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mTOR, VEGF, PDGFR, and c-kit signaling pathway activation in Kaposi sarcoma.

Identifieur interne : 000686 ( Main/Exploration ); précédent : 000685; suivant : 000687

mTOR, VEGF, PDGFR, and c-kit signaling pathway activation in Kaposi sarcoma.

Auteurs : Darcy A. Kerr [États-Unis] ; Satya Vara Prasad Busarla [Oman] ; Devon C. Gimbel [États-Unis] ; Aliyah R. Sohani [États-Unis] ; Rosalynn M. Nazarian [États-Unis]

Source :

RBID : pubmed:28506734

Descripteurs français

English descriptors

Abstract

Kaposi sarcoma (KS) is a locally progressive, intermediate-grade vascular neoplasm with no known cure, high recurrence rates, and potential for wide dissemination. Low efficacy and high toxicity limit current therapeutic options for advanced disease. Activation of mammalian target of rapamycin (mTOR), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and c-kit signaling pathways has been implicated in KS pathogenesis and may suggest a role for targeted inhibitors. KS cases were retrospectively retrieved (N=274), most (90%) associated with human immunodeficiency virus. Tissue microarray slides were stained with human herpes virus-8, Friend leukemia integration 1 transcription factor, CD117 (c-kit), phospho-S6 (pS6), PDGF receptor-β, VEGF, and phospho-mTOR. Both intensity and extent of staining were scored. Multiplying these scores for each core yielded total staining H-scores. Human herpes virus-8 was positive in 87% and Friend leukemia integration 1 transcription factor in 95.7% of cases. Most were also VEGF+ (97.6%), pS6+ (95.7%), CD117+ (92.5%), and PDGFRB+ (87.4%). Approximately half (55.6%) were phospho-mTOR+. There was no significant difference in staining among patients with low (<500 cells/mm3) or preserved CD4 T-cell counts. Immunohistochemistry confirms upregulation of the mTOR, PDGF, VEGF, and c-kit pathways in a large cohort of KS samples. Of proteins tested, pS6, downstream of mTOR, demonstrated the highest proportion of strong positivity (67.1%). These results support the possibility of using targeted inhibitors in KS. Overexpression was independent of CD4 count, suggesting that even patients with low counts may be targeted therapy candidates.

