Studying the influence of angiogenesis in in vitro cancer model systems.

Tumor angiogenesis is a hallmark of cancer that has been identified as a critical component of cancer progression, facilitating rapid tumor growth and metastasis. Anti-angiogenic therapies have exhibited only modest clinical success, highlighting a need for better models that can be used to gain a more thorough understanding of tumor angiogenesis and screen potential therapeutics more accurately. This review explores how recent progress in in vitro cancer and vascular models individually can be applied to the development of in vitro tumor angiogenesis models. Current in vitro tumor angiogenesis models are also discussed, with a focus on aspects of the process that have been successfully recapitulated and opportunities for applying new technologies to expand model complexity to better represent the tumor microenvironment. Continued advances in vascularized tumor models will provide tools to identify novel therapeutic targets and validate their therapeutic benefit.

[1]  Yair Anikster,et al.  CD59 deficiency is associated with chronic hemolysis and childhood relapsing immune-mediated polyneuropathy. , 2013, Blood.

[2]  Elias T. Zambidis,et al.  Human induced pluripotent stem cell-derived endothelial cells exhibit functional heterogeneity. , 2013, American journal of translational research.

[3]  R. Jain Normalization of Tumor Vasculature: An Emerging Concept in Antiangiogenic Therapy , 2005, Science.

[4]  Denys N Wheatley,et al.  Potential of fibroblasts to regulate the formation of three-dimensional vessel-like structures from endothelial cells in vitro. , 2006, American journal of physiology. Cell physiology.

[5]  S. Gerecht,et al.  Hypoxia Affects the Structure of Breast Cancer Cell-Derived Matrix to Support Angiogenic Responses of Endothelial Cells , 2013, Journal of carcinogenesis & mutagenesis.

[6]  Brendon M. Baker,et al.  Rapid casting of patterned vascular networks for perfusable engineered 3D tissues , 2012, Nature materials.

[7]  Ivan Martin,et al.  Three‐dimensional culture of melanoma cells profoundly affects gene expression profile: A high density oligonucleotide array study , 2005, Journal of cellular physiology.

[8]  S. Gerecht,et al.  Patterning microscale extracellular matrices to study endothelial and cancer cell interactions in vitro. , 2012, Lab on a chip.

[9]  G. Dubini,et al.  Human 3D vascularized organotypic microfluidic assays to study breast cancer cell extravasation , 2014, Proceedings of the National Academy of Sciences.

[10]  Dror Berel,et al.  Expression Signatures of Metastatic Capacity in a Genetic Mouse Model of Lung Adenocarcinoma , 2009, PloS one.

[11]  K. Illmensee,et al.  Normal genetically mosaic mice produced from malignant teratocarcinoma cells. , 1975, Proceedings of the National Academy of Sciences of the United States of America.

[12]  David J Mooney,et al.  Cancer cell angiogenic capability is regulated by 3D culture and integrin engagement , 2009, Proceedings of the National Academy of Sciences.

[13]  F. Auger,et al.  The pivotal role of vascularization in tissue engineering. , 2013, Annual review of biomedical engineering.

[14]  Carsten Werner,et al.  Tissue-engineered 3D tumor angiogenesis models: potential technologies for anti-cancer drug discovery. , 2014, Advanced drug delivery reviews.

[15]  I. Macara,et al.  Epithelial organization, cell polarity and tumorigenesis. , 2011, Trends in cell biology.

[16]  Roger D. Kamm,et al.  Erratum: Human 3D vascularized organotypic microfluidic assays to study breast cancer cell extravasation (Proc Natl Acad Sci USA (2015) 112:1 DOI: 10.1073/pnas.1501426112 (214-219)) , 2015 .

[17]  Jeremy N. Skepper,et al.  A Heterogeneous In Vitro Three Dimensional Model of Tumour-Stroma Interactions Regulating Sprouting Angiogenesis , 2012, PloS one.

[18]  H. Walles,et al.  Tissue Engineering of a Human 3D in vitro Tumor Test System , 2013, Journal of visualized experiments : JoVE.

[19]  H. V. von Recum,et al.  Endothelial stem cells and precursors for tissue engineering: cell source, differentiation, selection, and application. , 2008, Tissue engineering. Part B, Reviews.

[20]  K. McCoy,et al.  The Biochemical and Cellular Basis of Cell Proliferation Assays That Use Tetrazolium Salts , 1996 .

