Hostname: page-component-77c89778f8-m42fx Total loading time: 0 Render date: 2024-07-23T02:19:36.323Z Has data issue: false hasContentIssue false

Spatially graded hydrogels for preclinical testing of glioblastoma anticancer therapeutics

Published online by Cambridge University Press:  12 September 2017

S. Pedron
Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, 1206 West Gregory Drive, Urbana, IL 61801, USA
H. Polishetty
Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, 1206 West Gregory Drive, Urbana, IL 61801, USA
A.M. Pritchard
Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, 1206 West Gregory Drive, Urbana, IL 61801, USA
B.P. Mahadik
Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, 1206 West Gregory Drive, Urbana, IL 61801, USA
J.N. Sarkaria
Department of Radiation Oncology, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA
B.A.C. Harley*
Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, 1206 West Gregory Drive, Urbana, IL 61801, USA Department of Chemical and Biomolecular Engineering, Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, 110 Roger Adams Lab., 600 S. Mathews Avenue, Urbana, IL 61801, USA
Address all correspondence to B.A.C. Harley at
Get access


While preclinical models such as orthotopic tumors generated in mice from patient-derived specimens are widely used to predict sensitivity or therapeutic interventions for cancer, such xenografts can be slow, require extensive infrastructure, and can make in situ assessment difficult. Such concerns are heightened in highly aggressive cancers, such as glioblastoma (GBM), that display genetic diversity and short mean survival. Biomimetic biomaterial technologies offer an approach to create ex vivo models that reflect biophysical features of the tumor microenvironment (TME). We describe a microfluidic templating approach to generate spatially graded hydrogels containing patient-derived GBM cells to explore drug efficacy and resistance mechanisms.

Biomaterials for 3D Cell Biology Research Letters
Copyright © Materials Research Society 2017 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)


