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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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Imaging the biomechanical properties of the matrix. Breast tumors are typically identified by changes in tissue mechanics, which can be detected physically, through palpitation or via imaging modalities that exploit tumor-associated changes. (A,B) Images of human breast tumor identified by ultrasound echogram (A) and mammary elastography imaging (B). The dashed lines roughly outline the imaged lesion boundary. The elastogram seems to shows a larger apparent lesion width but a similar height, relative to the echogram. This seems to be due to lateral protrusions, which are consistent with a desmoplastic response associated with local invasion that takes advantage of existing ductal and vascular anatomy. (C,D) MRI images of a 1-methyl-1-nitrosourea (MNU)-induced mammary carcinoma in rat. Here, not only do the changes in tumor ECM provide enhanced tissue contrast, but the intrinsic susceptibility of MRI exploits the paramagnetic properties of deoxyhemoglobin in erythrocytes. Deoxyhemoglobin therefore acts as an intrinsic, blood-oxygenation-level-dependent contrast agent, further highlighting the highly vascular nature of tumors. Ultrasound and elastography images were supplied courtesy of Jeff Bamber (The Institute of Cancer Research, UK). MRI images were supplied courtesy of Simon P. Robinson (The Institute of Cancer Research, UK).
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f4-0040165: Imaging the biomechanical properties of the matrix. Breast tumors are typically identified by changes in tissue mechanics, which can be detected physically, through palpitation or via imaging modalities that exploit tumor-associated changes. (A,B) Images of human breast tumor identified by ultrasound echogram (A) and mammary elastography imaging (B). The dashed lines roughly outline the imaged lesion boundary. The elastogram seems to shows a larger apparent lesion width but a similar height, relative to the echogram. This seems to be due to lateral protrusions, which are consistent with a desmoplastic response associated with local invasion that takes advantage of existing ductal and vascular anatomy. (C,D) MRI images of a 1-methyl-1-nitrosourea (MNU)-induced mammary carcinoma in rat. Here, not only do the changes in tumor ECM provide enhanced tissue contrast, but the intrinsic susceptibility of MRI exploits the paramagnetic properties of deoxyhemoglobin in erythrocytes. Deoxyhemoglobin therefore acts as an intrinsic, blood-oxygenation-level-dependent contrast agent, further highlighting the highly vascular nature of tumors. Ultrasound and elastography images were supplied courtesy of Jeff Bamber (The Institute of Cancer Research, UK). MRI images were supplied courtesy of Simon P. Robinson (The Institute of Cancer Research, UK).

Mentions: New technologies based on fluorescence resonance energy transfer (FRET) (Jiang et al., 2004), magnetic resonance imaging (MRI), positron emission tomography (PET) and single photon emission computed tomography (SPECT) (for a review, see Scherer et al., 2008a) are being developed to image the dynamic status of ECM remodeling, including visualization of MMP activity (Scherer et al., 2008b; Littlepage et al., 2010). Similarly, advances in μ-ultrasound, optical coherence tomography (OCT), optical acoustic microscopy and scanning acoustic microscopy (SAM) (Akhtar et al., 2009a) are currently under development to facilitate quantitative measurement and imaging of stiffness at the microscopic scale (Jeff Bamber, personal communication) (Low et al., 2006). In addition, increasing the resolution and versatility of many of the above techniques will be possible with improved contrast agents, such as so-called ‘smart probes’, which are MRI contrast agents that can be used to study ECM components (Spuentrup et al., 2005; Stracke et al., 2007; Miserus et al., 2009), soluble proteins such as growth factors and MMPs (Tsien, 2005; Scherer et al., 2008a; Scherer et al., 2008b), specific immune- or tumor-cell populations (Reynolds et al., 2006; Korosoglou et al., 2008; McAteer et al., 2008; Radermacher et al., 2009), and even physiological conditions such as hypoxia (Fig. 4) (McPhail and Robinson, 2010). These contrast agents are typically highly selective, specific and undergo enhanced activation on interacting with their target. In summary, new techniques that image the dynamics of cell-ECM interactions to non-invasively quantify remodeling of the ECM at the sub-millimeter level – and, more importantly, on a temporal scale – will ultimately provide additional resources for basic research and in the clinic.


