Latent transforming growth factor β1 activation in situ: quantitative and functional evidence after low‐dose γ‐irradiation
            <sup>1</sup>

Ehrhart, E. J.; Segarini, Patricia R.; Tsang, Monica; Carroll, Alan G.; Barcellos‐Hoff, Mary Helen

doi:10.1096/fasebj.11.12.9337152

Cited by 213 publications

(133 citation statements)

References 0 publications

Supporting

Mentioning

124

Contrasting

Unclassified

Order By: Relevance

“…Detection of apoptosis by TUNEL analysis was performed using the Apoptag Detection Kit (Serologicals Corp., Norcross, GA, USA) according to the manufacturer's instructions. Immunofluorescence for Smad2 and active TGFb1 was performed using fresh frozen tissue cryosections as described previously (Ehrhart et al, 1997) using the following antibodies: active TGFb1 (cat # AF-101-NA, lot FS08, R&D Systems, Minneapolis, MN, USA), Smad2/3 (Santa Cruz Biotechnology, Santa Cruz, CA, USA), and secondary antibodies labeled with Alexa 488 or 594 fluorochromes (Molecular Probes, Eugene, OR, USA). Images were captured using a scientific-grade 12-bit charge-coupled device (KAF-1400, 1317 Â 1035 6.8-mm 2 pixels) digital camera (Xillix, Vancouver, Canada).…”

Section: Methodsmentioning

confidence: 99%

Activated type I TGFβ receptor kinase enhances the survival of mammary epithelial cells and accelerates tumor progression

et al. 2005

View full text Add to dashboard Cite

We have examined the effects of transforming growth factor-beta (TGFb) signaling on mammary epithelial cell survival. Transgenic mice expressing an active mutant of Alk5 in the mammary gland (MMTV-Alk5 T204D ) exhibited reduced apoptosis in terminal endbuds and during postlactational involution. Transgene-expressing mammary cells contained lower Smad2/3 and higher c-myc levels than controls, high ligand-independent phosphatidylinositol-3 kinase (PI3K) and Akt activities, and were insensitive to TGFb-mediated growth arrest. Treatment with a proteasome inhibitor increased Smad2/3 levels and ligand-independent Smad transcriptional reporter activity, as well as reduced both c-myc protein and basal cell proliferation. Treatment with an Alk5 kinase small-molecule inhibitor upregulated Smad2/3 levels, reduced PI3K activity, P-Akt, and c-myc, and inhibited cell survival. Although Alk5 T204D -expressing mice did not develop mammary tumors, bigenic MMTV-Alk T204D Â Neu mice developed cancers that were more metastatic than those occurring in MMTV-Neu transgenics. These data suggest that (1) TGFb can signal to PI3K/Akt and enhance mammary epithelial cell survival in vivo before cytological or histological evidence of transformation, and (2) TGFb signaling can provide epithelial cells with a 'gain-of-function' effect that synergizes with oncogene-induced transformation.

show abstract

Section: Methodsmentioning

confidence: 99%

Activated type I TGFβ receptor kinase enhances the survival of mammary epithelial cells and accelerates tumor progression

et al. 2005

View full text Add to dashboard Cite

show abstract

“…Barcellos-Hoff and colleagues 39 have shown that irradiation of the mammarygland stromal component promotes the tumorigenic potential of non-irradiated epithelial cells. These investigators had previously shown that even low levels of irradiation lead to remodelling of the ECM in breast tissue and activation of latent transforming growth factor-β (TGF-β), which affects tissue and organ function 40 . Moinfar et al 41 examined genetic alterations in tumour-associated stroma from several independent cases of mammary carcinoma, and found chromosomal rearrangements that were not present in the malignant carcinoma cells.…”

