scholarly journals RET mutation and increased angiogenesis in medullary thyroid carcinomas

2016 ◽  
Vol 23 (8) ◽  
pp. 665-676 ◽  
Author(s):  
Antonella Verrienti ◽  
Giovanni Tallini ◽  
Chiara Colato ◽  
Amélie Boichard ◽  
Saula Checquolo ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Germ Line ◽  
Smooth Muscle Actin ◽  
Antiangiogenic Therapy ◽  
Preliminary Treatment ◽  
Muscle Actin ◽  
Wild Type ◽  
Medullary Thyroid ◽  
Pericyte Marker ◽  
Medullary Thyroid Carcinomas

Advanced medullary thyroid cancers (MTCs) are now being treated with drugs that inhibit receptor tyrosine kinases, many of which involved in angiogenesis. Response rates vary widely, and toxic effects are common, so treatment should be reserved for MTCs likely to be responsive to these drugs.RETmutations are common in MTCs, but it is unclear how they influence the microvascularization of these tumors. We examined 45 MTCs with germ-line or somaticRETmutations (RETmut group) and 34 with wild-typeRET(RETwt). Taqman Low-Density Arrays were used to assess proangiogenic gene expression. Immunohistochemistry was used to assess intratumoral, peritumoral and nontumoral expression levels of VEGFR1, R2, R3, PDGFRa, PDGFB and NOTCH3. We also assessed microvessel density (MVD) and lymphatic vessel density (LVD) based on CD31-positive and podoplanin-positive vessel counts, respectively, and vascular pericyte density based on staining for a-smooth muscle actin (a-SMA), a pericyte marker. Compared withRETwt tumors,RETmut tumors exhibited upregulated expression of proangiogenic genes (mRNA and protein), especially VEGFR1, PDGFB and NOTCH3. MVDs and LVDs were similar in the two groups. However, microvessels inRETmut tumors were more likely to be a-SMA positive, indicating enhanced coverage by pericytes, which play key roles in vessel sprouting, maturation and stabilization. These data suggest that angiogenesis inRETmut MTCs may be more intense and complete than that found inRETwt tumors, a feature that might increase their susceptibility to antiangiogenic therapy. Given their increased vascular pericyte density,RETmut MTCs might also benefit from combined or preliminary treatment with PDGF inhibitors.

Abstract 15006: Serotonin Transporter (SERT) Knockout Leads to Increased Myocardial and Mitral Valvular Fibrosis in a Murine Model

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Alex D'Angelo ◽  
Estibaliz Castillero ◽  
Robert LEVY ◽  
Giovanni Ferrari
Keyword(s):  
Structural Changes ◽  
Smooth Muscle Actin ◽  
Heart Valve Disease ◽  
Ventricular Wall ◽  
Muscle Actin ◽  
Wild Type ◽  
Functional Differences ◽  
Ventricular Wall Thickness ◽  
Fractional Shortening ◽  
Ventricular Dimensions

Introduction: Heart valve disease attributed to serotonin (5HT) has been observed with 5HT-secreting carcinoid tumors and with the diet drug, Dexfenfluoramine, a 5HT transporter (SLC6A4, also known as SERT) inhibitor and 5HT receptor (HTR) 2B agonist. 5HT/SLC6A4 mechanisms had not been investigated in mitral valve (MV) regurgitation. SLC6A4 internalizes 5HT, limiting HTR signaling. Selective 5HT reuptake inhibitor (SSRI) antidepressants target SLC6A4 to increase 5HT. We showed that SLC6A4 reduction in human MV influences MV regurgitation through enhanced HTR signaling. We further investigate the cardiac impact of SLC6A4 deficiency in a SERT -/- mouse reported to have cardiac abnormalities. Hypothesis: Absence of SERT leads to increased myocardial and MV fibrosis. Methods: SERT -/- and wild type (WT) C57BL/6J mice underwent echocardiography at 8 and 16 weeks (w) of age (N=5 / group). Collagen staining was performed with Masson’s trichrome. Markers of myocardial fibrosis α-smooth muscle actin (αSMA) and collagen type1, alpha 1 (COL1A1) were measured by PCR. Results: 8w and 16w SERT -/- mice showed increased epicardial fibrosis and MV sub-valvular fibrosis, particularly at leaflet attachment points, and in 16w SERT -/- mice MV leaflet fibrosis was also present. At 8w, posterior ventricular wall thickness was greater in SERT -/- mice vs. WT, both in systole (1.30 ± 0.09mm vs. 1.61 ± 0.2mm, p=0.003) and diastole (0.78 ± 0.11mm vs. 1.22 ± 0.29mm, p=0.001). At 16 w, ventricular dimensions were larger in SERT -/- mice vs. WT at end-systole (2.29 ± 0.54mm vs. 3.0 ± 0.47mm, p=0.008) and end-diastole (3.48 ± 0.45mm vs. 4.07 ± 0.35, p=0.006). Fractional shortening was reduced in 16w SERT -/- mice vs. WT (35.20 ± 7.66 vs. 26.74 ± 6.14, p=0.017) and vs. 8w SERT -/- mice (38.85 ± 4.57 vs. 26.74 ± 6.14, p=0.002). PCR showed increased fibrosis markers αSMA and COL1A1 in SERT -/- mice (8w and 16w) vs. WT (all p<0.05). Conclusions: SERT -/- mice show pathologic structural changes and fibrosis in both myocardium and MV, corresponding to functional differences that worsen with age. As inhibition of SLC6A4, combined with active HTR2A/B signaling would hypothetically increase MV remodeling and regurgitation, these animals could be ideal to test 5HT pharmacology.