DOI: 10.1016/j.humpath.2017.05.002
PubMed: 28506734


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<term>Aged (MeSH)</term>
<term>Aged, 80 and over (MeSH)</term>
<term>Antineoplastic Agents (therapeutic use)</term>
<term>Biomarkers, Tumor (analysis)</term>
<term>CD4 Lymphocyte Count (MeSH)</term>
<term>Child (MeSH)</term>
<term>Child, Preschool (MeSH)</term>
<term>Female (MeSH)</term>
<term>HIV Infections (immunology)</term>
<term>HIV Infections (virology)</term>
<term>Herpesvirus 8, Human (isolation & purification)</term>
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<term>Immunohistochemistry (MeSH)</term>
<term>Male (MeSH)</term>
<term>Middle Aged (MeSH)</term>
<term>Molecular Targeted Therapy (MeSH)</term>
<term>Phosphorylation (MeSH)</term>
<term>Predictive Value of Tests (MeSH)</term>
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<term>Proto-Oncogene Proteins c-kit (antagonists & inhibitors)</term>
<term>Receptors, Platelet-Derived Growth Factor (analysis)</term>
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<term>Retrospective Studies (MeSH)</term>
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<term>Sarcoma, Kaposi (drug therapy)</term>
<term>Sarcoma, Kaposi (pathology)</term>
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<term>Adulte (MeSH)</term>
<term>Adulte d'âge moyen (MeSH)</term>
<term>Analyse sur puce à tissus (MeSH)</term>
<term>Antinéoplasiques (usage thérapeutique)</term>
<term>Enfant (MeSH)</term>
<term>Enfant d'âge préscolaire (MeSH)</term>
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<term>Facteur de croissance endothéliale vasculaire de type A (antagonistes et inhibiteurs)</term>
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<term>Herpèsvirus humain de type 8 (isolement et purification)</term>
<term>Humains (MeSH)</term>
<term>Immunohistochimie (MeSH)</term>
<term>Infections à VIH (immunologie)</term>
<term>Infections à VIH (virologie)</term>
<term>Jeune adulte (MeSH)</term>
<term>Marqueurs biologiques tumoraux (analyse)</term>
<term>Mâle (MeSH)</term>
<term>Numération des lymphocytes CD4 (MeSH)</term>
<term>Phosphorylation (MeSH)</term>
<term>Protéine ribosomique S6 (analyse)</term>
<term>Protéines proto-oncogènes c-kit (analyse)</term>
<term>Protéines proto-oncogènes c-kit (antagonistes et inhibiteurs)</term>
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<term>Récepteurs aux facteurs de croissance dérivés des plaquettes (antagonistes et inhibiteurs)</term>
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<term>Sarcome de Kaposi (virologie)</term>
<term>Sujet âgé (MeSH)</term>
<term>Sujet âgé de 80 ans ou plus (MeSH)</term>
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<term>Sérine-thréonine kinases TOR (antagonistes et inhibiteurs)</term>
<term>Thérapie moléculaire ciblée (MeSH)</term>
<term>Transduction du signal (effets des médicaments et des substances chimiques)</term>
<term>Valeur prédictive des tests (MeSH)</term>
<term>Études rétrospectives (MeSH)</term>
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<term>Ribosomal Protein S6</term>
<term>TOR Serine-Threonine Kinases</term>
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<term>Proto-Oncogene Proteins c-kit</term>
<term>Receptors, Platelet-Derived Growth Factor</term>
<term>TOR Serine-Threonine Kinases</term>
<term>Vascular Endothelial Growth Factor A</term>
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<term>Facteur de croissance endothéliale vasculaire de type A</term>
<term>Marqueurs biologiques tumoraux</term>
<term>Protéine ribosomique S6</term>
<term>Protéines proto-oncogènes c-kit</term>
<term>Récepteurs aux facteurs de croissance dérivés des plaquettes</term>
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<term>Protéines proto-oncogènes c-kit</term>
<term>Récepteurs aux facteurs de croissance dérivés des plaquettes</term>
<term>Sérine-thréonine kinases TOR</term>
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<term>Sarcome de Kaposi</term>
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<term>Signal Transduction</term>
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<keywords scheme="MESH" qualifier="drug therapy" xml:lang="en">
<term>Sarcoma, Kaposi</term>
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<term>Transduction du signal</term>
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<term>Infections à VIH</term>
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<keywords scheme="MESH" qualifier="immunology" xml:lang="en">
<term>HIV Infections</term>
</keywords>
<keywords scheme="MESH" qualifier="isolation & purification" xml:lang="en">
<term>Herpesvirus 8, Human</term>
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<keywords scheme="MESH" qualifier="isolement et purification" xml:lang="fr">
<term>Herpèsvirus humain de type 8</term>
</keywords>
<keywords scheme="MESH" qualifier="pathology" xml:lang="en">
<term>Sarcoma, Kaposi</term>
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<keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr">
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<term>Antinéoplasiques</term>
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<term>Infections à VIH</term>
<term>Sarcome de Kaposi</term>
</keywords>
<keywords scheme="MESH" qualifier="virology" xml:lang="en">
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<term>Sarcoma, Kaposi</term>
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<term>Adult</term>
<term>Aged</term>
<term>Aged, 80 and over</term>
<term>CD4 Lymphocyte Count</term>
<term>Child</term>
<term>Child, Preschool</term>
<term>Female</term>
<term>Humans</term>
<term>Immunohistochemistry</term>
<term>Male</term>
<term>Middle Aged</term>
<term>Molecular Targeted Therapy</term>
<term>Phosphorylation</term>
<term>Predictive Value of Tests</term>
<term>Retrospective Studies</term>
<term>Tissue Array Analysis</term>
<term>Young Adult</term>
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<term>Adulte</term>
<term>Adulte d'âge moyen</term>
<term>Analyse sur puce à tissus</term>
<term>Enfant</term>
<term>Enfant d'âge préscolaire</term>
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<term>Humains</term>
<term>Immunohistochimie</term>
<term>Jeune adulte</term>
<term>Mâle</term>
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<term>Phosphorylation</term>
