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1.
Cell Cycle ; 10(12): 2021-34, 2011 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-21646868

RESUMO

We have previously demonstrated that loss of stromal caveolin-1 (Cav-1) in cancer-associated fibroblasts is a strong and independent predictor of poor clinical outcome in human breast cancer patients. However, the signaling mechanism(s) by which Cav-1 downregulation leads to this tumor-promoting microenvironment are not well understood. To address this issue, we performed an unbiased comparative proteomic analysis of wild-type (WT) and Cav-1(-/-) null mammary stromal fibroblasts (MSFs). Our results show that plasminogen activator inhibitor type 1 and type 2 (PAI-1 and PAI-2) expression is significantly increased in Cav-1(-/-) MSFs. To establish a direct cause-effect relationship, we next generated immortalized human fibroblast lines stably overexpressing either PAI-1 or PAI-2. Importantly, PAI-1/2(+) fibroblasts promote the growth of MDA-MB-231 tumors (a human breast cancer cell line) in a murine xenograft model, without any increases in angiogenesis. Similarly, PAI-1/2(+) fibroblasts stimulate experimental metastasis of MDA-MB-231 cells using an in vivo lung colonization assay. Further mechanistic studies revealed that fibroblasts overexpressing PAI-1 or PAI-2 display increased autophagy ("self-eating") and are sufficient to induce mitochondrial biogenesis/activity in adjacent cancer cells, in co-culture experiments. In xenografts, PAI-1/2(+) fibroblasts significantly reduce the apoptosis of MDA-MB-231 tumor cells. The current study provides further support for the "Autophagic Tumor Stroma Model of Cancer" and identifies a novel "extracellular matrix"-based signaling mechanism, by which a loss of stromal Cav-1 generates a metastatic phenotype. Thus, the secretion and remodeling of extracellular matrix components (such as PAI-1/2) can directly regulate both (1) autophagy in stromal fibroblasts and (2) epithelial tumor cell mitochondrial metabolism.


Assuntos
Autofagia , Matriz Extracelular/metabolismo , Mitocôndrias/metabolismo , Metástase Neoplásica , Células Estromais/patologia , Animais , Neoplasias da Mama/patologia , Caveolina 1/metabolismo , Linhagem Celular Tumoral , Técnicas de Cocultura , Fibroblastos/patologia , Humanos , Camundongos , Mitocôndrias/patologia , Neoplasias/patologia , Neoplasias/ultraestrutura , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Inibidor 2 de Ativador de Plasminogênio/metabolismo , Transplante Heterólogo , Microambiente Tumoral
2.
Cell Cycle ; 10(13): 2140-50, 2011 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-21670602

RESUMO

Caveolin-1 (Cav-1), the principal structural component of caveolae, participates in the pathogenesis of several fibrotic diseases, including systemic sclerosis (SSc). Interestingly, affected skin and lung samples from patients with SSc show reduced levels of Cav-1, as compared to normal skin. In addition, restoration of Cav-1 function in skin fibroblasts from SSc patients reversed their pro-fibrotic phenotype. Here, we further investigated whether Cav-1 mice are a useful pre-clinical model for studying the pathogenesis of SSc. For this purpose, we performed quantitative transmission electron microscopy, as well as biochemical and immuno-histochemical analysis, of the skin from Cav-1 (-/-) null mice. Using these complementary approaches, we now show that skin from Cav-1 null mice exhibits many of the same characteristics as SSc skin from patients, including a decrease in collagen fiber diameter, increased tensile strength, and stiffness, as well as mononuclear cell infiltration. Furthermore, an increase in autophagy/mitophagy was observed in the stromal cells of the dermis from Cav-1 (-/-) mice. These findings suggest that changes in cellular energy metabolism (e.g., a shift towards aerobic glycolysis) in these stromal cells may be a survival mechanism in this "hostile" or pro-inflammatory microenvironment. Taken together, our results demonstrate that Cav-1 (-/-) null mice are a valuable new pre-clinical model for studying scleroderma. Most importantly, our results suggest that inhibition of autophagy and/or aerobic glycolysis may represent a new promising therapeutic strategy for halting fibrosis in SSc patients. Finally, Cav-1 (-/-) null mice are also a pre-clinical model for a "lethal" tumor micro-environment, possibly explaining the link between fibrosis, tumor progression, and cancer metastasis.


Assuntos
Caveolina 1/metabolismo , Camundongos Knockout , Esclerodermia Localizada , Escleroderma Sistêmico , Pele , Animais , Autofagia , Caveolina 1/genética , Colágeno/metabolismo , Modelos Animais de Doenças , Feminino , Fibronectinas/metabolismo , Fibrose/metabolismo , Fibrose/patologia , Humanos , Macrófagos/citologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Miofibroblastos/citologia , Miofibroblastos/metabolismo , Esclerodermia Localizada/metabolismo , Esclerodermia Localizada/patologia , Escleroderma Sistêmico/metabolismo , Escleroderma Sistêmico/patologia , Pele/citologia , Pele/metabolismo , Pele/patologia , Células Estromais/citologia , Células Estromais/metabolismo
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