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1.
Cancer Discov ; 14(2): 348-361, 2024 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-37966260

RESUMO

The sparse vascularity of pancreatic ductal adenocarcinoma (PDAC) presents a mystery: What prevents this aggressive malignancy from undergoing neoangiogenesis to counteract hypoxia and better support growth? An incidental finding from prior work on paracrine communication between malignant PDAC cells and fibroblasts revealed that inhibition of the Hedgehog (HH) pathway partially relieved angiosuppression, increasing tumor vascularity through unknown mechanisms. Initial efforts to study this phenotype were hindered by difficulties replicating the complex interactions of multiple cell types in vitro. Here we identify a cascade of paracrine signals between multiple cell types that act sequentially to suppress angiogenesis in PDAC. Malignant epithelial cells promote HH signaling in fibroblasts, leading to inhibition of noncanonical WNT signaling in fibroblasts and epithelial cells, thereby limiting VEGFR2-dependent activation of endothelial hypersprouting. This cascade was elucidated using human and murine PDAC explant models, which effectively retain the complex cellular interactions of native tumor tissues. SIGNIFICANCE: We present a key mechanism of tumor angiosuppression, a process that sculpts the physiologic, cellular, and metabolic environment of PDAC. We further present a computational and experimental framework for the dissection of complex signaling cascades that propagate among multiple cell types in the tissue environment. This article is featured in Selected Articles from This Issue, p. 201.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Animais , Humanos , Camundongos , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Proliferação de Células , Proteínas Hedgehog/genética , Neoplasias Pancreáticas/patologia , Fator A de Crescimento do Endotélio Vascular
3.
J Biol Chem ; 291(43): 22427-22441, 2016 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-27609517

RESUMO

Protein-tyrosine phosphatase TULA-2 has been shown to regulate receptor signaling in several cell types, including platelets. Platelets are critical for maintaining vascular integrity; this function is mediated by platelet aggregation in response to recognition of the exposed basement membrane collagen by the GPVI receptor, which is non-covalently associated with the signal-transducing FcRγ polypeptide chain. Our previous studies suggested that TULA-2 plays an important role in negatively regulating signaling through GPVI-FcRγ and indicated that the tyrosine-protein kinase Syk is a key target of the regulatory action of TULA-2 in platelets. However, the molecular basis of the down-regulatory effect of TULA-2 on Syk activation via FcRγ remained unclear. In this study, we demonstrate that suppression of Syk activation by TULA-2 is mediated, to a substantial degree, by dephosphorylation of Tyr(P)346, a regulatory site of Syk, which becomes phosphorylated soon after receptor ligation and plays a critical role in initiating the process that yields fully activated Syk. TULA-2 is capable of dephosphorylating Tyr(P)346 with high efficiency, thus controlling the overall activation of Syk, but is less efficient in dephosphorylating other regulatory sites of this kinase. Therefore, dephosphorylation of Tyr(P)346 may be considered an important "checkpoint" in the regulation of Syk activation process. Putative biological functions of TULA-2-mediated dephosphorylation of Tyr(P)346 may include deactivation of receptor-activated Syk or suppression of Syk activation by suboptimal stimulation.


Assuntos
Plaquetas/metabolismo , Glicoproteínas da Membrana de Plaquetas/metabolismo , Proteínas Tirosina Fosfatases/metabolismo , Quinase Syk/metabolismo , Animais , Camundongos , Camundongos Mutantes , Fosforilação/fisiologia , Glicoproteínas da Membrana de Plaquetas/genética , Proteínas Tirosina Fosfatases/genética , Quinase Syk/genética
4.
Cancer Cell ; 25(6): 735-47, 2014 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-24856585

RESUMO

Sonic hedgehog (Shh), a soluble ligand overexpressed by neoplastic cells in pancreatic ductal adenocarcinoma (PDAC), drives formation of a fibroblast-rich desmoplastic stroma. To better understand its role in malignant progression, we deleted Shh in a well-defined mouse model of PDAC. As predicted, Shh-deficient tumors had reduced stromal content. Surprisingly, such tumors were more aggressive and exhibited undifferentiated histology, increased vascularity, and heightened proliferation--features that were fully recapitulated in control mice treated with a Smoothened inhibitor. Furthermore, administration of VEGFR blocking antibody selectively improved survival of Shh-deficient tumors, indicating that Hedgehog-driven stroma suppresses tumor growth in part by restraining tumor angiogenesis. Together, these data demonstrate that some components of the tumor stroma can act to restrain tumor growth.


