Development and characterization of a microfluidic model of the tumour microenvironment

The physical microenvironment of tumours is characterized by heterotypic cell interactions and physiological gradients of nutrients, waste products and oxygen. This tumour microenvironment has a major impact on the biology of cancer cells and their response to chemotherapeutic agents. Despite this, most in vitro cancer research still relies primarily on cells grown in 2D and in isolation in nutrient- and oxygen-rich conditions. Here, a microfluidic device is presented that is easy to use and enables modelling and study of the tumour microenvironment in real-time. The versatility of this microfluidic platform allows for different aspects of the microenvironment to be monitored and dissected. This is exemplified here by real-time profiling of oxygen and glucose concentrations inside the device as well as effects on cell proliferation and growth, ROS generation and apoptosis. Heterotypic cell interactions were also studied. The device provides a live ‘window’ into the microenvironment and could be used to study cancer cells for which it is difficult to generate tumour spheroids. Another major application of the device is the study of effects of the microenvironment on cellular drug responses. Some data is presented for this indicating the device’s potential to enable more physiological in vitro drug screening.

[1]  T. Hagemann,et al.  The tumor microenvironment at a glance , 2012, Journal of Cell Science.

[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]  I. Tannock,et al.  Drug penetration in solid tumours , 2006, Nature Reviews Cancer.

[4]  D. Beebe,et al.  The present and future role of microfluidics in biomedical research , 2014, Nature.

[5]  D. Huh,et al.  Organs-on-chips at the frontiers of drug discovery , 2015, Nature Reviews Drug Discovery.

[6]  Angelo Corti,et al.  Improving chemotherapeutic drug penetration in tumors by vascular targeting and barrier alteration. , 2002, The Journal of clinical investigation.

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

[8]  M. Doblaré,et al.  Study of the Chemotactic Response of Multicellular Spheroids in a Microfluidic Device , 2015, PloS one.

[9]  A. Scally,et al.  Characterization of changes in the proteome in different regions of 3D multicell tumor spheroids. , 2012, Journal of proteome research.

[10]  F. Du,et al.  The emerging role of hypoxia-inducible factor-2 involved in chemo/radioresistance in solid tumors. , 2015, Cancer treatment reviews.

[11]  J. Tait,et al.  Challenges and opportunities. , 1996, Journal of psychiatric and mental health nursing.

[12]  S. Bersini,et al.  3D functional and perfusable microvascular networks for organotypic microfluidic models , 2015, Journal of Materials Science: Materials in Medicine.

[13]  J. Gelovani,et al.  Optimizing Imaging of Three-Dimensional Multicellular Tumor Spheroids with Fluorescent Reporter Proteins Using Confocal Microscopy , 2008, Molecular imaging.

[14]  M. Junttila,et al.  Influence of tumour micro-environment heterogeneity on therapeutic response , 2013, Nature.

[15]  G. Devi,et al.  Three-dimensional culture systems in cancer research: Focus on tumor spheroid model. , 2016, Pharmacology & therapeutics.

[16]  Kenichi Funamoto,et al.  A novel microfluidic platform for high-resolution imaging of a three-dimensional cell culture under a controlled hypoxic environment. , 2012, Lab on a chip.

[17]  G. Hu,et al.  New horizons in tumor microenvironment biology: challenges and opportunities , 2015, BMC Medicine.

[18]  D. Brat,et al.  Malignant Glioma Physiology: Cellular Response to Hypoxia and Its Role in Tumor Progression , 2003, Annals of Internal Medicine.

[19]  Ian F Tannock,et al.  Limited penetration of anticancer drugs through tumor tissue: a potential cause of resistance of solid tumors to chemotherapy. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[20]  D. Sabatini,et al.  Cancer cell metabolism: one hallmark, many faces. , 2012, Cancer discovery.

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

[22]  R. Kamm,et al.  Cell migration into scaffolds under co-culture conditions in a microfluidic platform. , 2009, Lab on a chip.

[23]  Jérôme Fehrenbach,et al.  Live cell division dynamics monitoring in 3D large spheroid tumor models using light sheet microscopy , 2011, Cell Division.

[24]  J. Morgan,et al.  Advances in the formation, use and understanding of multi-cellular spheroids , 2012, Expert opinion on biological therapy.

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

[26]  Andrew D J Pearson,et al.  How can attrition rates be reduced in cancer drug discovery? , 2013, Expert opinion on drug discovery.

[27]  D. Beebe,et al.  Simple microfluidic device for studying chemotaxis in response to dual gradients , 2015, Biomedical microdevices.

[28]  Ross Tonkens,et al.  An overview of the drug development process. , 2005, Physician executive.

[29]  A. Muntasell,et al.  Human NK cells activated by EBV+ lymphoblastoid cells overcome anti-apoptotic mechanisms of drug resistance in haematological cancer cells , 2015, Oncoimmunology.

[30]  M. Zou,et al.  Mitochondrial ROS and cancer drug resistance: Implications for therapy. , 2015, Pharmacological research.

[31]  P. Carmeliet,et al.  Hypoxia induces VEGF-C expression in metastatic tumor cells via a HIF-1α-independent translation-mediated mechanism. , 2014, Cell reports.

[32]  Francesco Pampaloni,et al.  Live spheroid formation recorded with light sheet-based fluorescence microscopy. , 2015, Methods in molecular biology.

[33]  Ross M Tonkens.  Breaking into clinical research. , 2005, Physician executive.

[34]  D. Quail,et al.  Microenvironmental regulation of tumor progression and metastasis , 2014 .

[35]  M. Doblaré,et al.  SU-8 Based Microdevices to Study Self-Induced Chemotaxis in 3D Microenvironments , 2015, Front. Mater..

[36]  Xian Xu,et al.  Three-dimensional in vitro tumor models for cancer research and drug evaluation. , 2014, Biotechnology advances.

[37]  J. Wollock.  4. Implications for the History of Speech Therapy , 1997 .

[38]  P. Schumacker,et al.  Mitochondrial ROS in cancer: initiators, amplifiers or an Achilles' heel? , 2014, Nature Reviews Cancer.