{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T10:32:18Z","timestamp":1761129138510,"version":"build-2065373602"},"reference-count":64,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2014,1,22]],"date-time":"2014-01-22T00:00:00Z","timestamp":1390348800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Micromachines"],"abstract":"<jats:p>We report a novel approach to study cell migration under physical stresses by utilizing established growth factor chemotaxis. This was achieved by studying cell migration in response to epidermal growth factor (EGF) chemoattraction in a gradually tapered space, imposing mechanical stresses. The device consisted of two 5-mm-diameter chambers connected by ten 600 \u00b5m-long and 10 \u00b5m-high tapered microchannels. The taper region gradually changes the width of the channel. The channels tapered from 20 \u00b5m to  5 \u00b5m over a transition length of 50 \u00b5m at a distance of 250 \u00b5m from one of the chambers. The chemoattractant drove cell migration into the narrow confines of the tapered channels, while the mechanical gradient clearly altered the migration of cells. Cells traversing the channels from the wider to narrow-end and vice versa were observed using time-lapsed imaging. Our results indicated that the impact of physical stress on cell migration patterns may be cell type specific.<\/jats:p>","DOI":"10.3390\/mi5010013","type":"journal-article","created":{"date-parts":[[2014,1,22]],"date-time":"2014-01-22T12:32:23Z","timestamp":1390393943000},"page":"13-26","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["The Migration of Cancer Cells in Gradually Varying Chemical Gradients and Mechanical Constraints"],"prefix":"10.3390","volume":"5","author":[{"given":"Smitha","family":"Rao","sequence":"first","affiliation":[{"name":"Department of Electrical Engineering, University of Texas at Arlington, NH 538, Box 19016, Arlington, TX 76019, USA"}]},{"given":"Uday","family":"Tata","sequence":"additional","affiliation":[{"name":"Department of Electrical Engineering, University of Texas at Arlington, NH 538, Box 19016, Arlington, TX 76019, USA"}]},{"given":"Victor","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Electrical Engineering, University of Texas at Arlington, NH 538, Box 19016, Arlington, TX 76019, USA"}]},{"given":"Jung-Chih","family":"Chiao","sequence":"additional","affiliation":[{"name":"Department of Electrical Engineering, University of Texas at Arlington, NH 538, Box 19016, Arlington, TX 76019, USA"}]}],"member":"1968","published-online":{"date-parts":[[2014,1,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of cancer: The next generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"ref_2","unstructured":"Jakowlew, S.B. (2008). Cancer Treatment and Therapy, Humana Press."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"13909","DOI":"10.1073\/pnas.0506517102","article-title":"Breast cancer bone metastasis mediated by the smad tumor suppressor pathway","volume":"102","author":"Kang","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2252","DOI":"10.1039\/c3lc41393d","article-title":"Microfluidic platforms for mechanobiology","volume":"13","author":"Polacheck","year":"2013","journal-title":"Lab Chip"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1073\/pnas.0308090100","article-title":"Cooperation of the ErbB2 receptor and transforming growth factor beta in induction of migration and invasion in mammary epithelial cells","volume":"101","author":"Lu","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1593\/neo.04241","article-title":"Activation of the Erk pathway is required for TGF-\u03b21-induced EMT in vitro","volume":"6","author":"Xie","year":"2004","journal-title":"Neoplasia"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2662","DOI":"10.1096\/fj.08-126920","article-title":"Multimodality imaging of TGF\u03b2 signaling in breast cancer metastases","volume":"23","author":"Serganova","year":"2009","journal-title":"FASEB J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"329","DOI":"10.18388\/abp.2005_3446","article-title":"TGF Beta signalling and its role in tumour pathogenesis","volume":"52","author":"Kaminska","year":"2005","journal-title":"Acta Biochim. Pol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1006\/bbrc.1998.8559","article-title":"Role of latent TGF-\u03b21 binding protein in vascular remodeling","volume":"246","author":"Kanzaki","year":"1998","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1002\/(SICI)1097-0045(19980915)37:1<19::AID-PROS4>3.0.CO;2-3","article-title":"Transforming growth factor \u03b21 is associated with angiogenesis, metastasis, and poor clinical outcome in prostate