ovoid or short spindle cells. Immunohistochemical staining of the tumor cells was positive for synaptophysin, chromogranin, and calcitonin but negative for CD56; the Ki-67 proliferation index was approximately 5%. The patient was diagnosed with atypical carcinoid tumor. In 2015, a hypermetabolic endobronchial tumor was identified in the left lower lobe by positron emission tomography-computed tomography. Bronchoscopic biopsy revealed palisading large tumor cells with high nuclear-cytoplasmic ratio, frequent mitoses, and necrosis. The tumor cells were positive for CD56 and negative for cytokeratin-7, thyroid transcription factor-1, P40, synaptophysin, chromogranin, and calcitonin; the Ki-67 proliferation index was approximately 90%. Overall histologic findings were consistent with large cell neuroendocrine carcinoma rather than metastatic atypical carcinoid tumor. Detailed clinical and pathological review are essential to differentiate between metastatic NET and double primary NETs and, therefore, to provide the best management of the patient.

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In vitro chemotherapy profiling of well-differentiated midgut neuroendocrine tumors (NETs) based on individual patient tumor biomarkers analysis.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.3_suppl.235 ◽

2014 ◽

Vol 32 (3_suppl) ◽

pp. 235-235

Author(s):

Yi-Zarn Wang ◽

Jean P. Carrasquillo ◽

Alexis Carimi ◽

Elizabeth McCord ◽

Maria M. Chester ◽

...

Keyword(s):

Cell Cycle ◽

Tumor Cells ◽

Neuroendocrine Tumors ◽

Tumor Biomarker ◽

Primary Tumors ◽

Sensitivity Assessment ◽

Biomarker Analysis ◽

Well Differentiated

235 Background: Midgut neuroendocrine tumors (NETs) are rare malignancies with indolent clinical courses. In general, they are well differentiated with most tumor cells in the G0 phase of the cell cycle, consistent with the poor response rate of NETs to chemotherapy in vivo. We hypothesize that insults, such as surgery, can drive NET cells from G0 into S phase and that biomarker analysis of individual patient tumors harvested and grown in the lab will provide useful practical guide for future intra and post operative adjuvant therapy. Methods: 97 well-differentiated midgut NET patients underwent cytoreductive surgery at our institution between 5/2012 and 10/2012. 148 surgical specimens were collected and submitted to a single commercial lab for processing. Primary tumors, lymph nodes and liver metastases were harvested and cultured. Their RNAs were then extracted to analyze the expressivity a total of 88 different biomarkers. Based on our patients specific tumor biomarker expressivity and known correlations between 36 anti-neoplastic agents with their linked biomarkers, recommendations were reported as clinically benefit or lacking such benefit. Results: A total of 148 specimens from 97 patients were tested. In four of the 97 patients, no clinically beneficial chemotherapy agent could be identified. Among the remaining 93 patients, the top three agents that are most likely to be clinically beneficial are: Fluorouracil, Cisplatin and Carboplatin. These were reported to be clinically beneficial in 135/148 (91.2%), 103/148 (69.6%), and 103/148 (69.6%) patients respectively. Conclusions: Midgut NETs are slow growing tumors which are chemotherapeutically inert owing to the fact that most of the tumor cells are in G0 cell cycle. Surgical insult drives NET cells into active synthetic phase where they begin to express biomarkers specific to their tumor cells. Analysis of these biomarkers guides further potential beneficial therapy based on the current known associations among biomarkers and chemotherapy agents. These results must then be compared and confirmed against a direct in-vitro chemo sensitivity assessment conducted simultaneously on the same patients.

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