Intravital fluorescence videomicroscopy to study tumor angiogenesis and microcirculation.

Angiogenesis and microcirculation play a central role in growth and metastasis of human neoplasms, and, thus, represent a major target for novel treatment strategies. Mechanistic analysis of processes involved in tumor vascularization, however, requires sophisticated in vivo experimental models and techniques. Intravital microscopy allows direct assessment of tumor angiogenesis, microcirculation and overall perfusion. Its application to the study of tumor-induced neovascularization further provides information on molecular transport and delivery, intra- and extravascular cell-to-cell and cell-to-matrix interaction, as well as tumor oxygenation and metabolism. With the recent advances in the field of bioluminescence and fluorescent reporter genes, appropriate for in vivo imaging, the intravital fluorescent microscopic approach has to be considered a powerful tool to study microvascular, cellular and molecular mechanisms of tumor growth.

[1]  H. Dvorak,et al.  Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. , 1983, Science.

[2]  B. Schoener,et al.  Intracellular Oxidation-Reduction States in Vivo , 1962, Science.

[3]  B Vojnovic,et al.  Combretastatin A-4 phosphate as a tumor vascular-targeting agent: early effects in tumors and normal tissues. , 1999, Cancer research.

[4]  T A Woolsey,et al.  Blood Flow in Single Surface Arterioles and Venules on the Mouse Somatosensory Cortex Measured with Videomicroscopy, Fluorescent Dextrans, Nonoccluding Fluorescent Beads, and Computer-Assisted Image Analysis , 1993, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[5]  U Bagge,et al.  A one-piece plexiglass access chamber for subcutaneous implantation in the dorsal skin fold of the mouse. , 1997, International journal of microcirculation, clinical and experimental.

[6]  S. Wallace,et al.  In vivo microscopy of hepatic tumors in animal models: a dynamic investigation of blood supply to hepatic metastases. , 1993, Radiology.

[7]  R K Jain,et al.  Geometric Resistance and Microvascular Network Architecture of Human Colorectal Carcinoma , 1997, Microcirculation.

[8]  R K Jain,et al.  Transport of molecules in the tumor interstitium: a review. , 1987, Cancer research.

[9]  D. Hanahan,et al.  Angiogenesis and apoptosis are cellular parameters of neoplastic progression in transgenic mouse models of tumorigenesis. , 1998, The International journal of developmental biology.

[10]  K. Messmer,et al.  Dorsal skinfold chamber technique for intravital microscopy in nude mice. , 1993, The American journal of pathology.

[11]  von Andrian Uh,et al.  Neutrophil-endothelial cell interactions in vivo: a chain of events characterized by distinct molecular mechanisms. , 1993, Agents and actions. Supplements.

[12]  J. Folkman Angiogenesis in cancer, vascular, rheumatoid and other disease , 1995, Nature Medicine.

[13]  M A Konerding,et al.  The vascular system of xenotransplanted tumors--scanning electron and light microscopic studies. , 1989, Scanning microscopy.

[14]  D. P. Jones,et al.  Hypoxia and drug metabolism. , 1981, Biochemical pharmacology.

[15]  M. Menger,et al.  High-resolution microscopic determination of hepatic NADH fluorescence for in vivo monitoring of tissue oxygenation during hemorrhagic shock and resuscitation. , 1997, Microvascular research.

[16]  R K Jain,et al.  Direct measurement of interstitial convection and diffusion of albumin in normal and neoplastic tissues by fluorescence photobleaching. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[17]  J. Gross,et al.  A transparent access chamber for the rat dorsal skin fold. , 1979, Microvascular research.

[18]  R. Pasqualini Vascular targeting with phage peptide libraries. , 1999, The quarterly journal of nuclear medicine : official publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology.

[19]  R K Jain,et al.  Effect of host microenvironment on the microcirculation of human colon adenocarcinoma. , 1997, The American journal of pathology.

[20]  G. Naumov,et al.  Cellular expression of green fluorescent protein, coupled with high-resolution in vivo videomicroscopy, to monitor steps in tumor metastasis. , 1999, Journal of cell science.

[21]  R. Jain,et al.  Cancer, angiogenesis and fractals , 1998, Nature Medicine.