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

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

Imaging the biomechanical properties of the matrix. Breast tumors are typically identified by changes in tissue mechanics, which can be detected physically, through palpitation or via imaging modalities that exploit tumor-associated changes. (A,B) Images of human breast tumor identified by ultrasound echogram (A) and mammary elastography imaging (B). The dashed lines roughly outline the imaged lesion boundary. The elastogram seems to shows a larger apparent lesion width but a similar height, relative to the echogram. This seems to be due to lateral protrusions, which are consistent with a desmoplastic response associated with local invasion that takes advantage of existing ductal and vascular anatomy. (C,D) MRI images of a 1-methyl-1-nitrosourea (MNU)-induced mammary carcinoma in rat. Here, not only do the changes in tumor ECM provide enhanced tissue contrast, but the intrinsic susceptibility of MRI exploits the paramagnetic properties of deoxyhemoglobin in erythrocytes. Deoxyhemoglobin therefore acts as an intrinsic, blood-oxygenation-level-dependent contrast agent, further highlighting the highly vascular nature of tumors. Ultrasound and elastography images were supplied courtesy of Jeff Bamber (The Institute of Cancer Research, UK). MRI images were supplied courtesy of Simon P. Robinson (The Institute of Cancer Research, UK).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f4-0040165: Imaging the biomechanical properties of the matrix. Breast tumors are typically identified by changes in tissue mechanics, which can be detected physically, through palpitation or via imaging modalities that exploit tumor-associated changes. (A,B) Images of human breast tumor identified by ultrasound echogram (A) and mammary elastography imaging (B). The dashed lines roughly outline the imaged lesion boundary. The elastogram seems to shows a larger apparent lesion width but a similar height, relative to the echogram. This seems to be due to lateral protrusions, which are consistent with a desmoplastic response associated with local invasion that takes advantage of existing ductal and vascular anatomy. (C,D) MRI images of a 1-methyl-1-nitrosourea (MNU)-induced mammary carcinoma in rat. Here, not only do the changes in tumor ECM provide enhanced tissue contrast, but the intrinsic susceptibility of MRI exploits the paramagnetic properties of deoxyhemoglobin in erythrocytes. Deoxyhemoglobin therefore acts as an intrinsic, blood-oxygenation-level-dependent contrast agent, further highlighting the highly vascular nature of tumors. Ultrasound and elastography images were supplied courtesy of Jeff Bamber (The Institute of Cancer Research, UK). MRI images were supplied courtesy of Simon P. Robinson (The Institute of Cancer Research, UK).
Mentions: New technologies based on fluorescence resonance energy transfer (FRET) (Jiang et al., 2004), magnetic resonance imaging (MRI), positron emission tomography (PET) and single photon emission computed tomography (SPECT) (for a review, see Scherer et al., 2008a) are being developed to image the dynamic status of ECM remodeling, including visualization of MMP activity (Scherer et al., 2008b; Littlepage et al., 2010). Similarly, advances in μ-ultrasound, optical coherence tomography (OCT), optical acoustic microscopy and scanning acoustic microscopy (SAM) (Akhtar et al., 2009a) are currently under development to facilitate quantitative measurement and imaging of stiffness at the microscopic scale (Jeff Bamber, personal communication) (Low et al., 2006). In addition, increasing the resolution and versatility of many of the above techniques will be possible with improved contrast agents, such as so-called ‘smart probes’, which are MRI contrast agents that can be used to study ECM components (Spuentrup et al., 2005; Stracke et al., 2007; Miserus et al., 2009), soluble proteins such as growth factors and MMPs (Tsien, 2005; Scherer et al., 2008a; Scherer et al., 2008b), specific immune- or tumor-cell populations (Reynolds et al., 2006; Korosoglou et al., 2008; McAteer et al., 2008; Radermacher et al., 2009), and even physiological conditions such as hypoxia (Fig. 4) (McPhail and Robinson, 2010). These contrast agents are typically highly selective, specific and undergo enhanced activation on interacting with their target. In summary, new techniques that image the dynamics of cell-ECM interactions to non-invasively quantify remodeling of the ECM at the sub-millimeter level – and, more importantly, on a temporal scale – will ultimately provide additional resources for basic research and in the clinic.

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