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Topics {✒️}

post-hoc tukey-kramer test nrsf-ctbp-dependent metabolic regulation pyvt/col1a1 tumor-bearing glands mammographically dense tissue flavin adenine dinucleotide multiphoton laser-scanning microscopy hepatocyte growth/scatter factor acquired z-stacks deconvolved collagen-dense breast tissue collagen-dense mammary glands collagen-dense glands continued pre-publication history collagen-dense mammary tissues fak integrates growth-factor epithelial-stromal interaction plays collagen-dense tissues continued elevated sdf-1/cxcl12 secretion erbb-2/erbb-3 receptor cooperation multiphoton-excited native fluorescence article download pdf actual lifetime/color mapping promoting tumor initiation directly promote growth nicotinamide adenine dinucleotide bi-transgenic tumor model bmc medicine acid-mediated tumor invasion time-resolved fluorescence properties epidermal growth factor collagen-dense tissues resulted low-density matrices form full size image wild-type tumors showing age-matched time points tumor-stromal collagen features tissue biopsy punch tumor-stromal interaction suggests collagen-dense tissue anti-mouse tetramethylrhodamine isothiocyanate growth factor signaling spectral-lifetime computational analysis breast tissue density hormone replacement therapy prostate cancer progression collagen-dense tumors shown collagen-dense microenvironment mouse mammary tissue lifetime fluorescence microscopy spectral lifetime imaging greatly increased occurrence

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         headline:Collagen density promotes mammary tumor initiation and progression
         description:Mammographically dense breast tissue is one of the greatest risk factors for developing breast carcinoma. Despite the strong clinical correlation, breast density has not been causally linked to tumorigenesis, largely because no animal model has existed for studying breast tissue density. Importantly, regions of high breast density are associated with increased stromal collagen. Thus, the influence of the extracellular matrix on breast carcinoma development and the underlying molecular mechanisms are not understood. To study the effects of collagen density on mammary tumor formation and progression, we utilized a bi-transgenic tumor model with increased stromal collagen in mouse mammary tissue. Imaging of the tumors and tumor-stromal interface in live tumor tissue was performed with multiphoton laser-scanning microscopy to generate multiphoton excitation and spectrally resolved fluorescent lifetimes of endogenous fluorophores. Second harmonic generation was utilized to image stromal collagen. Herein we demonstrate that increased stromal collagen in mouse mammary tissue significantly increases tumor formation approximately three-fold (p < 0.00001) and results in a significantly more invasive phenotype with approximately three times more lung metastasis (p < 0.05). Furthermore, the increased invasive phenotype of tumor cells that arose within collagen-dense mammary tissues remains after tumor explants are cultured within reconstituted three-dimensional collagen gels. To better understand this behavior we imaged live tumors using nonlinear optical imaging approaches to demonstrate that local invasion is facilitated by stromal collagen re-organization and that this behavior is significantly increased in collagen-dense tissues. In addition, using multiphoton fluorescence and spectral lifetime imaging we identify a metabolic signature for flavin adenine dinucleotide, with increased fluorescent intensity and lifetime, in invading metastatic cells. This study provides the first data causally linking increased stromal collagen to mammary tumor formation and metastasis, and demonstrates that fundamental differences arise and persist in epithelial tumor cells that progressed within collagen-dense microenvironments. Furthermore, the imaging techniques and signature identified in this work may provide useful diagnostic tools to rapidly assess fresh tissue biopsies.
         datePublished:2008-04-28T00:00:00Z
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            Second Harmonic Generation
            Flavin Adenine Dinucleotide
            Fluorescence Lifetime Imaging Microscopy
            Breast Tissue Density
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            Medicine/Public Health
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      headline:Collagen density promotes mammary tumor initiation and progression
      description:Mammographically dense breast tissue is one of the greatest risk factors for developing breast carcinoma. Despite the strong clinical correlation, breast density has not been causally linked to tumorigenesis, largely because no animal model has existed for studying breast tissue density. Importantly, regions of high breast density are associated with increased stromal collagen. Thus, the influence of the extracellular matrix on breast carcinoma development and the underlying molecular mechanisms are not understood. To study the effects of collagen density on mammary tumor formation and progression, we utilized a bi-transgenic tumor model with increased stromal collagen in mouse mammary tissue. Imaging of the tumors and tumor-stromal interface in live tumor tissue was performed with multiphoton laser-scanning microscopy to generate multiphoton excitation and spectrally resolved fluorescent lifetimes of endogenous fluorophores. Second harmonic generation was utilized to image stromal collagen. Herein we demonstrate that increased stromal collagen in mouse mammary tissue significantly increases tumor formation approximately three-fold (p < 0.00001) and results in a significantly more invasive phenotype with approximately three times more lung metastasis (p < 0.05). Furthermore, the increased invasive phenotype of tumor cells that arose within collagen-dense mammary tissues remains after tumor explants are cultured within reconstituted three-dimensional collagen gels. To better understand this behavior we imaged live tumors using nonlinear optical imaging approaches to demonstrate that local invasion is facilitated by stromal collagen re-organization and that this behavior is significantly increased in collagen-dense tissues. In addition, using multiphoton fluorescence and spectral lifetime imaging we identify a metabolic signature for flavin adenine dinucleotide, with increased fluorescent intensity and lifetime, in invading metastatic cells. This study provides the first data causally linking increased stromal collagen to mammary tumor formation and metastasis, and demonstrates that fundamental differences arise and persist in epithelial tumor cells that progressed within collagen-dense microenvironments. Furthermore, the imaging techniques and signature identified in this work may provide useful diagnostic tools to rapidly assess fresh tissue biopsies.
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         Second Harmonic Generation
         Flavin Adenine Dinucleotide
         Fluorescence Lifetime Imaging Microscopy
         Breast Tissue Density
         Stromal Collagen
         Medicine/Public Health
         general
         Biomedicine
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            name:Paolo P Provenzano
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      name:Curtis T Rueden
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      name:Patricia J Keely
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            name:University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, University of Wisconsin
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      name:Department of Pharmacology, University of Wisconsin, Madison, USA
      name:University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, University of Wisconsin, Madison, USA
      name:Molecular Biology Program, Laboratory for Optical and Computational Instrumentation, University of Wisconsin, Madison, USA
      name:Department of Pharmacology, University of Wisconsin, Madison, USA
      name:Molecular Biology Program, Laboratory for Optical and Computational Instrumentation, University of Wisconsin, Madison, USA
      name:Molecular Biology Program, Laboratory for Optical and Computational Instrumentation, University of Wisconsin, Madison, USA
      name:Molecular Biology Program, Laboratory for Optical and Computational Instrumentation, University of Wisconsin, Madison, USA
      name:Department of Pharmacology, University of Wisconsin, Madison, USA
      name:Molecular Biology Program, Laboratory for Optical and Computational Instrumentation, University of Wisconsin, Madison, USA
      name:University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, University of Wisconsin, Madison, USA

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