cancer","volume":"37","author":"Stattin","year":"1998","journal-title":"Prostate"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/(SICI)1097-0045(199601)28:1<1::AID-PROS1>3.0.CO;2-L","article-title":"Epidermal growth factor (EGF) promotes chemomigration of a human prostate tumor cell line, and EGF immunoreactive proteins are present at sites of metastasis in the stroma of lymph nodes and medullary bone","volume":"28","author":"Rajan","year":"1996","journal-title":"Prostate"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Wang, J.H., and Li, B. (2010). Mechanics rules cell biology. Sports Med. Arthrosc. Rehabil. Ther. Technol., 2.","DOI":"10.1186\/1758-2555-2-16"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1096\/fj.05-5424rev","article-title":"Cellular mechanotransduction: Putting all the pieces together again","volume":"20","author":"Ingber","year":"2006","journal-title":"FASEB J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1038\/nrc865","article-title":"Dissemination and growth of cancer cells in metastatic sites","volume":"2","author":"Chambers","year":"2002","journal-title":"Nat. Rev. Cancer"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1073\/pnas.0707603105","article-title":"Anomalous dynamics of cell migration","volume":"105","author":"Dieterich","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"S365","DOI":"10.1098\/rsif.2010.0042.focus","article-title":"Live cell imaging of mechanotransduction","volume":"7","author":"Liu","year":"2010","journal-title":"J. R. Soc. Interf."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.devcel.2005.12.006","article-title":"Mechanisms of mechanotransduction","volume":"10","author":"Orr","year":"2006","journal-title":"Dev. Cell"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Wang, W., and Soper, S.A. (2006). Bio-MEMS Technologies and Applications, CRC Press. [1st ed.].","DOI":"10.1201\/9781420018677"},{"key":"ref_19","unstructured":"Tian, W., and Finehout, E. (2008). Microfluidics for Biological Applications, Springer."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1507","DOI":"10.1039\/b803533d","article-title":"A platform for assessing chemotactic migration within a spatiotemporally defined 3D microenvironment","volume":"8","author":"Abhyankar","year":"2008","journal-title":"Lab Chip"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1098\/rsta.2003.1363","article-title":"Microfluidic mixers: From microfabricated to self-assembling devices","volume":"362","author":"Campbell","year":"2004","journal-title":"Philos. Transact. A Math. Phys. Eng. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1778","DOI":"10.1088\/0960-1317\/16\/9\/004","article-title":"A highly efficient 3D micromixer using soft PDMS bonding","volume":"16","author":"Cha","year":"2006","journal-title":"J. Micromech. Microeng."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1007\/s00542-003-0304-0","article-title":"Fabrication of the PDMS Microchip for Serially Diluting Sample with Buffer","volume":"Volume 9","author":"Chang","year":"2003","journal-title":"Microsystem Technologies"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1039\/B511958H","article-title":"A Three-channel microfluidic device for generating static linear gradients and its application to the quantitative analysis of bacterial chemotaxis","volume":"6","author":"Diao","year":"2006","journal-title":"Lab Chip"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4974","DOI":"10.1021\/ac980656z","article-title":"Rapid prototyping of microfluidic systems in poly(dimethylsiloxane)","volume":"70","author":"Duffy","year":"1998","journal-title":"Anal. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1002\/jssc.200500407","article-title":"Integrated microfluidic devices with enhanced separation performance: Application to phosphoproteome analyses of differentiated cell model systems","volume":"29","author":"Ghitun","year":"2006","journal-title":"J. Seper. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3472","DOI":"10.1021\/ac0518710","article-title":"Universal microfluidic gradient generator","volume":"78","author":"Irimia","year":"2006","journal-title":"Anal. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"8311","DOI":"10.1021\/la000600b","article-title":"Generation of solution and surface gradients using microfluidic systems","volume":"16","author":"Jeon","year":"2000","journal-title":"Langmuir"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1073\/pnas.0408954102","article-title":"Directing cell migration with asymmetric micropatterns","volume":"102","author":"Jiang","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_30","unstructured":"Leclerc, E., Sakai, Y., and Fujii, T. (2003, January 23). A Multi-Layer PDMS Microfluidic Device for Tissue Engineering Applications. Proceedings of the IEEE the 16th Annual International Conference on Micro Electro Mechanical Systems, Kyoto, Japan."