Tumor Microenvironment on a Chip: The Progress and Future Perspective

Tumors develop in intricate microenvironments required for their sustained growth, invasion, and metastasis. The tumor microenvironment plays a critical role in the malignant or drug resistant nature of tumors, becoming a promising therapeutic target. Microengineered physiological systems capable of mimicking tumor environments are one emerging platform that allows for quantitative and reproducible characterization of tumor responses with pathophysiological relevance. This review highlights the recent advancements of engineered tumor microenvironment systems that enable the unprecedented mechanistic examination of cancer progression and metastasis. We discuss the progress and future perspective of these microengineered biomimetic approaches for anticancer drug prescreening applications.

[1]  Donald E Ingber,et al.  Microengineered physiological biomimicry: organs-on-chips. , 2012, Lab on a chip.

[2]  F. Pampaloni,et al.  The third dimension bridges the gap between cell culture and live tissue , 2007, Nature Reviews Molecular Cell Biology.

[3]  E. Sahai,et al.  Fibroblast-led collective invasion of carcinoma cells with differing roles for RhoGTPases in leading and following cells , 2007, Nature Cell Biology.

[4]  Melissa H Wong,et al.  Tumor microenvironment complexity: emerging roles in cancer therapy. , 2012, Cancer research.

[5]  Jianhua Qin,et al.  A microfluidic-based device for study of transendothelial invasion of tumor aggregates in realtime. , 2012, Lab on a chip.

[6]  Justin C. Williams,et al.  Microfluidics-based devices: New tools for studying cancer and cancer stem cell migration. , 2011, Biomicrofluidics.

[7]  Daniel J Brat,et al.  Microregional extracellular matrix heterogeneity in brain modulates glioma cell invasion. , 2004, The international journal of biochemistry & cell biology.

[8]  Mikala Egeblad,et al.  Matrix Crosslinking Forces Tumor Progression by Enhancing Integrin Signaling , 2009, Cell.

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

[10]  I. Tannock,et al.  Drug resistance and the solid tumor microenvironment. , 2007, Journal of the National Cancer Institute.

[11]  P. Carmeliet,et al.  Angiogenesis in cancer and other diseases , 2000, Nature.

[12]  B. Mosadegh,et al.  Epidermal growth factor promotes breast cancer cell chemotaxis in CXCL12 gradients , 2008, Biotechnology and bioengineering.

[13]  G. Jobst,et al.  Cell culture monitoring for drug screening and cancer research: a transparent, microfluidic, multi-sensor microsystem. , 2014, Lab on a chip.

[14]  R. Jain,et al.  Normalization of tumour blood vessels improves the delivery of nanomedicines in a size-dependent manner , 2012, Nature nanotechnology.

[15]  Donald Wlodkowic,et al.  Microfluidic single-cell array cytometry for the analysis of tumor apoptosis. , 2009, Analytical chemistry.

[16]  L. Preziosi,et al.  Mechano-transduction in tumour growth modelling , 2013, The European Physical Journal E.

[17]  Noo Li Jeon,et al.  Microvasculature: An essential component for organ-on-chip systems , 2014 .

[18]  S. Thomas,et al.  Melanoma growth effects on molecular clearance from tumors and biodistribution into systemic tissues versus draining lymph nodes. , 2016, Journal of controlled release : official journal of the Controlled Release Society.

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

[20]  David J Beebe,et al.  Cellular observations enabled by microculture: paracrine signaling and population demographics. , 2009, Integrative biology : quantitative biosciences from nano to macro.

[21]  Stephen P. Cavnar,et al.  Microfluidic source-sink model reveals effects of biophysically distinct CXCL12 isoforms in breast cancer chemotaxis. , 2014, Integrative biology : quantitative biosciences from nano to macro.

[22]  Lei Yang,et al.  Enhancement of cell recognition in vitro by dual-ligand cancer targeting gold nanoparticles. , 2011, Biomaterials.

[23]  Xiancheng Li,et al.  Design and Construction of a Multi-Organ Microfluidic Chip Mimicking the in vivo Microenvironment of Lung Cancer Metastasis. , 2016, ACS applied materials & interfaces.

[24]  Shih-Hao Huang,et al.  Analysis of the paracrine loop between cancer cells and fibroblasts using a microfluidic chip. , 2011, Lab on a chip.

[25]  R. Jain,et al.  Solid stress generated by spheroid growth estimated using a linear poroelasticity model. , 2003, Microvascular research.

[26]  J. Karp,et al.  Nanocarriers as an Emerging Platform for Cancer Therapy , 2022 .

