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Remodeling and homeostasis of the extracellular matrix: implications for fibrotic diseases and cancer.

Cox TR, Erler JT - Dis Model Mech (2011)

Bottom Line: Fibrotic diseases, which include pulmonary fibrosis, systemic sclerosis, liver cirrhosis and cardiovascular disease, account for over 45% of deaths in the developed world.Here, we discuss current methodologies and models for understanding and quantifying the impact of environmental cues provided by the ECM on disease progression, and how improving our understanding of ECM remodeling in these pathological conditions is crucial for uncovering novel therapeutic targets and treatment strategies.This can only be achieved through the use of appropriate in vitro and in vivo models to mimic disease, and with technologies that enable accurate monitoring, imaging and quantification of the ECM.

View Article: PubMed Central - PubMed

Affiliation: Cancer Research UK Tumour Cell Signalling Unit, Section of Cell and Molecular Biology, The Institute of Cancer Research, London, UK.

ABSTRACT
Dynamic remodeling of the extracellular matrix (ECM) is essential for development, wound healing and normal organ homeostasis. Life-threatening pathological conditions arise when ECM remodeling becomes excessive or uncontrolled. In this Perspective, we focus on how ECM remodeling contributes to fibrotic diseases and cancer, which both present challenging obstacles with respect to clinical treatment, to illustrate the importance and complexity of cell-ECM interactions in the pathogenesis of these conditions. Fibrotic diseases, which include pulmonary fibrosis, systemic sclerosis, liver cirrhosis and cardiovascular disease, account for over 45% of deaths in the developed world. ECM remodeling is also crucial for tumor malignancy and metastatic progression, which ultimately cause over 90% of deaths from cancer. Here, we discuss current methodologies and models for understanding and quantifying the impact of environmental cues provided by the ECM on disease progression, and how improving our understanding of ECM remodeling in these pathological conditions is crucial for uncovering novel therapeutic targets and treatment strategies. This can only be achieved through the use of appropriate in vitro and in vivo models to mimic disease, and with technologies that enable accurate monitoring, imaging and quantification of the ECM.

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Second harmonic generation (SHG) imaging of collagen fibril linearization during mammary gland tumorigenesis. Images are representative of whole, unfixed mammary glands of MMTV-neu mice [which carry an activated neu oncogene driven by a mouse mammary tumor virus (MMTV) promoter] and show that collagen fibril linearity increases with malignant progression, correlating with increased tissue stiffness. Arrowheads indicate linearized collagen fibrils. Image adapted, with permission, from Levental et al. (Levental et al., 2009).
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f3-0040165: Second harmonic generation (SHG) imaging of collagen fibril linearization during mammary gland tumorigenesis. Images are representative of whole, unfixed mammary glands of MMTV-neu mice [which carry an activated neu oncogene driven by a mouse mammary tumor virus (MMTV) promoter] and show that collagen fibril linearity increases with malignant progression, correlating with increased tissue stiffness. Arrowheads indicate linearized collagen fibrils. Image adapted, with permission, from Levental et al. (Levental et al., 2009).

Mentions: The quantitative assessment of ECM properties is a requirement if the functional effects of complex remodeling processes are to be understood. Changes in matrix composition and stiffness can be measured in vitro, in vivo and ex vivo. Common methods include staining tissues for biochemical markers by immunohistochemistry or immunofluorescence to characterize changes in ECM composition. In addition, histological methods such as the use of Masson’s trichrome and picrosirius red to stain collagens can be used to examine collagen structure and quantify collagen linearization and orientation (Levental et al., 2009) (see Fig. 3). Although such standard procedures can provide highly informative data on matrix changes during development and disease progression, they give only a static snapshot of the ECM and cannot capture its complex dynamics. To address this limitation, specialist techniques [such as echocardiography and sonoelastography (using sound) and second harmonics imaging (SHG; using light) with two-photon microscopy of whole tissues ex vivo and in vivo] can be used to analyze the ECM, particularly the collagen structure, and quantify collagen linearization in a non-invasive manner (Levental et al., 2009). Similarly, these techniques have been used to monitor the interactions of epithelial and stromal cells with tumors, as well as the initiation of collagen remodeling (Brown et al., 2003; Condeelis and Segall, 2003; Perentes et al., 2009; Wolf et al., 2009). Most important, however, is the ability to monitor events on a temporal scale rather than relying on endpoint assays to help understand both ECM dynamics and the resulting cellular behavior. Recent work by Giampieri et al. involving non-invasive intravital SHG imaging identified the paradigmatic role of TGFβ during the intermediate steps of tumor progression. This work highlights how temporal switches in TGFβ expression induced by local microenvironmental cues can dramatically affect cell migration, intravasation into blood and lymphatics systems, and colonization of secondary sites (Giampieri et al., 2009).