scholarly journals Medullary thyroid carcinomas in transgenic mice expressing a Polyoma carboxyl-terminal truncated middle-T and wild type small-T antigens

Oncogene ◽  
1999 ◽  
Vol 18 (14) ◽  
pp. 2387-2395 ◽  
Author(s):  
A Felici ◽  
M Giorgio ◽  
N Krauzewicz ◽  
C Della Rocca ◽  
M Santoro ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Wild Type ◽  
T Antigens ◽  
Medullary Thyroid ◽  
Thyroid Carcinomas ◽  
Carboxyl Terminal ◽  
Medullary Thyroid Carcinomas

scholarly journals Identification of selective inhibitors of RET and comparison with current clinical candidates through development and validation of a robust screening cascade

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 1005 ◽  
Author(s):  
Amanda J. Watson ◽  
Gemma V. Hopkins ◽  
Samantha Hitchin ◽  
Habiba Begum ◽  
Stuart Jones ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Vascular Endothelial ◽  
Pharmacological Activities ◽  
Medullary Thyroid ◽  
Development And Validation ◽  
Endothelial Growth Factor ◽  
Medullary Thyroid Carcinomas ◽  
Dose Limiting Toxicity ◽  
Screening Cascade

RET (REarranged during Transfection) is a receptor tyrosine kinase, which plays pivotal roles in regulating cell survival, differentiation, proliferation, migration and chemotaxis. Activation of RET is a mechanism of oncogenesis in medullary thyroid carcinomas where both germline and sporadic activating somatic mutations are prevalent. At present, there are no known specific RET inhibitors in clinical development, although many potent inhibitors of RET have been opportunistically identified through selectivity profiling of compounds initially designed to target other tyrosine kinases. Vandetanib and cabozantinib, both multi-kinase inhibitors with RET activity, are approved for use in medullary thyroid carcinoma, but additional pharmacological activities, most notably inhibition of vascular endothelial growth factor - VEGFR2 (KDR), lead to dose-limiting toxicity. The recent identification of RET fusions present in ~1% of lung adenocarcinoma patients has renewed interest in the identification and development of more selective RET inhibitors lacking the toxicities associated with the current treatments. In an earlier publication [Newton et al, 2016; 1] we reported the discovery of a series of 2-substituted phenol quinazolines as potent and selective RET kinase inhibitors. Here we describe the development of the robust screening cascade which allowed the identification and advancement of this chemical series.  Furthermore we have profiled a panel of RET-active clinical compounds both to validate the cascade and to confirm that none display a RET-selective target profile.

scholarly journals Identification of selective inhibitors of RET and comparison with current clinical candidates through development and validation of a robust screening cascade

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 1005 ◽  
Author(s):  
Amanda J. Watson ◽  
Gemma V. Hopkins ◽  
Samantha Hitchin ◽  
Habiba Begum ◽  
Stuart Jones ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Vascular Endothelial ◽  
Pharmacological Activities ◽  
Medullary Thyroid ◽  
Development And Validation ◽  
Endothelial Growth Factor ◽  
Medullary Thyroid Carcinomas ◽  
Dose Limiting Toxicity ◽  
Screening Cascade