[21]  Jennifer L West,et al.  Modeling the tumor extracellular matrix: Tissue engineering tools repurposed towards new frontiers in cancer biology. , 2014, Journal of biomechanics.

[22]  K. Alitalo,et al.  Mouse models for studying angiogenesis and lymphangiogenesis in cancer , 2013, Molecular oncology.

[23]  D. Radisky,et al.  Epithelial-mesenchymal transition: general principles and pathological relevance with special emphasis on the role of matrix metalloproteinases. , 2012, Cold Spring Harbor perspectives in biology.

[24]  T. Boland,et al.  Human microvasculature fabrication using thermal inkjet printing technology. , 2009, Biomaterials.

[25]  D. Mikhailidis Foreword [ Current Vascular Pharmacology is 10 Years Old! ] , 2012 .

[26]  Ali Khademhosseini,et al.  3D biofabrication strategies for tissue engineering and regenerative medicine. , 2014, Annual review of biomedical engineering.

[27]  Mary E Dickinson,et al.  Biomimetic hydrogels with pro-angiogenic properties. , 2010, Biomaterials.

[28]  Angélica Figueroa,et al.  New Insights into Molecular Mechanisms of Sunitinib-Associated Side Effects , 2011, Molecular Cancer Therapeutics.

[29]  J. West,et al.  A synthetic matrix with independently tunable biochemistry and mechanical properties to study epithelial morphogenesis and EMT in a lung adenocarcinoma model. , 2012, Cancer research.

[30]  Marilena Loizidou,et al.  3D tumour models: novel in vitro approaches to cancer studies , 2011, Journal of Cell Communication and Signaling.

[31]  T. Mosmann Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. , 1983, Journal of immunological methods.

[32]  J. Jardillier,et al.  Multicellular resistance: a paradigm for clinical resistance? , 2000, Critical reviews in oncology/hematology.

[33]  Shuichi Takayama,et al.  Microfluidic Endothelium for Studying the Intravascular Adhesion of Metastatic Breast Cancer Cells , 2009, PloS one.

[34]  Mary E. Dickinson,et al.  Three‐Dimensional Biomimetic Patterning in Hydrogels to Guide Cellular Organization , 2012, Advanced materials.

[35]  R. Weichselbaum,et al.  Tumour-endothelium interactions in co-culture: coordinated changes of gene expression profiles and phenotypic properties of endothelial cells , 2003, Journal of Cell Science.

[36]  A novel in vitro model of tumor angiogenesis , 2000, In Vitro Cellular & Developmental Biology - Animal.

[37]  R. Kamm,et al.  Three-dimensional microfluidic model for tumor cell intravasation and endothelial barrier function , 2012, Proceedings of the National Academy of Sciences.

[38]  P. Vlachos,et al.  Three-dimensional microfluidic collagen hydrogels for investigating flow-mediated tumor-endothelial signaling and vascular organization. , 2014, Tissue engineering. Part C, Methods.

[39]  Christine Unger,et al.  In vitro cell migration and invasion assays. , 2013, Mutation research.

[40]  S. Takayama,et al.  Opportunities and challenges for use of tumor spheroids as models to test drug delivery and efficacy. , 2012, Journal of controlled release : official journal of the Controlled Release Society.

[41]  J. Huot,et al.  Development of a tridimensional microvascularized human skin substitute to study melanoma biology , 2012, Clinical & Experimental Metastasis.

[42]  Carsten Werner,et al.  Glycosaminoglycan-based hydrogels to modulate heterocellular communication in in vitro angiogenesis models , 2014, Scientific Reports.

[43]  A. Puisieux,et al.  Metastasis: a question of life or death , 2006, Nature Reviews Cancer.

[44]  M. Koutsilieris,et al.  Stromal fibroblasts are required for PC-3 human prostate cancer cells to produce capillary-like formation of endothelial cells in a three-dimensional co-culture system. , 1997, Anticancer research.

[45]  Nasim Akhtar,et al.  Angiogenesis assays: a critical overview. , 2003, Clinical chemistry.

[46]  Judah Folkman,et al.  Angiogenesis in vitro , 1980, Nature.

[47]  Laure Gibot,et al.  A preexisting microvascular network benefits in vivo revascularization of a microvascularized tissue-engineered skin substitute. , 2010, Tissue engineering. Part A.

[48]  D. Ribatti,et al.  Transferrin Promotes Endothelial Cell Migration and Invasion: Implication in Cartilage Neovascularization , 1997, The Journal of cell biology.

