Cancer Modeling-on-a-Chip with Future Artificial Intelligence Integration.

Cancer is one of the leading causes of death worldwide, despite the large efforts to improve the understanding of cancer biology and development of treatments. The attempts to improve cancer treatment are limited by the complexity of the local milieu in which cancer cells exist. The tumor microenvironment (TME) consists of a diverse population of tumor cells and stromal cells with immune constituents, microvasculature, extracellular matrix components, and gradients of oxygen, nutrients, and growth factors. The TME is not recapitulated in traditional models used in cancer investigation, limiting the translation of preliminary findings to clinical practice. Advances in 3D cell culture, tissue engineering, and microfluidics have led to the development of "cancer-on-a-chip" platforms that expand the ability to model the TME in vitro and allow for high-throughput analysis. The advances in the development of cancer-on-a-chip platforms, implications for drug development, challenges to leveraging this technology for improved cancer treatment, and future integration with artificial intelligence for improved predictive drug screening models are discussed.

[1]  Ali Khademhosseini,et al.  The emergence of 3D bioprinting in organ-on-chip systems , 2019, Progress in Biomedical Engineering.

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

[3]  A. Barra,et al.  Organs on chip approach: a tool to evaluate cancer -immune cells interactions , 2017, Scientific Reports.

[4]  S. Varghese,et al.  Chemotaxis-driven assembly of endothelial barrier in a tumor-on-a-chip platform. , 2016, Lab on a chip.

[5]  Pierre Baldi,et al.  Deep Learning for Drug Discovery and Cancer Research: Automated Analysis of Vascularization Images , 2019, IEEE/ACM Transactions on Computational Biology and Bioinformatics.

[6]  R. Weinberg,et al.  A Perspective on Cancer Cell Metastasis , 2011, Science.

[7]  Chi-Ping Day,et al.  Preclinical Mouse Cancer Models: A Maze of Opportunities and Challenges , 2015, Cell.

[8]  John S. Condeelis,et al.  Chemotaxis in cancer , 2011, Nature Reviews Cancer.

[9]  Y. S. Zhang,et al.  Cancer-on-a-chip systems at the frontier of nanomedicine. , 2017, Drug discovery today.

[10]  Zhongze Gu,et al.  Organ-on-a-Chip Systems: Microengineering to Biomimic Living Systems. , 2016, Small.

[11]  V. Virador,et al.  In vitro three‐dimensional (3D) models in cancer research: An update , 2013, Molecular carcinogenesis.

[12]  Charles N. Baroud,et al.  Multiscale cytometry and regulation of 3D cell cultures on a chip , 2017, Nature Communications.

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

[14]  L. O’Driscoll,et al.  Three-dimensional cell culture: the missing link in drug discovery. , 2013, Drug discovery today.

[15]  K. Śmietana,et al.  Trends in clinical success rates , 2016, Nature Reviews Drug Discovery.

[16]  D. Huh,et al.  A microengineered pathophysiological model of early-stage breast cancer. , 2015, Lab on a chip.

[17]  Noo Li Jeon,et al.  A microfluidic platform for quantitative analysis of cancer angiogenesis and intravasation. , 2014, Biomicrofluidics.

[18]  Aaron Goldman,et al.  Preclinical Cancer Models and Biomarkers for Drug Development: New Technologies and Emerging Tools , 2017, Journal of molecular biomarkers & diagnosis.

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

[20]  T. Saif,et al.  Biophysics of Tumor Microenvironment and Cancer Metastasis - A Mini Review , 2018, Computational and structural biotechnology journal.

[21]  Gang Bao,et al.  Tumour-on-a-chip: microfluidic models of tumour morphology, growth and microenvironment , 2017, Journal of The Royal Society Interface.

[22]  M. Cekanova,et al.  Animal models and therapeutic molecular targets of cancer: utility and limitations , 2014, Drug design, development and therapy.

[23]  Li V. Yang,et al.  In vitro cell migration and invasion assays. , 2014, Journal of visualized experiments : JoVE.

[24]  Gordana Vunjak-Novakovic,et al.  Organs-on-a-Chip: A Fast Track for Engineered Human Tissues in Drug Development. , 2018, Cell stem cell.

[25]  Yibin Kang,et al.  Transplantable mouse tumor models of breast cancer metastasis. , 2015, Methods in molecular biology.

