Apoptosis and Proliferation of Fibroblasts During Postnatal Skin Development and Scleroderma in the Tight-skin Mouse

Pablos, José L.; Carreira, Patrícia; Serrano, Lourdes; Castillo, Pilar; Gómez-Reino, Juan J.

doi:10.1177/002215549704500509

Cited by 29 publications

(15 citation statements)

References 28 publications

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“…Maintenance of Bcl-2's constitutive expression in cardiac fibroblasts is interesting because Bcl-2 is down-regulated in most tissues after birth and remains restricted to lymphoid tissue, precursor hematopoietic cells, thymocytes, glandular epithelia, stem cells within the gastrointestinal system, and differentiated long lived cells such as neurons (46). In particular, bcl-2 is expressed in many cell types of the skin during embryonic life but is repressed after birth in all skin cells but the epithelium (29). Down-regulation of Bcl-2 expression in dermal fibroblasts must involve transcriptional regulation and/or alteration of the Bcl-2 mRNA stability because, as presented here, Bcl-2 transcript was almost undetectable in these cells.…”

Section: Discussionmentioning

confidence: 99%

“…Our data pointed to the blockade of cytochrome c translocation as the main mechanism of cardiac fibroblast resistance to apoptosis. Furthermore, cardiac fibroblasts expressed an easily detectable level of the antiapoptotic protein Bcl-2, which is repressed in many cell types after development (28), including dermal (29) and lung (30) fibroblasts. Here, we provide evidence supporting the notion that the maintenance of Bcl-2 expression in cardiac fibroblasts confers their resistance to mitochondria-dependent apoptosis.…”

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confidence: 99%

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Bcl-2 Is a Key Factor for Cardiac Fibroblast Resistance to Programmed Cell Death

Mayorga

Bahí

Ballester

et al. 2004

Journal of Biological Chemistry

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Cardiac fibroblasts play an essential role in the physiology of the heart. These produce extracellular matrix proteins and synthesize angiogenic and cardioprotective factors. Although fibroblasts of cardiac origin are known to be resistant to apoptosis and to remain metabolically active in situations compromising cell survival, the underlying mechanisms are unknown. Here, we report that cardiac fibroblasts were more resistant than dermal or pulmonary fibroblasts to mitochondriadependent cell death. Cytochrome c release was blocked in cardiac fibroblasts but not in dermal fibroblasts treated with staurosporine, etoposide, serum deprivation, or simulated ischemia, precluding caspase-3 activation and DNA fragmentation. Resistance to apoptosis of cardiac fibroblasts correlated with the expression of the anti-apoptotic protein Bcl-2, whereas skin and lung fibroblasts did not express detectable levels of this protein. Bcl-x L, Bax, and Bak were expressed at similar levels in cardiac, dermal, and lung fibroblasts. In addition, the death of cardiac fibroblasts during hypoxia was not associated with the cleavage of Bid but rather with Bcl-2 disappearance, suggesting the requirement of the mitochondrial apoptotic machinery to execute death receptor-induced programmed cell death. Knockdown of bcl-2 expression by siRNA in cardiac fibroblasts increased their apoptotic response to staurosporine, serum, and glucose deprivation and to simulated ischemia. Moreover, dermal fibroblasts overexpressing Bcl-2 achieved a similar level of resistance to these stimuli as cardiac fibroblasts. Thus, our data demonstrate that Bcl-2 is an important effector of heart fibroblast resistance to apoptosis and highlight a probable mechanism for promoting survival advantage in fibroblasts of cardiac origin.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Bcl-2 Is a Key Factor for Cardiac Fibroblast Resistance to Programmed Cell Death

Mayorga

Bahí

Ballester

et al. 2004

Journal of Biological Chemistry

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“…In addition to these hypotheses, proliferating intratumoral fibroblasts may deviate from the mechanism of apoptosis and form FF in IDCs (32,33). If FF is formed only by a paracrine or autocrine growth mechanism of intratumoral fibroblasts, a FIGURE 6.…”