Remodeling and homeostasis of the extracellular matrix: implications for fibrotic diseases and cancer.

Cox TR, Erler JT - Dis Model Mech (2011)

Second harmonic generation (SHG) imaging of collagen fibril linearization during mammary gland tumorigenesis. Images are representative of whole, unfixed mammary glands of MMTV-neu mice [which carry an activated neu oncogene driven by a mouse mammary tumor virus (MMTV) promoter] and show that collagen fibril linearity increases with malignant progression, correlating with increased tissue stiffness. Arrowheads indicate linearized collagen fibrils. Image adapted, with permission, from Levental et al. (Levental et al., 2009).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3046088&req=5

f3-0040165: Second harmonic generation (SHG) imaging of collagen fibril linearization during mammary gland tumorigenesis. Images are representative of whole, unfixed mammary glands of MMTV-neu mice [which carry an activated neu oncogene driven by a mouse mammary tumor virus (MMTV) promoter] and show that collagen fibril linearity increases with malignant progression, correlating with increased tissue stiffness. Arrowheads indicate linearized collagen fibrils. Image adapted, with permission, from Levental et al. (Levental et al., 2009).
Mentions: The quantitative assessment of ECM properties is a requirement if the functional effects of complex remodeling processes are to be understood. Changes in matrix composition and stiffness can be measured in vitro, in vivo and ex vivo. Common methods include staining tissues for biochemical markers by immunohistochemistry or immunofluorescence to characterize changes in ECM composition. In addition, histological methods such as the use of Masson’s trichrome and picrosirius red to stain collagens can be used to examine collagen structure and quantify collagen linearization and orientation (Levental et al., 2009) (see Fig. 3). Although such standard procedures can provide highly informative data on matrix changes during development and disease progression, they give only a static snapshot of the ECM and cannot capture its complex dynamics. To address this limitation, specialist techniques [such as echocardiography and sonoelastography (using sound) and second harmonics imaging (SHG; using light) with two-photon microscopy of whole tissues ex vivo and in vivo] can be used to analyze the ECM, particularly the collagen structure, and quantify collagen linearization in a non-invasive manner (Levental et al., 2009). Similarly, these techniques have been used to monitor the interactions of epithelial and stromal cells with tumors, as well as the initiation of collagen remodeling (Brown et al., 2003; Condeelis and Segall, 2003; Perentes et al., 2009; Wolf et al., 2009). Most important, however, is the ability to monitor events on a temporal scale rather than relying on endpoint assays to help understand both ECM dynamics and the resulting cellular behavior. Recent work by Giampieri et al. involving non-invasive intravital SHG imaging identified the paradigmatic role of TGFβ during the intermediate steps of tumor progression. This work highlights how temporal switches in TGFβ expression induced by local microenvironmental cues can dramatically affect cell migration, intravasation into blood and lymphatics systems, and colonization of secondary sites (Giampieri et al., 2009).

Bottom Line: Fibrotic diseases, which include pulmonary fibrosis, systemic sclerosis, liver cirrhosis and cardiovascular disease, account for over 45% of deaths in the developed world.Here, we discuss current methodologies and models for understanding and quantifying the impact of environmental cues provided by the ECM on disease progression, and how improving our understanding of ECM remodeling in these pathological conditions is crucial for uncovering novel therapeutic targets and treatment strategies.This can only be achieved through the use of appropriate in vitro and in vivo models to mimic disease, and with technologies that enable accurate monitoring, imaging and quantification of the ECM.

View Article: PubMed Central - PubMed

Affiliation: Cancer Research UK Tumour Cell Signalling Unit, Section of Cell and Molecular Biology, The Institute of Cancer Research, London, UK.

ABSTRACT
Dynamic remodeling of the extracellular matrix (ECM) is essential for development, wound healing and normal organ homeostasis. Life-threatening pathological conditions arise when ECM remodeling becomes excessive or uncontrolled. In this Perspective, we focus on how ECM remodeling contributes to fibrotic diseases and cancer, which both present challenging obstacles with respect to clinical treatment, to illustrate the importance and complexity of cell-ECM interactions in the pathogenesis of these conditions. Fibrotic diseases, which include pulmonary fibrosis, systemic sclerosis, liver cirrhosis and cardiovascular disease, account for over 45% of deaths in the developed world. ECM remodeling is also crucial for tumor malignancy and metastatic progression, which ultimately cause over 90% of deaths from cancer. Here, we discuss current methodologies and models for understanding and quantifying the impact of environmental cues provided by the ECM on disease progression, and how improving our understanding of ECM remodeling in these pathological conditions is crucial for uncovering novel therapeutic targets and treatment strategies. This can only be achieved through the use of appropriate in vitro and in vivo models to mimic disease, and with technologies that enable accurate monitoring, imaging and quantification of the ECM.

Show MeSH
Related in: MedlinePlus