[26]  Yu Sun,et al.  A review of microfluidic approaches for investigating cancer extravasation during metastasis , 2018, Microsystems & Nanoengineering.

[27]  P. Graziano,et al.  Crosstalk between the Tumor Microenvironment and Immune System in Pancreatic Ductal Adenocarcinoma: Potential Targets for New Therapeutic Approaches , 2018, Gastroenterology research and practice.

[28]  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.

[29]  B. Ruggeri,et al.  Animal models of disease: pre-clinical animal models of cancer and their applications and utility in drug discovery. , 2014, Biochemical pharmacology.

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

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

[32]  Noo Li Jeon,et al.  Three-dimensional biomimetic model to reconstitute sprouting lymphangiogenesis in vitro. , 2016, Biomaterials.

[33]  N. Ashammakhi,et al.  Cancer-on-a-Chip and Artificial Intelligence: Tomorrow's Cancer Management. , 2018, The Journal of craniofacial surgery.

[34]  M. Dhiman,et al.  Role of immune system in tumor progression and carcinogenesis , 2018, Journal of cellular biochemistry.

[35]  Kin Fong Lei,et al.  Quantitative Study of Cell Invasion Process under Extracellular Stimulation of Cytokine in a Microfluidic Device , 2016, Scientific Reports.

[36]  Gong Cheng,et al.  A Spontaneous 3D Bone-On-a-Chip for Bone Metastasis Study of Breast Cancer Cells. , 2018, Small.

[37]  Donald E. Ingber,et al.  Modelling cancer in microfluidic human organs-on-chips , 2019, Nature Reviews Cancer.

[38]  J. Cuevas,et al.  A modular approach to create a neurovascular unit-on-a-chip. , 2013, Lab on a chip.

[39]  Stephanie J Hachey,et al.  Applications of tumor chip technology. , 2018, Lab on a chip.

[40]  Li-Hsin Han,et al.  Modeling Physiological Events in 2D vs. 3D Cell Culture. , 2017, Physiology.

[41]  Qing Yang,et al.  Recreating blood-brain barrier physiology and structure on chip: A novel neurovascular microfluidic bioreactor. , 2015, Biomicrofluidics.

[42]  James C. Weaver,et al.  Mature induced-pluripotent-stem-cell-derived human podocytes reconstitute kidney glomerular-capillary-wall function on a chip , 2017, Nature Biomedical Engineering.

[43]  Jaap M. J. den Toonder,et al.  Metastasis in context: modeling the tumor microenvironment with cancer-on-a-chip approaches , 2018, Disease Models & Mechanisms.

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

[45]  S. Oesterreich,et al.  Three-Dimensional Breast Cancer Models Mimic Hallmarks of Size-Induced Tumor Progression. , 2016, Cancer research.

[46]  Boyang Zhang,et al.  Synergistic Engineering: Organoids Meet Organs-on-a-Chip. , 2017, Cell stem cell.

[47]  D. Ingber,et al.  Human gut-on-a-chip inhabited by microbial flora that experiences intestinal peristalsis-like motions and flow. , 2012, Lab on a chip.

[48]  D. Ingber,et al.  Reconstituting Organ-Level Lung Functions on a Chip , 2010, Science.

[49]  R. Reis,et al.  Organ-on-chip models of cancer metastasis for future personalized medicine: From chip to the patient. , 2017, Biomaterials.

[50]  Hanseup Kim,et al.  Characterization of a microfluidic in vitro model of the blood-brain barrier (μBBB). , 2012, Lab on a chip.

[51]  R. Kuchta,et al.  Introduction to cancer chemotherapeutics. , 2009, Chemical reviews.

[52]  U. Pastorino,et al.  Establishment of patient derived xenografts as functional testing of lung cancer aggressiveness , 2017, Scientific Reports.

[53]  Keekyoung Kim,et al.  Organ-on-a-Chip Platforms for Drug Screening and Tissue Engineering , 2016 .

[54]  Manuel Ochoa,et al.  Disease-on-a-chip: mimicry of tumor growth in mammary ducts. , 2014, Lab on a chip.

[55]  Bahar Firoozabadi,et al.  Organ-Tumor-on-a-Chip for Chemosensitivity Assay: A Critical Review , 2016, Micromachines.

[56]  I. Kola,et al.  Can the pharmaceutical industry reduce attrition rates? , 2004, Nature Reviews Drug Discovery.