[27]  Mikala Egeblad,et al.  Dynamic interplay between the collagen scaffold and tumor evolution. , 2010, Current opinion in cell biology.

[28]  Qizhi Zhang,et al.  Dual-functional nanoparticles targeting amyloid plaques in the brains of Alzheimer's disease mice. , 2014, Biomaterials.

[29]  Ronald C. Chen,et al.  Revival of the abandoned therapeutic wortmannin by nanoparticle drug delivery , 2012, Proceedings of the National Academy of Sciences.

[30]  K. Barbee,et al.  An in vitro model of the tumor-lymphatic microenvironment with simultaneous transendothelial and luminal flows reveals mechanisms of flow enhanced invasion. , 2015, Integrative biology : quantitative biosciences from nano to macro.

[31]  John P Wikswo,et al.  The relevance and potential roles of microphysiological systems in biology and medicine , 2014, Experimental biology and medicine.

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

[33]  R. Sandberg,et al.  Gene expression perturbation in vitro--a growing case for three-dimensional (3D) culture systems. , 2005, Seminars in cancer biology.

[34]  A. deMello,et al.  Microfluidics: Analog-to-digital drug screening , 2012, Nature.

[35]  Dai Fukumura,et al.  Tumor microvasculature and microenvironment: targets for anti-angiogenesis and normalization. , 2007, Microvascular research.

[36]  Y. Shao,et al.  Angiogenesis in Liquid Tumors: An In Vitro Assay for Leukemic‐Cell‐Induced Bone Marrow Angiogenesis , 2016, Advanced healthcare materials.

[37]  Shuichi Takayama,et al.  Microfluidic platform for chemotaxis in gradients formed by CXCL12 source-sink cells. , 2010, Integrative biology : quantitative biosciences from nano to macro.

[38]  Jörg Huwyler,et al.  Nanomedicine in cancer therapy: challenges, opportunities, and clinical applications. , 2015, Journal of controlled release : official journal of the Controlled Release Society.

[39]  Bingcheng Lin,et al.  Carcinoma-associated fibroblasts promoted tumor spheroid invasion on a microfluidic 3D co-culture device. , 2010, Lab on a chip.

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

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

[42]  H. Dvorak,et al.  VEGF-A and the induction of pathological angiogenesis. , 2007, Annual review of pathology.

[43]  T. Mcclanahan,et al.  Involvement of chemokine receptors in breast cancer metastasis , 2001, Nature.

[44]  Rakesh K. Jain,et al.  Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels , 2013, Nature Communications.

[45]  Robert A. Weinberg,et al.  Stromal Fibroblasts in Cancer: A Novel Tumor-Promoting Cell Type , 2006, Cell cycle.

[46]  Hiroshi Maeda,et al.  Toward a full understanding of the EPR effect in primary and metastatic tumors as well as issues related to its heterogeneity. , 2015, Advanced drug delivery reviews.

[47]  T. Yamano,et al.  CCL21 Chemokine Regulates Chemokine Receptor CCR7 Bearing Malignant Melanoma Cells , 2004, Clinical Cancer Research.

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

[49]  A. Lee,et al.  Engineering microscale cellular niches for three-dimensional multicellular co-cultures. , 2009, Lab on a chip.

[50]  Christopher S. Chen,et al.  Engineering cellular microenvironments to improve cell-based drug testing. , 2002, Drug discovery today.

[51]  M. Skobe,et al.  Molecular characterization of lymphatic endothelial cells , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[52]  Roger D Kamm,et al.  On-chip human microvasculature assay for visualization and quantification of tumor cell extravasation dynamics , 2017, Nature Protocols.

[53]  D E Ingber,et al.  Role of basal lamina in neoplastic disorganization of tissue architecture. , 1981, Proceedings of the National Academy of Sciences of the United States of America.

[54]  P. Friedl,et al.  Tumour-cell invasion and migration: diversity and escape mechanisms , 2003, Nature Reviews Cancer.

[55]  Roger D Kamm,et al.  A quantitative microfluidic angiogenesis screen for studying anti-angiogenic therapeutic drugs. , 2014, Lab on a chip.

[56]  U. Nielsen,et al.  Antibody targeting of long-circulating lipidic nanoparticles does not increase tumor localization but does increase internalization in animal models. , 2006, Cancer research.

[57]  R. Ferris,et al.  CCR7 mediates inflammation-associated tumor progression , 2006, Immunologic research.

[58]  I. Fidler,et al.  The pathogenesis of cancer metastasis: the 'seed and soil' hypothesis revisited , 2003, Nature Reviews Cancer.