[49]  Malcolm W R Reed,et al.  A critical analysis of current in vitro and in vivo angiogenesis assays , 2009, International journal of experimental pathology.

[50]  Claudia Fischbach,et al.  3D culture broadly regulates tumor cell hypoxia response and angiogenesis via pro-inflammatory pathways. , 2015, Biomaterials.

[51]  Roger D Kamm,et al.  Mechanisms of tumor cell extravasation in an in vitro microvascular network platform. , 2013, Integrative biology : quantitative biosciences from nano to macro.

[52]  D. Hanahan,et al.  Patterns and Emerging Mechanisms of the Angiogenic Switch during Tumorigenesis , 1996, Cell.

[53]  Cynthia A. Reinhart-King,et al.  Tensional homeostasis and the malignant phenotype. , 2005, Cancer cell.

[54]  Giulia De Sena,et al.  Zebrafish embryo, a tool to study tumor angiogenesis. , 2011, The International journal of developmental biology.

[55]  Joo L. Ong,et al.  Diffusion in Musculoskeletal Tissue Engineering Scaffolds: Design Issues Related to Porosity, Permeability, Architecture, and Nutrient Mixing , 2004, Annals of Biomedical Engineering.

[56]  A. Khademhosseini,et al.  Hydrogel bioprinted microchannel networks for vascularization of tissue engineering constructs. , 2014, Lab on a chip.

[57]  Emily Burdett,et al.  Engineering tumors: a tissue engineering perspective in cancer biology. , 2010, Tissue engineering. Part B, Reviews.

[58]  F. Bussolino,et al.  Modeling human tumor angiogenesis in a three-dimensional culture system. , 2013, Blood.

[59]  A. M. Goodwin In vitro assays of angiogenesis for assessment of angiogenic and anti-angiogenic agents. , 2007, Microvascular research.

[60]  Claudia Fischbach,et al.  Microfluidic culture models of tumor angiogenesis. , 2010, Tissue engineering. Part A.

[61]  Daniel J. Gould,et al.  Biomimetic hydrogels with immobilized ephrinA1 for therapeutic angiogenesis. , 2011, Biomacromolecules.

[62]  J. West,et al.  Vascularization of engineered tissues: approaches to promote angio-genesis in biomaterials. , 2008, Current topics in medicinal chemistry.

[63]  M. Ponce,et al.  Tube formation: an in vitro matrigel angiogenesis assay. , 2009, Methods in molecular biology.

[64]  Kyongbum Lee,et al.  Vascularization strategies for tissue engineering. , 2009, Tissue engineering. Part B, Reviews.

[65]  Christine P. Tan,et al.  Parylene peel-off arrays to probe the role of cell-cell interactions in tumour angiogenesis. , 2009, Integrative biology : quantitative biosciences from nano to macro.

[66]  C. Larabell,et al.  Reciprocal interactions between beta1-integrin and epidermal growth factor receptor in three-dimensional basement membrane breast cultures: a different perspective in epithelial biology. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[67]  A. Ridley,et al.  Crossing the endothelial barrier during metastasis , 2013, Nature Reviews Cancer.

[68]  G. Nicolson Metastatic tumor cell attachment and invasion assay utilizing vascular endothelial cell monolayers. , 1982, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[69]  V. Bautch,et al.  Ups and downs of guided vessel sprouting: the role of polarity. , 2011, Physiology.

[70]  Jennifer L West,et al.  Biofunctional materials for directing vascular development. , 2012, Current vascular pharmacology.

[71]  Daniel J. Gould,et al.  Covalently immobilized platelet-derived growth factor-BB promotes angiogenesis in biomimetic poly(ethylene glycol) hydrogels. , 2011, Acta biomaterialia.

[72]  M. Waterman,et al.  A three-dimensional in vitro model of tumor cell intravasation. , 2014, Integrative biology : quantitative biosciences from nano to macro.

[73]  B. Teicher,et al.  Myofibroblasts enable invasion of endothelial cells into three-dimensional tumor cell clusters: a novel in vitro tumor model , 2003, Cancer Chemotherapy and Pharmacology.

[74]  Daniel J. Gould,et al.  Integration of Self‐Assembled Microvascular Networks with Microfabricated PEG‐Based Hydrogels , 2012, Advanced functional materials.

[75]  G. G. Stokes "J." , 1890, The New Yale Book of Quotations.

