Soluble Collagen VI Drives Serum-starved Fibroblasts through S Phase and Prevents Apoptosis via Down-regulation of Bax

Rühl, Martin; Sahin, Ergün; Johannsen, Manfred; Somasundaram, Rajan; Manski, Dirk; Riecken, E. O.; Schuppan, Detlef

doi:10.1074/jbc.274.48.34361

Cited by 107 publications

(76 citation statements)

References 55 publications

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“…For example, we detected the presence of type VI collagen that has been described previously by Scherer and colleagues (12) in adipocyte tissue as an adipocyteenriched secretory protein that promotes pro-oncogenic pathways in breast cancer cells and that may play a key role in the regulation of normal and transformed mesenchymal cell proliferation in vitro (91) as well as in preventing apoptosis (92). It has also been shown that type VI collagen promotes the phosphorylation of glycogen synthase kinase-3␤ in malignant ductal epithelial cells, leading to increased ␤-catenin stabilization and transcriptional activity (7).…”

Section: Cytokines and Growth Factors Secreted By Adipocytesmentioning

confidence: 89%

Identification of Extracellular and Intracellular Signaling Components of the Mammary Adipose Tissue and Its Interstitial Fluid in High Risk Breast Cancer Patients

Celis

Moreira

Cabezón

et al. 2005

Molecular & Cellular Proteomics

208

164

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It has become clear that growth and progression of breast tumor cells not only depend on their malignant potential but also on factors present in the tumor microenvironment. Of the cell types that constitute the mammary stroma, the adipocytes are perhaps the least well studied despite the fact that they represent one of the most prominent cell types surrounding the breast tumor cells. There is compelling evidence demonstrating a role for the mammary fat pad in mammary gland development, and some studies have revealed the ability of fat tissue to augment the growth and ability to metastasize of mammary carcinoma cells. Very little is known, however, about which factors adipocytes produce that may orchestrate these actions and how this may come about. In an effort to shed some light on these questions, we present here a detailed proteomic analysis, using two-dimensional gel-based technology, mass spectrometry, immunoblotting, and antibody arrays, of adipose cells and interstitial fluid of fresh fat tissue samples collected from sites topologically distant from the tumors of high risk breast cancer patients that underwent mastectomy and that were not treated prior to surgery. A total of 359 unique proteins were identified, including numerous signaling molecules, hormones, cytokines, and growth factors, involved in a variety of biological processes such as signal transduction and cell communication; energy metabolism; protein metabolism; cell growth and/or maintenance; immune response; transport; regulation of nucleobase, nucleoside, and nucleic acid metabolism; and apoptosis. Apart from providing a comprehensive overview of the mammary fat proteome and its interstitial fluid, the results offer some insight as to the role of adipocytes in the breast tumor microenvironment and provide a first glance of their molecular cellular circuitry. In addition, the results open new possibilities to the study of obesity, which has a strong association with type 2 diabetes, hypertension, and coronary heart disease. Molecular & Cellular Proteomics 4: 492-522, 2005.During the last years there have been numerous reports indicating that growth and progression of breast as well as other tumor cells depend not only on their malignant potential but also on stromal factors present in the tumor microenvironment, the insoluble extracellular matrix as well as cell-cell interactions (Refs.

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Section: Cytokines and Growth Factors Secreted By Adipocytesmentioning

confidence: 89%

Identification of Extracellular and Intracellular Signaling Components of the Mammary Adipose Tissue and Its Interstitial Fluid in High Risk Breast Cancer Patients

Celis

Moreira

Cabezón

et al. 2005

Molecular & Cellular Proteomics

208

164

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“…PTN stimulates new collagen of different subtypes and new elastin synthesis (L. Ezquerra, G. Herradon, and T.F.D., unpublished data). Collagen fragments are known to stimulate growth of carcinoma cells and to stimulate antiapoptotic pathways, favoring growth of the carcinoma cells (21). Through activation of integrins and ''outside-in'' signaling, both elastin and collagens are known to activate the ERK pathway in epithelial cells and function to prevent caspase 8 activation and apoptosis (18).…”

Section: Discussionmentioning

confidence: 99%

Secretion of pleiotrophin stimulates breast cancer progression through remodeling of the tumor microenvironment