[59]  Kinam Park,et al.  Simulation of complex transport of nanoparticles around a tumor using tumor-microenvironment-on-chip. , 2014, Journal of controlled release : official journal of the Controlled Release Society.

[60]  Hyunjae Lee,et al.  Engineering of functional, perfusable 3D microvascular networks on a chip. , 2013, Lab on a chip.

[61]  Lei Xu,et al.  Normalization of the vasculature for treatment of cancer and other diseases. , 2011, Physiological reviews.

[62]  T. Whiteside The tumor microenvironment and its role in promoting tumor growth , 2008, Oncogene.

[63]  Yuejun Kang,et al.  A microfluidic co-culture system to monitor tumor-stromal interactions on a chip. , 2014, Biomicrofluidics.

[64]  D. Hanahan,et al.  The Hallmarks of Cancer , 2000, Cell.

[65]  H. Yoshida,et al.  Assessing liver tumor stiffness by transient elastography , 2007, Hepatology international.

[66]  R. Weinberg,et al.  Tackling the cancer stem cells — what challenges do they pose? , 2014, Nature Reviews Drug Discovery.

[67]  Xiaoyang Xu,et al.  Cancer nanotechnology: the impact of passive and active targeting in the era of modern cancer biology. , 2014, Advanced drug delivery reviews.

[68]  S. Hwang,et al.  Chemokines, chemokine receptors, and cancer metastasis , 2006, Journal of leukocyte biology.

[69]  Joseph M. Negri,et al.  The role of tumour–stromal interactions in modifying drug response: challenges and opportunities , 2013, Nature Reviews Drug Discovery.

[70]  G. Whitesides The origins and the future of microfluidics , 2006, Nature.

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

[72]  Rakesh K Jain,et al.  Vascular normalization as a therapeutic strategy for malignant and nonmalignant disease. , 2012, Cold Spring Harbor perspectives in medicine.

[73]  M. Lopes,et al.  Mutual paracrine effects of oral squamous cell carcinoma cells and normal oral fibroblasts: induction of fibroblast to myofibroblast transdifferentiation and modulation of tumor cell proliferation. , 2008, Oral oncology.

[74]  H. Kuh,et al.  Improving drug delivery to solid tumors: priming the tumor microenvironment. , 2015, Journal of controlled release : official journal of the Controlled Release Society.

[75]  Marissa Nichole Rylander,et al.  Flow shear stress regulates endothelial barrier function and expression of angiogenic factors in a 3D microfluidic tumor vascular model , 2014, Cell adhesion & migration.

[76]  Sanjay Kumar,et al.  Mechanics, malignancy, and metastasis: The force journey of a tumor cell , 2009, Cancer and Metastasis Reviews.

[77]  Triantafyllos Stylianopoulos,et al.  Stress-mediated progression of solid tumors: effect of mechanical stress on tissue oxygenation, cancer cell proliferation, and drug delivery , 2015, Biomechanics and Modeling in Mechanobiology.

[78]  Annaïck Desmaison,et al.  Mechanical Stress Impairs Mitosis Progression in Multi-Cellular Tumor Spheroids , 2013, PloS one.

[79]  Amit Pathak,et al.  Biophysical regulation of tumor cell invasion: moving beyond matrix stiffness. , 2011, Integrative biology : quantitative biosciences from nano to macro.

[80]  Liju Yang,et al.  Three-dimensional cell culture systems and their applications in drug discovery and cell-based biosensors. , 2014, Assay and drug development technologies.

[81]  Wenxin Wang,et al.  Application of a microfluidic chip-based 3D co-culture to test drug sensitivity for individualized treatment of lung cancer. , 2013, Biomaterials.

[82]  R. Jain,et al.  Challenges and key considerations of the enhanced permeability and retention effect for nanomedicine drug delivery in oncology. , 2013, Cancer research.

[83]  D. Tyler,et al.  Long-Term Survival in 2,505 Patients With Melanoma With Regional Lymph Node Metastasis , 2002, Annals of surgery.

[84]  K. Cheung,et al.  Droplet-based microfluidic system for multicellular tumor spheroid formation and anticancer drug testing. , 2010, Lab on a chip.

[85]  R. Assoian,et al.  Effects of Rho Kinase and Actin Stress Fibers on Sustained Extracellular Signal-Regulated Kinase Activity and Activation of G1 Phase Cyclin-Dependent Kinases , 2003, Molecular and Cellular Biology.

[86]  Ignacio Ochoa,et al.  Development and characterization of a microfluidic model of the tumour microenvironment , 2016, Scientific Reports.

[87]  P. Ciarletta,et al.  Buckling instability in growing tumor spheroids. , 2013, Physical review letters.