[76]  L. Devy,et al.  Induction of endothelial cell apoptosis by solid tumor cells. , 1998, Experimental cell research.

[77]  S. Eccles,et al.  In Vitro Assays for Endothelial Cell Functions Required for Angiogenesis: Proliferation, Motility, Tubular Differentiation, and Matrix Proteolysis. , 2016, Methods in molecular biology.

[78]  A. Papadimitropoulos,et al.  Bioreactor-engineered cancer tissue-like structures mimic phenotypes, gene expression profiles and drug resistance patterns observed "in vivo". , 2015, Biomaterials.

[79]  M J Bissell,et al.  Functional differentiation and alveolar morphogenesis of primary mammary cultures on reconstituted basement membrane. , 1989, Development.

[80]  R. Kozłowski,et al.  The use of ATP bioluminescence as a measure of cell proliferation and cytotoxicity. , 1993, Journal of immunological methods.

[81]  S. Eccles,et al.  In vitro assays for endothelial cell functions related to angiogenesis: proliferation, motility, tubular differentiation, and proteolysis. , 2009, Methods in molecular biology.

[82]  R. Huang,et al.  Epithelial-Mesenchymal Transitions in Development and Disease , 2009, Cell.

[83]  D. Hanahan,et al.  Hallmarks of Cancer: The Next Generation , 2011, Cell.

[84]  C. Szot,et al.  In vitro angiogenesis induced by tumor-endothelial cell co-culture in bilayered, collagen I hydrogel bioengineered tumors. , 2013, Tissue engineering. Part C, Methods.

[85]  Alexander Pertsemlidis,et al.  Contextual extracellular cues promote tumor cell EMT and metastasis by regulating miR-200 family expression. , 2009, Genes & development.

[86]  Jennifer L. West,et al.  Three-dimensional photolithographic patterning of multiple bioactive ligands in poly(ethylene glycol) hydrogels , 2010 .

[87]  J. Peterse,et al.  Breast cancer metastasis: markers and models , 2005, Nature Reviews Cancer.

[88]  M. Bissell,et al.  Interaction with basement membrane serves to rapidly distinguish growth and differentiation pattern of normal and malignant human breast epithelial cells. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[89]  Gerhard Christofori,et al.  The angiogenic switch in carcinogenesis. , 2009, Seminars in cancer biology.

[90]  Valerie M. Weaver,et al.  Three-dimensional context regulation of metastasis , 2008, Clinical & Experimental Metastasis.

[91]  J. Folkman,et al.  Tumor growth and neovascularization: an experimental model using the rabbit cornea. , 1974, Journal of the National Cancer Institute.

[92]  Jens Friedrichs,et al.  Multi-parametric hydrogels support 3D in vitro bioengineered microenvironment models of tumour angiogenesis. , 2015, Biomaterials.

[93]  Mina J. Bissell,et al.  Putting tumours in context , 2001, Nature Reviews Cancer.

[94]  Rakesh K. Jain,et al.  Lessons from multidisciplinary translational trials on anti-angiogenic therapy of cancer , 2008, Nature Reviews Cancer.

[95]  Jing Yang,et al.  Targeting invadopodia to block breast cancer metastasis , 2011, Oncotarget.

[96]  Miss A.O. Penney (b) , 1974, The New Yale Book of Quotations.

[97]  D. Hayes Bevacizumab treatment for solid tumors: boon or bust? , 2011, JAMA.

[98]  C. Larabell,et al.  Reversion of the Malignant Phenotype of Human Breast Cells in Three-Dimensional Culture and In Vivo by Integrin Blocking Antibodies , 1997, The Journal of cell biology.

[99]  S. Gerecht,et al.  Breast cancer cell-derived matrix supports vascular morphogenesis. , 2012, American journal of physiology. Cell physiology.

[100]  Walter L Murfee,et al.  Printing cancer cells into intact microvascular networks: a model for investigating cancer cell dynamics during angiogenesis. , 2015, Integrative biology : quantitative biosciences from nano to macro.

[101]  Nak Won Choi,et al.  Oxygen-controlled three-dimensional cultures to analyze tumor angiogenesis. , 2010, Tissue engineering. Part A.

[102]  G. Gillies,et al.  In vitro angiogenesis by human umbilical vein endothelial cells (HUVEC) induced by three-dimensional co-culture with glioblastoma cells , 2009, Journal of Neuro-Oncology.