Chang

Zuka

Pérez-Piñera

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Pleiotrophin (PTN,Ptnangiogenesis ͉ collagen ͉ polyoma virus middle T ͉ scirrhous carcinoma ͉ stromal fibroblasts B reast cancers progress through stages of increasing malignancy triggered by genetic and epigenetic mutations that promote their growth, invasiveness, and metastasis. Because mortality from breast cancer is most often due to growth of distant metastases that are not controlled by existing therapies, there is a vital need to better understand the molecular pathogenesis of breast cancer and to identify mutations in breast cancer cells that promote breast cancer progression and lead to metastasis (1).Pleiotrophin [PTN (the protein), Ptn (the gene)] is a 136-aa heparin-binding cytokine (2, 3) frequently detected in human breast cancers (4). Its expression is constitutive in human breast cancer cells in which it has been tested (5). Furthermore, PTN stimulates functional responses that are known to stimulate breast cancer progression, such as proliferation (2, 3), cytoskeletal rearrangements, and loss of cell-cell adhesion (6, 7), transformation (8), induction of an epithelial to mesenchymal transition (6), and stimulation of tumor angiogenesis (9, 10), in cultured cells or in cells that ectopically express Ptn. These functional responses to PTN are likely to be significant in progression of breast cancers, because interruption of constitutive PTN signaling in human breast cancer cells that inappropriately express Ptn reverses their transformed phenotype in vitro and in vivo (5); these PTN-stimulated functional responses thus support the possibility that mutations in breast cancer cells, which deregulate endogenous Ptn expression, may initiate similar functional responses and lead to breast cancer progression.In the following studies, three models were tested to determine whether inappropriate expression of Ptn alone is sufficient to induce breast cancer or whether inappropriate expression of Ptn cooperates with different pathogenic mechanisms that stimulate breast cancer progression. Together, the studies demonstrate both in vivo and in vitro that inappropriate expression of Ptn promotes breast cancer progression; the studies also demonstrate that PTN secretion from human breast cancer cells alone is sufficient to promote progression of breast cancer to a more aggressive breast cancer phenotype through activation of stromal cells and extensive remodeling of the microenvironment. Results Mouse Mammary Tumor Virus (MMTV)-Ptn Fails to Induce BreastCancer in MMTV-Ptn Transgenic Mice. To test whether inappropriate expression of Ptn alone is sufficient to induce breast cancers in mice, MMTV-long terminal repeat-driven-Ptn (MMTV-Ptn) transgenic mice were generated [see supporting information (SI) Materials and Methods and SI Fig. 5]. Female MMTV-Ptn mice had normal mammary gland development and lactation and developed pups in normal numbers and in size equal to that of control mouse pups. Expression of the MMTV-Ptn transgene was detected in high levels in breast epithelial cells. In extensive microscopic exami...

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“…For the double immunostaining of p53 and Bax, cells were stained with anti-p53 antibody (clone pBP53-12) and anti-Bax antibody (N-20, rabbit polyclonal, Santa Cruz Biotechnology). 25,26 Bound antibodies were detected by goat anti-mouse IgG2a-Alexa 568 and goat anti-rabbit IgG-Alexa 488, respectively (both from Molecular Probes). Nuclei were counterstained with DAPI.…”

Section: Immunostaining Of P53 and Downstream Genesmentioning

confidence: 99%

“…Cells were then exposed to Medium 231 containing serum and harvested at 0, 4, 8, 24, 48, and 72 hours after a 1-time medium change at time 0. Western blot and densitometric analysis of HAVSMCs was performed as described previously, 19 -21 with well-characterized antibodies against p53 (clone DO-1), 22 p21 WAF1/CIP1 (Clone 187), 23,24 and Bax (N-20) 25,26 (all from Santa Cruz Biotechnology). The densitometric signal intensities of p53, p21…”

Section: Western Blot Analysis Of Vsmcsmentioning

confidence: 99%

Paradoxical Upregulation of Tumor Suppressor Protein p53 in Serum-Stimulated Vascular Smooth Muscle Cells

et al. 2003

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Background-The proliferative response of vascular smooth muscle cells (VSMCs) to various growth stimuli is critical for atherosclerosis and postangioplasty restenosis. Although tumor suppressor protein p53 plays a critical role in the elimination of cancerous cells, recent genetic studies have indicated that it also protects against atherosclerosis and restenosis. Methods and Results-We examined the levels of p53 protein in normal VSMCs before and after serum stimulation. The p53 protein levels increased robustly on stimulation. Upregulated p53 protein was capable of binding to the p53 consensus sequence, as shown by electrophoretic mobility shift assay. In addition, p53 upregulation was associated with increases in the transcript and protein levels of p21 WAF1/CIP1 and Bax, as shown by real-time reverse transcriptasepolymerase chain reaction and Western blot analysis, respectively. Furthermore, the upregulation of p21 WAF1/CIP1 and Bax was followed by cell-cycle arrest and apoptosis induction, as shown by 5-bromo-2Ј-dUTP incorporation assay and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling staining, respectively. Finally, double-staining analyses showed that the majority of p53-expressing cells also expressed p21 WAF1/CIP1 and Bax proteins. Conclusions-p53 protein expression in quiescent VSMCs is paradoxically increased by application of a growth stimulus.Through the mediation of p21 WAF1/CIP1 and Bax, the induced p53 protein negatively regulates the growth of dividing VSMCs, thereby minimizing the inappropriate accumulation of VSMCs. Therefore, p53 may be a negative regulator of VSMC growth.

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Soluble Collagen VI Drives Serum-starved Fibroblasts through S Phase and Prevents Apoptosis via Down-regulation of Bax

Cited by 107 publications

References 55 publications

Identification of Extracellular and Intracellular Signaling Components of the Mammary Adipose Tissue and Its Interstitial Fluid in High Risk Breast Cancer Patients

Identification of Extracellular and Intracellular Signaling Components of the Mammary Adipose Tissue and Its Interstitial Fluid in High Risk Breast Cancer Patients

Secretion of pleiotrophin stimulates breast cancer progression through remodeling of the tumor microenvironment

Paradoxical Upregulation of Tumor Suppressor Protein p53 in Serum-Stimulated Vascular Smooth Muscle Cells

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