[22]  U. Andrian Intravital Microscopy of the Peripheral Lymph Node Microcirculation in Mice , 1996 .

[23]  O. Ohtani Microcirculation of the pancreas: a correlative study of intravital microscopy with scanning electron microscopy of vascular corrosion casts. , 1983, Archivum histologicum Japonicum = Nihon soshikigaku kiroku.

[24]  H. Ohtani,et al.  Cell Adhesion Molecule Expression by Vascular Endothelial Cells as an Immune/Inflammatory Reaction in Human Colon Carcinoma , 1995, Japanese journal of cancer research : Gann.

[25]  P. Falk Differences in vascular pattern between the spontaneous and the transplanted C3H mouse mammary carcinoma. , 1982, European journal of cancer & clinical oncology.

[26]  J F Gross,et al.  Morphologic and hemodynamic comparison of tumor and healing normal tissue microvasculature. , 1989, International journal of radiation oncology, biology, physics.

[27]  Rakesh K. Jain,et al.  Interstitial pH and pO2 gradients in solid tumors in vivo: High-resolution measurements reveal a lack of correlation , 1997, Nature Medicine.

[28]  K. Messmer,et al.  Platelet-endothelial cell interactions during ischemia/reperfusion : The role of P-selectin , 1998 .

[29]  R K Jain,et al.  Vascular permeability in a human tumor xenograft: molecular size dependence and cutoff size. , 1995, Cancer research.

[30]  T. Oostendorp,et al.  Vascularity and perfusion of human gliomas xenografted in the athymic nude mouse. , 1995, British Journal of Cancer.

[31]  H. Lehr,et al.  Intravital fluorescence microscopy for the study of leukocyte interaction with platelets and endothelial cells. , 1999, Methods in Enzymology.

[32]  K Messmer,et al.  Quantitative analysis of microvascular structure and function in the amelanotic melanoma A-Mel-3. , 1981, Cancer research.

[33]  H. Lehr,et al.  Intravital Fluorescence Microscopy: Impact of Light-induced Phototoxicity on Adhesion of Fluorescently Labeled Leukocytes , 1997, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[34]  J. Griffiths,et al.  Differences in vascular response between primary and transplanted tumours. , 1991, British Journal of Cancer.

[35]  R K Jain,et al.  Endothelial cell death, angiogenesis, and microvascular function after castration in an androgen-dependent tumor: role of vascular endothelial growth factor. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[36]  M. Westphal,et al.  Glioma invasion in the central nervous system. , 1996, Neurosurgery.

[37]  R. Jain,et al.  Monitoring transport in the rabbit ear chamber. , 1982, Microvascular research.

[38]  M A Konerding,et al.  Evidence for characteristic vascular patterns in solid tumours: quantitative studies using corrosion casts , 1999, British Journal of Cancer.

[39]  R. Vessella,et al.  Correlation of vascular permeability and blood flow with monoclonal antibody uptake by human Clouser and renal cell xenografts. , 1988, Cancer research.

[40]  William Arbuthnot Sir Lane,et al.  Endostatin: An Endogenous Inhibitor of Angiogenesis and Tumor Growth , 1997, Cell.

[41]  K. Messmer,et al.  In vivo fluorescence microscopy for quantitative analysis of the hepatic microcirculation in hamsters and rats. , 1991, European surgical research. Europaische chirurgische Forschung. Recherches chirurgicales europeennes.

[42]  G. Kuhnle,et al.  Measurement of microhemodynamics in the ventilated rabbit lung by intravital fluorescence microscopy. , 1993, Journal of applied physiology.

[43]  H. Bertalanffy,et al.  In vivo rat closed spinal window for spinal microcirculation: observation of pial vessels, leukocyte adhesion, and red blood cell velocity. , 1999, Neurosurgery.

[44]  J. Sandison,et al.  A new method for the microscopic study of living growing tissues by the introduction of a transparent chamber in the rabbit's ear , 1924 .

[45]  R. Bing,et al.  The Effect of Nicotine on the Coronary Microcirculation in the Cat Heart , 1974, Journal of clinical pharmacology.

[46]  J F Gross,et al.  Analysis of oxygen transport to tumor tissue by microvascular networks. , 1993, International journal of radiation oncology, biology, physics.