[88]  Robert Langer,et al.  Single step reconstitution of multifunctional high-density lipoprotein-derived nanomaterials using microfluidics. , 2013, ACS nano.

[89]  Ji‐Hyun Lee,et al.  Co-Culture of Tumor Spheroids and Fibroblasts in a Collagen Matrix-Incorporated Microfluidic Chip Mimics Reciprocal Activation in Solid Tumor Microenvironment , 2016, PloS one.

[90]  A. Bignami,et al.  Hyaluronic acid and hyaluronic acid-binding proteins in brain extracellular matrix , 1993, Anatomy and Embryology.

[91]  Adrian C. Shieh,et al.  Biomechanical Forces Shape the Tumor Microenvironment , 2011, Annals of Biomedical Engineering.

[92]  E. Young Cells, tissues, and organs on chips: challenges and opportunities for the cancer tumor microenvironment. , 2013, Integrative biology : quantitative biosciences from nano to macro.

[93]  D. Bates,et al.  CCR7 Mediates Directed Growth of Melanomas Towards Lymphatics , 2011, Microcirculation.

[94]  Rafael Sirera,et al.  The Role of Tumor Stroma in Cancer Progression and Prognosis: Emphasis on Carcinoma-Associated Fibroblasts and Non-small Cell Lung Cancer , 2011, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[95]  R. N. Saha,et al.  Nanoparticulate drug delivery systems for cancer chemotherapy , 2010, Molecular membrane biology.

[96]  N. Jeon,et al.  The effect of matrix density on the regulation of 3-D capillary morphogenesis. , 2008, Biophysical journal.

[97]  Jacques Prost,et al.  Compressive stress inhibits proliferation in tumor spheroids through a volume limitation. , 2014, Biophysical journal.

[98]  Matija Snuderl,et al.  Coevolution of solid stress and interstitial fluid pressure in tumors during progression: implications for vascular collapse. , 2013, Cancer research.

[99]  Lance L. Munn,et al.  Fluid forces control endothelial sprouting , 2011, Proceedings of the National Academy of Sciences.

[100]  B. Munos Lessons from 60 years of pharmaceutical innovation , 2009, Nature Reviews Drug Discovery.

[101]  Z. Fayad,et al.  Probing nanoparticle translocation across the permeable endothelium in experimental atherosclerosis , 2014, Proceedings of the National Academy of Sciences.

[102]  L. weiswald,et al.  Spherical Cancer Models in Tumor Biology1 , 2015, Neoplasia.

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

[104]  G. Dubini,et al.  A microfluidic 3D in vitro model for specificity of breast cancer metastasis to bone. , 2014, Biomaterials.

[105]  L. Munn,et al.  Aberrant vascular architecture in tumors and its importance in drug-based therapies. , 2003, Drug discovery today.

[106]  Kevin W Eliceiri,et al.  Transition to invasion in breast cancer: a microfluidic in vitro model enables examination of spatial and temporal effects. , 2011, Integrative biology : quantitative biosciences from nano to macro.

[107]  Jennifer L West,et al.  Studying the influence of angiogenesis in in vitro cancer model systems. , 2016, Advanced drug delivery reviews.

[108]  R. Kamm,et al.  In Vitro Model of Tumor Cell Extravasation , 2013, PloS one.

[109]  Triantafyllos Stylianopoulos,et al.  Causes, consequences, and remedies for growth-induced solid stress in murine and human tumors , 2012, Proceedings of the National Academy of Sciences.

[110]  Dai Fukumura,et al.  Scaling rules for diffusive drug delivery in tumor and normal tissues , 2011, Proceedings of the National Academy of Sciences.

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

[112]  P. Kantoff,et al.  Cancer nanomedicine: progress, challenges and opportunities , 2016, Nature Reviews Cancer.

[113]  Noo Li Jeon,et al.  Interstitial flow regulates the angiogenic response and phenotype of endothelial cells in a 3D culture model. , 2016, Lab on a chip.

[114]  Donald E Ingber,et al.  Cell tension, matrix mechanics, and cancer development. , 2005, Cancer cell.

[115]  Triantafyllos Stylianopoulos,et al.  The role of mechanical forces in tumor growth and therapy. , 2014, Annual review of biomedical engineering.

[116]  Resham Bhattacharya,et al.  Efficient Delivery of Gold Nanoparticles by Dual Receptor Targeting , 2011, Advanced materials.

[117]  E. A. Sykes,et al.  Tumour-on-a-chip provides an optical window into nanoparticle tissue transport , 2013, Nature Communications.