Section: Activated Stroma As a Carcinogenmentioning

confidence: 99%

Putting tumours in context

2001

View full text Add to dashboard Cite

The interactions between cancer cells and their micro-and macroenvironment create a context that promotes tumour growth and protects it from immune attack. The functional association of cancer cells with their surrounding tissues forms a new 'organ' that changes as malignancy progresses. Investigation of this process might provide new insights into the mechanisms of tumorigenesis and could also lead to new therapeutic targets.Under normal conditions, ORGANS are made up of TISSUES that exchange information with other cell types via cell-cell contact, cytokines and the EXTRACELLULAR MATRIX (ECM). The ECM, which is produced by collaboration between STROMAL fibroblasts and EPITHELIAL cells, provides structural scaffolding for cells, as well as contextual information. The endothelial vasculature provides nutrients and oxygen, and cells of the immune system combat pathogens and remove apoptotic cells. Epithelial cells associate into intact, polarized sheets. These tissues communicate through a complex network of interactions: physically, through direct contact or through the intervening ECM, and biochemically, through both soluble and insoluble signalling molecules. In combination, these interactions provide the information that is necessary to maintain cellular differentiation and to create complex tissue structures.Occasionally, the intercellular signals that define the normal context become disrupted. Alterations in epithelial tissues can lead to movement of epithelial sheets and proliferationfor example, after activation of mesenchymal fibroblasts due to wounding. Normally, these conditions are temporary and reversible, but when inflammation is sustained, an escalating feedback loop ensues. Under persistent inflammatory conditions, continual upregulation of enzymes such as matrix metalloproteinases (MMPs) by stromal fibroblasts can disrupt the ECM, and invading immune cells can overproduce factors that promote abnormal proliferation.As this process progresses, the normal organization of the organ is replaced by a functional disorder (FIG. 1). If there are pre-existing epithelial cells within this changing context that possess tumorigenic potential, they can start to proliferate. Alternatively, the abnormal An innate anticancer mechanismAn important feature of the normal stromal context is the generation and maintenance of epithelial-cell polarity. Epithelial cells receive a variety of orientational cues from the environment that help them establish cellular apical and basal surfaces and to maintain the differentiated state. Loss of polarity has been shown to lead to increased cell proliferation and tumorigenesis (BOX 1). The basal surface of epithelial cells associates with the BASEMENT MEMBRANE, a specialized form of ECM that provides both structural support and polarization signals to epithelia. The basement membrane is a dynamic structure. Changes in its composition lead to changes in cell shape and behaviour 1 , altered binding affinity or cellular distribution of cell-surface receptors 2 , and cellu...

show abstract

“…Tais resultados indicam ativação "in situ" da proteína TGFβ1 em células do parênquima pulmonar. Em outros tecidos, como a glândula mamária, observou-se ativação da TGFβ em horas e em dias após irradiação 19,33 . Sugeriu-se que a ativação precoce seria conseqüente ao "stress" oxidativo induzido pelos radicais livres produzidos pela radiação e a elevação continuada e tardia da proteína devido aos mecanismos celulares via plasmina.…”

Section: Figura 2 -Medianas Dos Valores Das Contagens De Fibras Colágunclassified

Ativação da proteína TGFbetaI latente em pulmão irradiado in vivo

Mattos¹,

Kimura²,

Silva³

et al. 2002

Rev. Assoc. Med. Bras.