[47]  A. Unterberg,et al.  Effects of Bradykinin on Permeability and Diameter of Pial Vessels In vivo , 1984, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[48]  R. Jain,et al.  Tumor necrosis factor alpha-induced leukocyte adhesion in normal and tumor vessels: effect of tumor type, transplantation site, and host strain. , 1995, Cancer research.

[49]  M Intaglietta,et al.  Microvessel PO2 measurements by phosphorescence decay method. , 1993, The American journal of physiology.

[50]  D. Kleinfeld,et al.  Fluctuations and stimulus-induced changes in blood flow observed in individual capillaries in layers 2 through 4 of rat neocortex. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[51]  T. Springer,et al.  Traffic signals on endothelium for lymphocyte recirculation and leukocyte emigration. , 1995, Annual review of physiology.

[52]  R K Jain,et al.  Vascular permeability and microcirculation of gliomas and mammary carcinomas transplanted in rat and mouse cranial windows. , 1994, Cancer research.

[53]  A. Ullrich,et al.  Inhibition of tumor growth, angiogenesis, and microcirculation by the novel Flk-1 inhibitor SU5416 as assessed by intravital multi-fluorescence videomicroscopy. , 1999, Neoplasia.

[54]  Richard O. Hynes,et al.  Hematopoietic Progenitor Cell Rolling in Bone Marrow Microvessels: Parallel Contributions by Endothelial Selectins and Vascular Cell Adhesion Molecule 1 , 1998, The Journal of experimental medicine.

[55]  R. Tsien,et al.  Engineering green fluorescent protein for improved brightness, longer wavelengths and fluorescence resonance energy transfer , 1996, Current Biology.

[56]  B. Zweifach,et al.  Microcirculatory basis of fluid exchange. , 1974, Advances in biological and medical physics.

[57]  Mihaela Skobe,et al.  Halting angiogenesis suppresses carcinoma cell invasion , 1997, Nature Medicine.

[58]  P. Johnson,et al.  Intestinal muscle and mucosal blood flow during direct sympathetic stimulation. , 1978, The American journal of physiology.

[59]  R K Jain,et al.  Determinants of tumor blood flow: a review. , 1988, Cancer research.

[60]  K. Black,et al.  Inflammatory cell infiltrates vary in experimental primary and metastatic brain tumors. , 1992, Neurosurgery.

[61]  M. Dewhirst,et al.  A pial window model for the intracranial study of human glioma microvascular function. , 1995, Neurosurgery.

[62]  A. Paetau,et al.  Expression of endothelial cell-specific receptor tyrosine kinases and growth factors in human brain tumors. , 1995, The American journal of pathology.

[63]  A. Hirano,et al.  Vascular structures in brain tumors. , 1975, Human pathology.

[64]  Ulrich Dirnagl,et al.  In‐vivo confocal scanning laser microscopy of the cerebral microcirculation , 1992, Journal of microscopy.

[65]  David K. Stevenson,et al.  Bioluminescent indicators in living mammals , 1998, Nature Medicine.

[66]  S. Skinner,et al.  Microvascular architecture of experimental colon tumors in the rat. , 1990, Cancer research.

[67]  G. Schmid-Schönbein,et al.  In vivo visualization of oxidative changes in microvessels during neutrophil activation. , 1993, The American journal of physiology.

[68]  G. Yancopoulos,et al.  Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. , 1999, Science.

[69]  R. Bjerkvig,et al.  Effects of EGF, BFGF, NGF and PDGF(bb) on cell proliferative, migratory and invasive capacities of human brain‐tumour biopsies In Vitro , 1993, International journal of cancer.

[70]  R. Xavier,et al.  Tumor Induction of VEGF Promoter Activity in Stromal Cells , 1998, Cell.

[71]  M. Menger,et al.  Characterization of Angiogenesis and Microcirculation of High–Grade Glioma: An Intravital Multifluorescence Microscopic Approach in the Athymic Nude Mouse , 1998, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[72]  K. Hillan,et al.  Complete inhibition of angiogenesis and growth of microtumors by anti-vascular endothelial growth factor neutralizing antibody: novel concepts of angiostatic therapy from intravital videomicroscopy. , 1996, Cancer research.