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1074\/mcp.M100022-MCP200","article-title":"Application of microfluidic devices to proteomics research: Identification of trace-level protein digests and affinity capture of target peptides","volume":"1","author":"Li","year":"2002","journal-title":"Mol. Cell. Proteomics"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1039\/b611041j","article-title":"Microfluidic technologies as platforms for performing quantitative cellular analyses in an in vitro environment","volume":"131","author":"Martin","year":"2006","journal-title":"Analyst"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1002\/(SICI)1522-2683(20000101)21:1<27::AID-ELPS27>3.0.CO;2-C","article-title":"Fabrication of microfluidic systems in poly(Dimethylsiloxane)","volume":"21","author":"McDonald","year":"2000","journal-title":"Electrophoresis"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1021\/ar010110q","article-title":"Poly(Dimethylsiloxane) as a Material for fabricating microfluidic devices","volume":"35","author":"McDonald","year":"2002","journal-title":"Acc. Chem. Res."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Nie, F., Kobayashi, J., Yamada, M., Yamato, M., Kikuchi, A., and Okano, T. (2007, January 11\u201314). Cell Migration Assay Using Multiple Laminar Flows in PDMS Microchannel. Proceedings of the International Symposium on Micro-NanoMechatronics and Human Science MHS \u201907, Nagoya, Japan.","DOI":"10.1109\/MHS.2007.4420889"},{"key":"ref_36","first-page":"2836","article-title":"A serial dilution microfluidic device for cytotoxicity assays","volume":"1","author":"Walker","year":"2006","journal-title":"Conf. Proc. IEEE Eng. Med. Biol. Soc."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2128","DOI":"10.1038\/nprot.2006.316","article-title":"Microfluidic culture platform for neuroscience research","volume":"1","author":"Park","year":"2006","journal-title":"Nat. Protoc."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1007\/s10544-006-7706-6","article-title":"A parallel-gradient microfluidic chamber for quantitative analysis of breast cancer cell chemotaxis","volume":"8","author":"Saadi","year":"2006","journal-title":"Biomed. Microdevices"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1007\/s10544-007-9051-9","article-title":"Generation of stable concentration gradients in 2D and 3D environments using a microfluidic ladder chamber","volume":"9","author":"Saadi","year":"2007","journal-title":"Biomed. Microdevices"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3563","DOI":"10.1002\/elps.200305584","article-title":"Microfluidic devices fabricated in poly(Dimethylsiloxane) for biological studies","volume":"24","author":"Sia","year":"2003","journal-title":"Electrophoresis"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.bioeng.2006.03.002","article-title":"Merging microfluidics with microarray-based bioassays","volume":"23","author":"Situma","year":"2006","journal-title":"Biomol. Eng."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1163\/156856201753113105","article-title":"Microscale three-dimensional polymeric platforms for in vitro cell culture systems","volume":"12","author":"Snyder","year":"2001","journal-title":"J. Biomater. Sci. Polym. Ed."},{"key":"ref_43","first-page":"167","article-title":"Microfluidic chambers for cell migration and neuroscience research","volume":"321","author":"Taylor","year":"2006","journal-title":"Methods Mol. Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1039\/B608990A","article-title":"A linear dilution microfluidic device for cytotoxicity assays","volume":"7","author":"Walker","year":"2007","journal-title":"Lab Chip"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1038\/nbt712","article-title":"Neutrophil chemotaxis in linear and complex gradients of interleukin-8 formed in a microfabricated device","volume":"20","author":"Baskaran","year":"2002","journal-title":"Nat. Biotechnol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1007\/s10439-005-2503-6","article-title":"Neutrophil migration in opposing chemoattractant gradients using microfluidic chemotaxis devices","volume":"33","author":"Lin","year":"2005","journal-title":"Ann. Biomed. Eng."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1039\/b908595e","article-title":"Spontaneous migration of cancer cells under conditions of mechanical confinement","volume":"1","author":"Irimia","year":"2009","journal-title":"Integr. Biol."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Rao, S.M.N., Lin, V.K., Tata, U., Raj, G.V., Hsieh, J.-T., Nguyen, K., and Chiao, J.