<term>Sujet âgé</term>
<term>Sujet âgé de 80 ans ou plus</term>
<term>Thérapie moléculaire ciblée</term>
<term>Valeur prédictive des tests</term>
<term>Études rétrospectives</term>
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<front>
<div type="abstract" xml:lang="en">Kaposi sarcoma (KS) is a locally progressive, intermediate-grade vascular neoplasm with no known cure, high recurrence rates, and potential for wide dissemination. Low efficacy and high toxicity limit current therapeutic options for advanced disease. Activation of mammalian target of rapamycin (mTOR), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and c-kit signaling pathways has been implicated in KS pathogenesis and may suggest a role for targeted inhibitors. KS cases were retrospectively retrieved (N=274), most (90%) associated with human immunodeficiency virus. Tissue microarray slides were stained with human herpes virus-8, Friend leukemia integration 1 transcription factor, CD117 (c-kit), phospho-S6 (pS6), PDGF receptor-β, VEGF, and phospho-mTOR. Both intensity and extent of staining were scored. Multiplying these scores for each core yielded total staining H-scores. Human herpes virus-8 was positive in 87% and Friend leukemia integration 1 transcription factor in 95.7% of cases. Most were also VEGF+ (97.6%), pS6+ (95.7%), CD117+ (92.5%), and PDGFRB+ (87.4%). Approximately half (55.6%) were phospho-mTOR+. There was no significant difference in staining among patients with low (<500 cells/mm
<sup>3</sup>
) or preserved CD4 T-cell counts. Immunohistochemistry confirms upregulation of the mTOR, PDGF, VEGF, and c-kit pathways in a large cohort of KS samples. Of proteins tested, pS6, downstream of mTOR, demonstrated the highest proportion of strong positivity (67.1%). These results support the possibility of using targeted inhibitors in KS. Overexpression was independent of CD4 count, suggesting that even patients with low counts may be targeted therapy candidates.</div>
</front>
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<AbstractText>Kaposi sarcoma (KS) is a locally progressive, intermediate-grade vascular neoplasm with no known cure, high recurrence rates, and potential for wide dissemination. Low efficacy and high toxicity limit current therapeutic options for advanced disease. Activation of mammalian target of rapamycin (mTOR), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and c-kit signaling pathways has been implicated in KS pathogenesis and may suggest a role for targeted inhibitors. KS cases were retrospectively retrieved (N=274), most (90%) associated with human immunodeficiency virus. Tissue microarray slides were stained with human herpes virus-8, Friend leukemia integration 1 transcription factor, CD117 (c-kit), phospho-S6 (pS6), PDGF receptor-β, VEGF, and phospho-mTOR. Both intensity and extent of staining were scored. Multiplying these scores for each core yielded total staining H-scores. Human herpes virus-8 was positive in 87% and Friend leukemia integration 1 transcription factor in 95.7% of cases. Most were also VEGF+ (97.6%), pS6+ (95.7%), CD117+ (92.5%), and PDGFRB+ (87.4%). Approximately half (55.6%) were phospho-mTOR+. There was no significant difference in staining among patients with low (<500 cells/mm
<sup>3</sup>
) or preserved CD4 T-cell counts. Immunohistochemistry confirms upregulation of the mTOR, PDGF, VEGF, and c-kit pathways in a large cohort of KS samples. Of proteins tested, pS6, downstream of mTOR, demonstrated the highest proportion of strong positivity (67.1%). These results support the possibility of using targeted inhibitors in KS. Overexpression was independent of CD4 count, suggesting that even patients with low counts may be targeted therapy candidates.</AbstractText>
<CopyrightInformation>Copyright © 2017 Elsevier Inc. All rights reserved.</CopyrightInformation>
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<ForeName>Darcy A</ForeName>
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<Affiliation>Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114. Electronic address: dkerr@med.miami.edu.</Affiliation>
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<ForeName>Satya Vara Prasad</ForeName>
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<AffiliationInfo>
<Affiliation>Department of Pathology, Aga Khan Hospital, Kisumu, Kenya 40100. Electronic address: satyabsv@yahoo.com.</Affiliation>
</AffiliationInfo>
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<ForeName>Devon C</ForeName>
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<Affiliation>Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114. Electronic address: devon.gimbel@gmail.com.</Affiliation>
</AffiliationInfo>
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<Affiliation>Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114. Electronic address: arsohani@mgh.harvard.edu.</Affiliation>
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<Affiliation>Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114. Electronic address: rmnazarian@mgh.harvard.edu.</Affiliation>
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<Year>2017</Year>
<Month>04</Month>
<Day>27</Day>
</PubMedPubDate>
<PubMedPubDate PubStatus="accepted">
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<li>États-Unis</li>
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<li>Massachusetts</li>
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<name sortKey="Kerr, Darcy A" sort="Kerr, Darcy A" uniqKey="Kerr D" first="Darcy A" last="Kerr">Darcy A. Kerr</name>
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<name sortKey="Gimbel, Devon C" sort="Gimbel, Devon C" uniqKey="Gimbel D" first="Devon C" last="Gimbel">Devon C. Gimbel</name>
<name sortKey="Nazarian, Rosalynn M" sort="Nazarian, Rosalynn M" uniqKey="Nazarian R" first="Rosalynn M" last="Nazarian">Rosalynn M. Nazarian</name>
<name sortKey="Sohani, Aliyah R" sort="Sohani, Aliyah R" uniqKey="Sohani A" first="Aliyah R" last="Sohani">Aliyah R. Sohani</name>
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</noRegion>
</country>
</tree>
</affiliations>
</record>

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   |texte=   mTOR, VEGF, PDGFR, and c-kit signaling pathway activation in Kaposi sarcoma.
}}

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