[73]  R. Jain,et al.  Angiogenesis, microvascular architecture, microhemodynamics, and interstitial fluid pressure during early growth of human adenocarcinoma LS174T in SCID mice. , 1992, Cancer research.

[74]  H A Lehr,et al.  Scope and perspectives of intravital microscopy--bridge over from in vitro to in vivo. , 1993, Immunology today.

[75]  J. Bedford,et al.  The effect of hypoxia on the growth and radiation response of mammalian cells in culture. , 1974, The British journal of radiology.

[76]  M. Steinhausen,et al.  Intraglomerular microcirculation: measurements of single glomerular loop flow in rats. , 1981, Kidney international.

[77]  M. Menger,et al.  Glioma cell migration is associated with glioma-induced angiogenesis in vivo , 1999, International Journal of Developmental Neuroscience.

[78]  I. Hart,et al.  Inhibitors of nitric oxide synthase selectively reduce flow in tumour‐associated neovasculature , 1992, British journal of pharmacology.

[79]  R. Jain,et al.  Microvascular permeability of albumin, vascular surface area, and vascular volume measured in human adenocarcinoma LS174T using dorsal chamber in SCID mice. , 1993, Microvascular research.

[80]  M. Menger,et al.  Hepatic microcirculatory perfusion failure is a determinant of liver dysfunction in warm ischemia-reperfusion. , 1994, The American journal of pathology.

[81]  R K Jain,et al.  Quantitation and physiological characterization of angiogenic vessels in mice: effect of basic fibroblast growth factor, vascular endothelial growth factor/vascular permeability factor, and host microenvironment. , 1996, The American journal of pathology.

[82]  Grietje Molema,et al.  Tumor Infarction in Mice by Antibody-Directed Targeting of Tissue Factor to Tumor Vasculature , 1997, Science.

[83]  K. Messmer,et al.  Angiogenesis and vascularization of murine pancreatic islet isografts. , 1995, Transplantation.

[84]  P. Stewart,et al.  A Quantitative Assessment of Microvessel Ultrastructure in C6 Astrocytoma Spheroids Transplanted to Brain and to Muscle , 1988, Journal of neuropathology and experimental neurology.

[85]  Waggener Jd,et al.  Vasculature of Neural Neoplasms. , 1976 .

[86]  K. Hillan,et al.  Neutralizing anti‐vascular endothelial growth factor antibody completely inhibits angiogenesis and growth of human prostate carcinoma micro tumors in vivo , 1998, The Prostate.

[87]  M. Menger,et al.  Adhesion molecules as determinants of disease: From molecular biology to surgical research , 1996, The British journal of surgery.

[88]  R. Jain,et al.  Role of tumor vascular architecture in nutrient and drug delivery: an invasion percolation-based network model. , 1996, Microvascular research.

[89]  A. Ullrich,et al.  SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk-1/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types. , 1999, Cancer research.

[90]  J. Folkman Tumor angiogenesis: therapeutic implications. , 1971, The New England journal of medicine.

[91]  D J Ruiter,et al.  Quantitative immunohistological analysis of the microvasculature in untreated human glioblastoma multiforme. Computer-assisted image analysis of whole-tumor sections. , 1994, Journal of neurosurgery.

[92]  M. Menger,et al.  Lymph vessel expansion and function in the development of hepatic fibrosis and cirrhosis. , 1997, The American journal of pathology.

[93]  K. Luzzi,et al.  Multistep nature of metastatic inefficiency: dormancy of solitary cells after successful extravasation and limited survival of early micrometastases. , 1998, The American journal of pathology.

[94]  K. Messmer,et al.  Microvascular ischemia-reperfusion injury in striated muscle: significance of "reflow paradox". , 1992, The American journal of physiology.

[95]  R K Jain,et al.  Direct in vivo measurement of targeted binding in a human tumor xenograft. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[96]  K. Messmer,et al.  Technical report—a new chamber technique for microvascular studies in unanesthetized hamsters , 1980, Research in experimental medicine. Zeitschrift fur die gesamte experimentelle Medizin einschliesslich experimenteller Chirurgie.

[97]  J. Gross,et al.  Hemodynamic characteristics in microcirculatory blood channels during early tumor growth. , 1979, Cancer research.

[98]  R. Jain,et al.  Microvascular permeability of normal and neoplastic tissues. , 1986, Microvascular research.