RET (REarranged during Transfection) is a receptor tyrosine kinase, which plays pivotal roles in regulating cell survival, differentiation, proliferation, migration and chemotaxis. Activation of RET is a mechanism of oncogenesis in medullary thyroid carcinomas where both germline and sporadic activating somatic mutations are prevalent. At present, there are no known specific RET inhibitors in clinical development, although many potent inhibitors of RET have been opportunistically identified through selectivity profiling of compounds initially designed to target other tyrosine kinases. Vandetanib and cabozantinib, both multi-kinase inhibitors with RET activity, are approved for use in medullary thyroid carcinoma, but additional pharmacological activities, most notably inhibition of vascular endothelial growth factor - VEGFR2 (KDR), lead to dose-limiting toxicity. The recent identification of RET fusions present in ~1% of lung adenocarcinoma patients has renewed interest in the identification and development of more selective RET inhibitors lacking the toxicities associated with the current treatments. In an earlier publication [Newton et al, 2016; 1] we reported the discovery of a series of 2-substituted phenol quinazolines as potent and selective RET kinase inhibitors. Here we describe the development of the robust screening cascade which allowed the identification and advancement of this chemical series.  Furthermore we have profiled a panel of RET-active clinical compounds both to validate the cascade and to confirm that none display a RET-selective target profile.

Proteomics study of medullary thyroid carcinomas expressing RET germ-line mutations: Identification of new signaling elements

2008 ◽  
Vol 48 (3) ◽  
pp. 220-231 ◽  
Author(s):  
L. Gorla ◽  
P. Mondellini ◽  
G. Cuccuru ◽  
F. Miccichè ◽  
G. Cassinelli ◽  
...  
Keyword(s):  
Germ Line ◽  
Medullary Thyroid ◽  
Thyroid Carcinomas ◽  
Proteomics Study ◽  
Germ Line Mutations ◽  
Medullary Thyroid Carcinomas

The CCK2-receptor is expressed in human medullary thyroid carcinomas as well as in normal thyroid tissue

2001 ◽  
Vol 120 (5) ◽  
pp. A507-A507
Author(s):  
M BLAEKER ◽  
A WEERTH ◽  
L JONAS ◽  
M TOMETTEN ◽  
M SCHUTZ ◽  
...  
Keyword(s):  
Thyroid Tissue ◽  
Normal Thyroid Tissue ◽  
Normal Thyroid ◽  
Medullary Thyroid ◽  
Thyroid Carcinomas ◽  
Cck2 Receptor ◽  
Medullary Thyroid Carcinomas

scholarly journals Preoperatively diagnosed gastric collision tumor with mixed adenocarcinoma and gastrointestinal stromal tumor: a case report and literature review

2021 ◽  
Author(s):  
Kunihiko Matsuno ◽  
Yoshikazu Kanazawa ◽  
Daisuke Kakinuma ◽  
Nobutoshi Hagiwara ◽  
Fumihiko Ando ◽  
...  
Keyword(s):  
Gastrointestinal Stromal Tumor ◽  
Distal Gastrectomy ◽  
Submucosal Tumor ◽  
Smooth Muscle Actin ◽  
Collision Tumor ◽  
Stromal Tumor ◽  
Lower Body ◽  
Muscle Actin ◽  
First Case ◽  
S 100

AbstractReports of gastric collision tumors, comprising adenocarcinoma and gastrointestinal stromal tumor, are extremely rare. Here, we report the case of a 68-year-old male who was diagnosed with a lower-body, moderately differentiated, tubular-type adenocarcinoma and submucosal tumor and underwent an elective D2 distal gastrectomy. The tumor cells of the gastrointestinal stromal tumor were positive for H-caldesmon and CD117, weakly positive for smooth muscle actin and DOG-1, and negative for desmin, S-100 protein, CD31, and AE1/AE3. The tumor had grown into a mixed form of adenocarcinoma and gastrointestinal stromal tumor. Thus, we report the first case of a preoperatively diagnosed collision tumor in the stomach consisting of adenocarcinoma and gastrointestinal stromal tumor.

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