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1.
J Clin Invest ; 126(11): 4187-4204, 2016 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-27721236

RESUMO

Different tumor microenvironments (TMEs) induce stromal cell plasticity that affects tumorigenesis. The impact of TME-dependent heterogeneity of tumor endothelial cells (TECs) on tumorigenesis is unclear. Here, we isolated pure TECs from human colorectal carcinomas (CRCs) that exhibited TMEs with either improved (Th1-TME CRCs) or worse clinical prognosis (control-TME CRCs). Transcriptome analyses identified markedly different gene clusters that reflected the tumorigenic and angiogenic activities of the respective TMEs. The gene encoding the matricellular protein SPARCL1 was most strongly upregulated in Th1-TME TECs. It was also highly expressed in ECs in healthy colon tissues and Th1-TME CRCs but low in control-TME CRCs. In vitro, SPARCL1 expression was induced in confluent, quiescent ECs and functionally contributed to EC quiescence by inhibiting proliferation, migration, and sprouting, whereas siRNA-mediated knockdown increased sprouting. In human CRC tissues and mouse models, vessels with SPARCL1 expression were larger and more densely covered by mural cells. SPARCL1 secretion from quiescent ECs inhibited mural cell migration, which likely led to stabilized mural cell coverage of mature vessels. Together, these findings demonstrate TME-dependent intertumoral TEC heterogeneity in CRC. They further indicate that TEC heterogeneity is regulated by SPARCL1, which promotes the cell quiescence and vessel homeostasis contributing to the favorable prognoses associated with Th1-TME CRCs.


Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Neoplasias Colorretais/irrigação sanguínea , Neoplasias Colorretais/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Proteínas de Neoplasias/metabolismo , Neovascularização Patológica/metabolismo , Microambiente Tumoral , Animais , Neoplasias Colorretais/patologia , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Células Jurkat , Camundongos , Neovascularização Patológica/patologia
2.
Am J Pathol ; 183(6): 1897-1909, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24121019

RESUMO

Interferon (IFN)-α and IFN-γ are cytokines with potent immunomodulating and anti-tumor activities. It is unknown which of the two IFNs may be more potent in the regulation of an anti-tumorigenic response in colorectal carcinoma or whether both cytokines cooperate. We, therefore, established human myxovirus resistance protein A and human guanylate-binding protein-1 as markers for the differential detection of IFN-α- and IFN-γ-driven tumor micromilieus, respectively. In vitro studies with different cultures of tumor cells from colorectal carcinoma and stroma cells showed that the expression of myxovirus resistance protein A was exclusively induced by IFN-α, whereas guanylate-binding protein-1 was strongly induced by IFN-γ and only weakly by IFN-α. This expression pattern was used to distinguish cell activation caused by the two cytokines in a clinical cohort of patients with colon carcinoma (n = 378). Patients with primary tumors expressing only guanylate-binding protein-1 exhibited the highest cancer-specific 5-year survival (94.0%, P = 0.006) compared with those expressing both factors (90.3%, P = 0.006), myxovirus resistance protein A alone (83.5%, P = 0.096), or none (72.8%). Our study describes a successful proof-of-principle approach that complex cytokine interaction networks can be dissected in human tissues and demonstrates that an IFN-γ-driven tumor microenvironment exhibits a superior prognostic effect compared with an IFN-α-driven tumor microenvironment in colon carcinoma.


Assuntos
Neoplasias do Colo , Interferon-alfa/metabolismo , Interferon gama/metabolismo , Proteínas de Neoplasias/metabolismo , Microambiente Tumoral , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Colo/metabolismo , Neoplasias do Colo/mortalidade , Neoplasias do Colo/patologia , Citocinas/metabolismo , Intervalo Livre de Doença , Feminino , Seguimentos , Proteínas de Ligação ao GTP/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Resistência a Myxovirus/metabolismo , Estudos Retrospectivos , Taxa de Sobrevida
3.
Int J Colorectal Dis ; 28(11): 1469-78, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23702820

RESUMO

PURPOSE: Aberrant activation of the Wnt/ß-catenin pathway plays a major role in the development of colorectal carcinoma (CRC). Axin 2 is a key protein of this pathway and is upregulated in CRC. Here, we investigated RNA- and protein expression of axin 2 in CRC tissues at the single cell level. Moreover, the association of axin 2 with prognosis and survival was investigated in a large cohort of CRC patients (n = 280). METHODS: Localization and expression of axin 2 and ß-catenin was investigated using in situ hybridization and immunohistochemical staining. The quantitative expression levels of axin 2 were determined using RT-qPCR. The association of axin 2 expression with prognosis and survival of the patients was determined by statistical analysis (logrank test, Kaplan-Meier). RESULTS: Our results confirmed the upregulation of axin 2 in CRC and showed that it is broadly expressed in the cytoplasm of the tumor epithelial cells both, in the tumor center and at the invasion front. Axin 2 was rarely expressed by tumor stromal cells and only weakly by normal colonic epithelial cells. Staining of ß-catenin and axin 2 in consecutive CRC tissue sections revealed that nuclear translocation of ß-catenin in the tumor front was not associated with changes in the cytoplasmic localization of axin 2. Axin 2 did not show any association with proven prognostic factors or survival of the CRC patients. CONCLUSION: The generally increased expression of axin 2 in all tumor stages as compared to normal tissue suggests an initiating pathogenic function in the development of CRC.


Assuntos
Proteína Axina/metabolismo , Neoplasias Colorretais/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Neoplasias Colorretais/patologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Transporte Proteico , Frações Subcelulares/metabolismo , Análise Serial de Tecidos , beta Catenina/metabolismo
4.
Neurosci Lett ; 472(1): 19-23, 2010 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-20105452

RESUMO

Complex regional pain syndrome (CRPS) is a condition that is characterized by severe pain and exaggerated neurogenic inflammation, which may develop after injury or surgery. Neurogenic inflammation is mediated by neuropeptides, such as calcitonin gene-related peptide (CGRP) and substance P (SP) that are released from nociceptors. Genetic factors may play a role in CRPS as was suggested by the occurrence of familial cases and several genetic association studies investigating mainly the human leukocyte antigen (HLA) system. Here we investigated the role of neutral endopeptidase (NEP), a key enzyme in neuropeptide catabolism. NEP dysfunction resulting in reduced inactivation of neuropeptides may be a possible pathomechanism in CRPS. To this end, we tested a GT-repeat polymorphism in the NEP promoter region as well as 18 tag-SNPs in six linkage disequilibrium (LD) blocks in the NEP gene region in 320 CRPS patients and 376 controls. No significant genetic association was observed. Thus, we conclude that the NEP gene does not seem to be a major risk factor for CRPS.


Assuntos
Síndromes da Dor Regional Complexa/genética , Neprilisina/genética , Região 5'-Flanqueadora , Adulto , Estudos de Casos e Controles , Repetições de Dinucleotídeos , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Regiões Promotoras Genéticas
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