Section: Discussionmentioning

confidence: 99%

Highly Proliferative Fibroblasts Forming Fibrotic Focus Govern Metastasis of Invasive Ductal Carcinoma of the Breast

et al. 2001

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We have already reported that invasive ductal carcinomas (IDCs) with fibrotic focus (FF) have more aggressive characteristics than those without FF. FF is composed of a mixture of fibroblasts and various amounts of collagen fibers, suggesting that highly proliferative fibroblasts forming FF increase the malignant potential of IDCs with FF. The purpose of this study was to examine whether there is a difference of proliferative activity of fibroblasts forming and not forming FF, which plays an important role in the tumor progression of IDCs. Two hundred three consecutive cases of IDC of the breast surgically treated at the National Cancer Center Hospital East formed the basis for this study. The proliferative activity of the fibroblasts forming the FF was immunohistochemically evaluated by using mouse MIB-1 monoclonal antibody against Ki-67 antigen. We have already reported that invasive ductal carcinomas (IDCs) with fibrotic focus (FF) have more aggressive characteristics than IDCs without FF (1) and that the former are associated with significantly poorer survival course in short-and long-term survival periods than the latter (2, 3). We also found that IDCs with FF exhibit significantly greater tumor angiogenesis and higher tumor cell proliferative activity and that the presence of FF is an independent prognostic parameter for IDC patients (4). These findings indicate that the presence of FF in IDCs is a very important histological parameter for predicting the outcome of patients with IDC of the breast. FF is composed of a mixture of fibroblasts and various amounts of collagen fibers, and they occupy almost the entire center of the IDC. In routine examination, mitotic figures of fibroblasts forming FF as well as those of the tumor cells are seen in some areas within FF. This suggests that highly proliferative fibroblasts make up FF and heighten the malignant potential of IDCs having FF.The purposes of this study were to determine whether there are biological characteristic differences between fibroblasts forming and not forming FF by evaluating their proliferative activity and also whether their proliferative activity plays a important role in tumor progression of IDC. The significance of the proliferative activity of fibroblasts forming and not forming FF on lymph node metastasis (LNM) and distant-organ metastasis (DOM) in IDC patients was assessed by comparing it with well-known histological parameters, tumor cell

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“…ibroblasts are a relatively quiescent and long-lived cell population in adult tissues, where fibroblast proliferation or death is not detectable (1,2). During inflammation and tissue repair, fibroblast proliferation and apoptosis have been observed, and the balance between both processes seems to participate in the initiation and resolution of fibroproliferative responses (2-6).…”

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confidence: 99%

Intracellular Regulation of Fas-Induced Apoptosis in Human Fibroblasts by Extracellular Factors and Cycloheximide

Santiago

Galindo²,

Palao

et al. 2004

The Journal of Immunology

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Fibroblasts play an important role in reparative and inflammatory processes by synthesizing extracellular matrix components and releasing growth factors and cytokines. Fibroblast apoptosis has been observed at the termination phase of reparative or fibrotic responses, but its regulation in this context is poorly known. We investigated the susceptibility of human dermal fibroblasts (DF) to Fas-induced apoptosis and its regulation by extracellular factors potentially involved in immune-mediated inflammation and repair. DF expressed all components of the Fas apoptotic pathway: surface Fas, Fas-associated protein with death domain, and caspase-8 proteins. However, Fas activation resulted in caspase-8 activation and apoptosis only in the presence of cycloheximide (CHX). DF constitutively expressed Fas-associated death domain-like IL-1-converting enzyme-like inhibitory protein (FLIP) that was drastically down-regulated by CHX. Exogenous growth factors, cytokines, and adherence to the extracellular matrix shifted the balance of FLIP-caspase-8 proteins and modified the susceptibility of DF to Fas- or Fas-CHX-induced apoptosis. Short-term serum deprivation, suspension culture, and pretreatment with IFN-γ or TNF-α increased, whereas long-term serum-free culture and pretreatment with TGF-β or IL-10 decreased the apoptotic susceptibility of DF. Surface Fas expression was only modified by TNF-α and IFN-γ, whereas all studied factors modified FLIP-caspase-8 protein expression, consistently with their pro- or antiapoptotic effects. Antisense FLIP oligonucleotides prevented resistance to Fas-induced apoptosis in DF. FLIP-caspase-8 balance seems tightly regulated in fibroblasts by extracellular factors that determine their susceptibility to Fas- or Fas-CHX-induced apoptosis. Th1 and Th regulatory cytokines display opposite effects on fibroblast apoptosis that suggest that their pro- or antifibrotic effects involve direct effects on fibroblast survival.

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Apoptosis and Proliferation of Fibroblasts During Postnatal Skin Development and Scleroderma in the Tight-skin Mouse

Cited by 29 publications

References 28 publications

Bcl-2 Is a Key Factor for Cardiac Fibroblast Resistance to Programmed Cell Death

Bcl-2 Is a Key Factor for Cardiac Fibroblast Resistance to Programmed Cell Death

Highly Proliferative Fibroblasts Forming Fibrotic Focus Govern Metastasis of Invasive Ductal Carcinoma of the Breast

Intracellular Regulation of Fas-Induced Apoptosis in Human Fibroblasts by Extracellular Factors and Cycloheximide

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