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

[58]  Donald E Ingber,et al.  Human Organ Chip Models Recapitulate Orthotopic Lung Cancer Growth, Therapeutic Responses, and Tumor Dormancy In Vitro. , 2017, Cell reports.

[59]  Xingyu Jiang,et al.  Investigation of Tumor Cell Behaviors on a Vascular Microenvironment-Mimicking Microfluidic Chip , 2015, Scientific Reports.

[60]  N. Annabi,et al.  Microengineered cancer-on-a-chip platforms to study the metastatic microenvironment. , 2016, Lab on a chip.

[61]  Jia Yu,et al.  Therapy response testing of breast cancer in a 3D high-throughput perfused microfluidic platform , 2017, BMC Cancer.

[62]  Hanry Yu,et al.  A 3D Microfluidic Model to Recapitulate Cancer Cell Migration and Invasion , 2018, Bioengineering.

[63]  A. Jemal,et al.  Cancer statistics, 2018 , 2018, CA: a cancer journal for clinicians.

[64]  Wei Xiong,et al.  Role of tumor microenvironment in tumorigenesis , 2017, Journal of Cancer.

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

[66]  Large-Scale Drug Screens Support Precision Medicine. , 2015, Cancer discovery.

[67]  Rebecca L. Siegel Mph,et al.  Cancer statistics, 2018 , 2018 .

[68]  B. Rini,et al.  Angiogenesis and the tumor microenvironment: vascular endothelial growth factor and beyond. , 2014, Seminars in oncology.

[69]  A. Mammoto,et al.  Primary Human Lung Alveolus‐on‐a‐chip Model of Intravascular Thrombosis for Assessment of Therapeutics , 2018, Clinical pharmacology and therapeutics.

[70]  K. Lamperska,et al.  2D and 3D cell cultures – a comparison of different types of cancer cell cultures , 2016, Archives of medical science : AMS.

[71]  Lidong Qin,et al.  High-Throughput 3D Cell Invasion Chip Enables Accurate Cancer Metastatic Assays , 2014, Journal of the American Chemical Society.

[72]  Thomas Hankemeier,et al.  Membrane-free culture and real-time barrier integrity assessment of perfused intestinal epithelium tubes , 2017, Nature Communications.

[73]  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.

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

[75]  A. Khademhosseini,et al.  Concise Review: Organ Engineering: Design, Technology, and Integration , 2016, Stem cells.

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

[77]  D. Ingber,et al.  Human kidney proximal tubule-on-a-chip for drug transport and nephrotoxicity assessment. , 2013, Integrative biology : quantitative biosciences from nano to macro.

[78]  Peng Li,et al.  Current status and perspectives of patient-derived xenograft models in cancer research , 2017, Journal of Hematology & Oncology.

[79]  Hao Zhang,et al.  Microfluidics for Cancer Nanomedicine: From Fabrication to Evaluation. , 2018, Small.

[80]  Y. S. Zhang,et al.  Bioprinted thrombosis-on-a-chip. , 2016, Lab on a chip.

[81]  Elena Agliari,et al.  Cancer-driven dynamics of immune cells in a microfluidic environment , 2014, Scientific Reports.

[82]  Rui L Reis,et al.  Evaluating Biomaterial- and Microfluidic-Based 3D Tumor Models. , 2015, Trends in biotechnology.

[83]  Noo Li Jeon,et al.  Tumor Microenvironment on a Chip: The Progress and Future Perspective , 2017, Bioengineering.

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

[85]  Peter C. Searson,et al.  In Vitro Tumor Models: Advantages, Disadvantages, Variables, and Selecting the Right Platform , 2016, Front. Bioeng. Biotechnol..

[86]  Milica Radisic,et al.  Advances in organ-on-a-chip engineering , 2018, Nature Reviews Materials.

[87]  Donald E Ingber,et al.  Gut-on-a-Chip microenvironment induces human intestinal cells to undergo villus differentiation. , 2013, Integrative biology : quantitative biosciences from nano to macro.

[88]  Holger Becker,et al.  A novel microfluidic 3D platform for culturing pancreatic ductal adenocarcinoma cells: comparison with in vitro cultures and in vivo xenografts , 2017, Scientific Reports.

[89]  Alan Wells,et al.  Novel three-dimensional organotypic liver bioreactor to directly visualize early events in metastatic progression. , 2007, Advances in cancer research.