Assuntos
Carcinoma Ductal Pancreático/patologia , Neoplasias Pancreáticas/patologia , Células Estromais/patologia , Animais , Anticorpos Monoclonais/farmacologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Linhagem Celular Tumoral , Modelos Animais de Doenças , Progressão da Doença , Técnicas de Silenciamento de Genes , Proteínas Hedgehog/deficiência , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Humanos , Imunoglobulina G/farmacologia , Camundongos , Camundongos Transgênicos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Distribuição Aleatória , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Transdução de Sinais , Células Estromais/metabolismo
5.
Head Neck ; 35(3): 335-42, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22422571

RESUMO

BACKGROUND: The aim of this study was to investigate oral cancer in pregnant women, a rare but therapeutically challenging patient subset. METHODS: After institutional review board approval, an EMERSE search was used to identify all women treated at the University of Michigan from 1998 to 2010 with head and neck squamous cell carcinoma (HNSCC) during pregnancy. This identified 4 patients with tongue cancer. Biomarkers and human papillomavirus (HPV) were assessed by immunohistochemistry and multiplex PCR/mass spectrometry, respectively. RESULTS: Two patients responded well to therapy and are alive more than 10 years after diagnosis; 2 patients died of disease. All tumors overexpressed EGFR and Bcl-xL, 3 of 4 overexpressed c-Met, both tumors that progressed overexpressed p53. All tumors were negative for HPV, p16, estrogen receptor, progesterone receptor, and HER-2. CONCLUSIONS: Biomarkers of aggressive tumors (high EGFR, c-Met; high Bcl-xL-low p53) did not correlate with outcome. Additional studies are needed to determine whether perineural invasion, delay in diagnosis, and p53 overexpression are factors in poor survival.


Assuntos
Carcinoma de Células Escamosas/diagnóstico , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias Bucais/diagnóstico , Complicações Neoplásicas na Gravidez/diagnóstico , Adulto , Biomarcadores Tumorais/análise , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/virologia , Feminino , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/virologia , Humanos , Imuno-Histoquímica , Espectrometria de Massas , Neoplasias Bucais/mortalidade , Neoplasias Bucais/virologia , Reação em Cadeia da Polimerase Multiplex , Papillomaviridae/isolamento & purificação , Gravidez , Complicações Neoplásicas na Gravidez/mortalidade , Complicações Neoplásicas na Gravidez/virologia , Fatores de Risco , Carcinoma de Células Escamosas de Cabeça e Pescoço
6.
Blood ; 116(14): 2570-8, 2010 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-20585042

RESUMO

T-cell ubiquitin ligand-2 (TULA-2) is a recently discovered histidine tyrosine phosphatase thought to be ubiquitously expressed. In this work, we have investigated whether TULA-2 has a key role in platelet glycoprotein VI (GPVI) signaling. This study indicates that TULA-2 is expressed in human and murine platelets and is able to associate with Syk and dephosphorylate it. Ablation of TULA-2 resulted in hyperphosphorylation of Syk and its downstream effector phospholipase C-γ2 as well as enhanced GPVI-mediated platelet functional responses. In addition, shorter bleeding times and a prothrombotic phenotype were observed in mice lacking TULA-2. We therefore propose that TULA-2 is the primary tyrosine phosphatase mediating the dephosphorylation of Syk and thus functions as a negative regulator of GPVI signaling in platelets.


Assuntos
Plaquetas/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Glicoproteínas da Membrana de Plaquetas/metabolismo , Proteínas Tirosina Fosfatases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Animais , Tempo de Sangramento , Cálcio/metabolismo , Expressão Gênica , Técnicas de Inativação de Genes , Humanos , Camundongos , Fosfolipase C gama/metabolismo , Fosforilação , Proteínas Tirosina Fosfatases/genética , Transdução de Sinais , Quinase Syk
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