-C. (2010). Demonstration of cancer cell migration using a novel microfluidic device. J. Nanotechnol. Eng. Med., 1.","DOI":"10.1115\/1.4001280"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Tata, U., Rao, S.M.N., Sharma, A., Pabba, K., Pokhrel, K., Adhikari, B., Lin, V.K., and Chiao, J.C. (2012). Study of lung-metastasized prostate cancer cell line chemotaxis to epidermal growth factor with a BIOMEMS device. Adv. Nat. Sci. Nanosci. Nanotechnol., 3.","DOI":"10.1088\/2043-6262\/3\/3\/035007"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1016\/S0092-8674(00)81380-X","article-title":"Getting membrane flow and the cytoskeleton to cooperate in moving cells","volume":"87","author":"Bretscher","year":"1996","journal-title":"Cell"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1016\/S1534-5807(02)00292-7","article-title":"Temporal and spatial regulation of chemotaxis","volume":"3","author":"Iijima","year":"2002","journal-title":"Dev. Cell"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/j.gde.2006.06.016","article-title":"Feedback signaling controls leading-edge formation during chemotaxis","volume":"16","author":"Charest","year":"2006","journal-title":"Curr. Opin. Genet. Dev."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1016\/j.ejcb.2006.04.007","article-title":"Regulation of chemotaxis by the orchestrated activation of ras, PI3K, and TOR","volume":"85","author":"Sasaki","year":"2006","journal-title":"Eur. J. Cell Biol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2075","DOI":"10.1016\/j.febslet.2008.04.035","article-title":"Directional sensing during chemotaxis","volume":"582","author":"Janetopoulos","year":"2008","journal-title":"FEBS Lett."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1038\/nrc967","article-title":"Metastasis suppressors alter the signal transduction of cancer cells","volume":"3","author":"Steeg","year":"2003","journal-title":"Nat. Rev. Cancer"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"R485","DOI":"10.1016\/j.cub.2008.04.048","article-title":"Moving towards a better understanding of chemotaxis","volume":"18","author":"Stephens","year":"2008","journal-title":"Curr. Biol."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Wu, W., and Hu, C.H. (2010). Signal Transduction in Cancer Metastasis, Springer.","DOI":"10.1007\/978-90-481-9522-0"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Mak, M., Reinhart-King, C.A., and Erickson, D. (2011). Microfabricated physical spatial gradients for investigating cell migration and invasion dynamics. PLoS One, 6.","DOI":"10.1371\/journal.pone.0020825"},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Harris, J., Lee, H., Vahidi, B., Tu, C., Cribbs, D., Cotman, C., and Jeon, N.L. (2007). Non-plasma bonding of PDMS for inexpensive fabrication of microfluidic devices. J. Vis. Exp., 9.","DOI":"10.3791\/410"},{"key":"ref_60","unstructured":"ata, U., Rao, S., Nguyen, K., Lin, V.K., and Chiao, J.C. (2011, January 12\u201315). A Microfluidic Approach to Study the Effect of Growth Factors on PC3 Cell Migration. Proceedings of the BMES Biomedical Engineering Society Annual Meeting 2011, Hartford, CT, USA."},{"key":"ref_61","first-page":"16","article-title":"Establishment and characterization of a human prostatic carcinoma cell line (PC-3)","volume":"17","author":"Kaighn","year":"1979","journal-title":"Invest. Urol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1016\/S0022-5347(17)37953-3","article-title":"Immortalization of human adult normal prostatic epithelial cells by liposomes containing large T-SV40 gene","volume":"146","author":"Cussenot","year":"1991","journal-title":"J. Urol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1126\/science.7914033","article-title":"A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells","volume":"265","author":"Han","year":"1994","journal-title":"Science"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"12411","DOI":"10.1073\/pnas.0602443103","article-title":"Myosin-X is a molecular motor that functions in filopodia formation","volume":"103","author":"Bohil","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"}],"container-title":["Micromachines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-666X\/5\/1\/13\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T21:07:36Z","timestamp":1760216856000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-666X\/5\/1\/13"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,1,22]]},"references-count":64,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2014,3]]}},"alternative-id":["mi5010013"],"URL":"https:\/\/doi.org\/10.3390\/mi5010013","relation":{},"ISSN":["2072-666X"],"issn-type":[{"type":"electronic","value":"2072-666X"}],"subject":[],"published":{"date-parts":[[2014,1,22]]}}}