View full text Add to dashboard Cite

RESUMO -OBJETIVO. Investigar no pulmão, por imunohistoquímica, a localização das proteínas TGFβ β β β β1 latente e TGFβ β β β β1 ativa, se ocorre ativação radioinduzida da proteína TGFβ β β β β1 latente e a distribuição das fibras colágenas em diversos períodos de tempo após irradiação.MÉTODOS. 32 camundongos isogênicos (C57BL) foram divididos em dois grupos: GI (não irradiado) com 12 animais e GII (irradiado) com 20 animais. Os animais do GII receberam radiação gama (telecobaltoterapia, 60Co, com rendimento de 0,97Gy/min, dose única de 7Gy em corpo inteiro). Os camundongos dos grupos I e II foram sacrificados por estiramento cervical nos períodos de 1, 14, 30 e 90 dias após irradiação.RESULTADOS. Os pulmões irradiados apresentaram: 1) congestão vascular e espessamento dos septos alveolares aos 30 dias e mais intensamente aos 90 dias depois da irradiação; 2) aumento significante da deposição de colágeno em todos os períodos de tempo após irradiação; 3) fraca ativação da proteína TGFβ β β β β1 latente em um dia e intensa aos 14 dias depois da irradiação em brônquios e alvéolos. Nossos resultados sugerem que células dos brônquios e alvéolos podem participar do complexo mecanismo de fibrose pulmonar radioinduzida atuando como fontes da proteína TGFβ β β β β1 ativa.UNITERMOS: Radiação ionizante. Fibrose pulmonar. Fator β de transformação do crescimento (TGFβ). INTRODUÇÃOA radiossensibilidade pulmonar e a formação de fibrose radioinduzida são importantes fatores a serem considerados nas irradiações torácicas localizadas em campos restritos bem como na irradiação de corpo inteiro 1,2 . A resposta do pulmão à radiação depende do volume do órgão irradiado 1 , dose total 3,4 , fracionamento da dose 1,5 e da taxa de dose utilizada (6,7) . Dessa forma, as alterações histopatológicas observadas no pulmão irradiado podem variar desde edema e congestão da parede alveolar até a deposição de fibras colágenas e fibrose pulmonar 3,8 . Quanto ao mecanismo da fibrose pulmonar radioinduzida, o fator β de transformação do crescimento, TGFβ, parece exercer um papel importante no processo. A TGFβ é uma citoquina multifuncional envolvida no controle da proliferação e diferenciação celular 9 . Promove inibição da proliferação de células do tecido conjuntivo 10,11 e diminuição da degradação do colágeno 12 . Parte da resposta fibrótica induzida pelo TGFβ parece estar relacionada com a modulação do sistema fibroblasto/ fibrócito, levando ao acúmulo de colágeno tipo I e tipo III [13][14][15] . Em células de mamíferos, a TGFβ está presente sob três isoformas, TGFβ1, TGFβ2 e TGFβ3, sendo as proteínas produzidas na forma inativa e ligadas ao peptídeo associado à latência (LAP) 10,[16][17][18] . Dessa forma, a atividade biológica desta proteí-na depende da dissociação da TGFβ madura do complexo latente 19 . In vivo, são ativadas por proteases que clivam o complexo latente, e a plasmina é uma das proteases envolvidas no processo de ativação 20 . Observou-se ativação da proteína TGFβ1 em células da glândula mamária, horas depois da irradiação 19 ....

show abstract

Latent transforming growth factor β1 activation in situ: quantitative and functional evidence after low‐dose γ‐irradiation ¹

Cited by 213 publications

References 0 publications

Activated type I TGFβ receptor kinase enhances the survival of mammary epithelial cells and accelerates tumor progression

Activated type I TGFβ receptor kinase enhances the survival of mammary epithelial cells and accelerates tumor progression

Putting tumours in context

Ativação da proteína TGFbetaI latente em pulmão irradiado in vivo

Contact Info

Product

Resources

About

Latent transforming growth factor β1 activation in situ: quantitative and functional evidence after low‐dose γ‐irradiation 1

Cited by 213 publications

References 0 publications

Activated type I TGFβ receptor kinase enhances the survival of mammary epithelial cells and accelerates tumor progression

Activated type I TGFβ receptor kinase enhances the survival of mammary epithelial cells and accelerates tumor progression

Putting tumours in context

Ativação da proteína TGFbetaI latente em pulmão irradiado in vivo

Contact Info

Product

Resources

About

Latent transforming growth factor β1 activation in situ: quantitative and functional evidence after low‐dose γ‐irradiation ¹