1.Louis, D.N., Perry, A., Reifenberger, G., von Deimling, A., Figarella-Branger, D., Cavenee, W.K., Ohgaki, H., Wiestler, O.D., Kleihues, P., and Ellison, D.W.: The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol. 131, 803 (2016).Google Scholar
2.Furnari, F.B., Fenton, T., Bachoo, R.M., Mukasa, A., Stommel, J.M., Stegh, A., Hahn, W.C., Ligon, K.L., Louis, D.N., Brennan, C., Chin, L., DePinho, R.A., and Cavenee, W.K.: Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes Dev. 21, 2683 (2007).Google Scholar
3.Johnson, D.R. and O'Neill, B.P.: Glioblastoma survival in the United States before and during the temozolomide era. J. Neurooncol. 107, 359 (2012).Google Scholar
4.Charles, N.A., Holland, E.C., Gilbertson, R., Glass, R., and Kettenmann, H.: The brain tumor microenvironment. Glia 59, 1169 (2011).Google Scholar
5.Jackson, C., Ruzevick, J., Phallen, J., Belcaid, Z., and Lim, M.: Challenges in immunotherapy presented by the glioblastoma multiforme microenvironment. Clin. Dev. Immunol. 2011, 20 (2011).Google Scholar
6.Stupp, R., Mason, W.P., van den Bent, M.J., Weller, M., Fisher, B., Taphoorn, M.J., Belanger, K., Brandes, A.A., Marosi, C., Bogdahn, U., Curschmann, J., Janzer, R.C., Ludwin, S.K., Gorlia, T., Allgeier, A., Lacombe, D., Cairncross, J.G., Eisenhauer, E., and Mirimanoff, R.O.: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N. Engl. J. Med. 352, 987 (2005).Google Scholar
7.Okada, M., Saio, M., Kito, Y., Ohe, N., Yano, H., Yoshimura, S., Iwama, T., and Takami, T.: Tumor-associated macrophage/microglia infiltration in human gliomas is correlated with MCP-3, but not MCP-1. Int. J. Oncol. 34, 1621 (2009).Google Scholar
8.Lathia, J.D., Mack, S.C., Mulkearns-Hubert, E.E., Valentim, C.L., and Rich, J.N.: Cancer stem cells in glioblastoma. Genes Dev. 29, 1203 (2015).Google Scholar
9.Thaker, N.G. and Pollack, I.F.: Molecularly targeted therapies for malignant glioma: rationale for combinatorial strategies. Expert Rev. Neurother. 9, 1815 (2009).Google Scholar
10.Huang, T.T., Sarkaria, S.M., Cloughesy, T.F., and Mischel, P.S.: Targeted therapy for malignant glioma patients: lessons learned and the road ahead. Neurotherapeutics 6, 500 (2009).Google Scholar
11.Misra, S., Toole, B.P., and Ghatak, S.: Hyaluronan constitutively regulates activation of multiple receptor tyrosine kinases in epithelial and carcinoma cells. J. Biol. Chem. 281, 34936 (2006).Google Scholar
12.Rape, A., Ananthanarayanan, B., and Kumar, S.: Engineering strategies to mimic the glioblastoma microenvironment. Adv. Drug Delivery. Rev. 79–80, 172 (2014).Google Scholar
13.Roth, P. and Weller, M.: Challenges to targeting epidermal growth factor receptor in glioblastoma: escape mechanisms and combinatorial treatment strategies. Neuro Oncol. 16, viii14 (2014).Google Scholar
14.Taylor, T.E., Furnari, F.B., and Cavenee, W.K.: Targeting EGFR for treatment of glioblastoma: molecular basis to overcome resistance. Curr. Cancer Drug Targets 12, 197 (2012).Google Scholar
15.Schulte, A., Liffers, K., Kathagen, A., Riethdorf, S., Zapf, S., Merlo, A., Kolbe, K., Westphal, M., and Lamszus, K.: Erlotinib resistance in EGFR-amplified glioblastoma cells is associated with upregulation of EGFRvIII and PI3Kp110δ. Neuro Oncol. 15, 1289 (2013).Google Scholar
16.Slomiany, M.G., Dai, L., Bomar, P.A., Knackstedt, T.J., Kranc, D.A., Tolliver, L., Maria, B.L., and Toole, B.P.: Abrogating drug resistance in malignant peripheral nerve sheath tumors by disrupting hyaluronan-CD44 interactions with small hyaluronan oligosaccharides. Cancer Res. 69, 4992 (2009).Google Scholar
17.Pedron, S., Becka, E., and Harley, B.A.: Spatially gradated hydrogel platform as a 3D engineered tumor microenvironment. Adv. Mater. 27, 1567 (2015).Google Scholar
18.Heddleston, J.M., Hitomi, M., Venere, M., Flavahan, W.A., Yan, K., Kim, Y., Minhas, S., Rich, J.N., and Hjelmeland, A.B.: Glioma stem cell maintenance: the role of the microenvironment. Curr. Pharm. Des. 17, 2386 (2011).Google Scholar
19.Verhaak, R.G.W., Hoadley, K.A., Purdom, E., Wang, V., Qi, Y., Wilkerson, M.D., Miller, C.R., Ding, L., Golub, T., Mesirov, J.P., Alexe, G., Lawrence, M., O'Kelly, M., Tamayo, P., Weir, B.A., Gabriel, S., Winckler, W., Gupta, S., Jakkula, L., Feiler, H.S., Hodgson, J.G., James, C.D., Sarkaria, J.N., Brennan, C., Kahn, A., Spellman, P.T., Wilson, R.K., Speed, T.P., Gray, J.W., Meyerson, M., Getz, G., Perou, C.M., Hayes, D.N., and Canc Genome Atlas Res, N.: Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17, 98 (2010).Google Scholar
20.Westermark, B.: Glioblastoma—a moving target. Ups. J. Med. Sci. 117, 251 (2012).Google Scholar
21.Hambardzumyan, D., Cheng, Y.-K., Haeno, H., Holland, E.C., and Michor, F.: The probable cell of origin of NF1- and PDGF-driven glioblastomas. PLoS ONE 6, e24454 (2011).Google Scholar
22.Labussiere, M., Sanson, M., Idbaih, A., and Delattre, J.Y.: IDH1 gene mutations: a new paradigm in glioma prognosis and therapy? Oncologist 15, 196 (2010).Google Scholar
23.Rich, J.N., Hans, C., Jones, B., Iversen, E.S., McLendon, R.E., Rasheed, B.K., Dobra, A., Dressman, H.K., Bigner, D.D., Nevins, J.R., and West, M.: Gene expression profiling and genetic markers in glioblastoma survival. Cancer Res. 65, 4051 (2005).Google Scholar
24.Sarkaria, J.N., Yang, L., Grogan, P.T., Kitange, G.J., Carlson, B.L., Schroeder, M.A., Galanis, E., Giannini, C., Wu, W., Dinca, E.B., and James, C.D.: Identification of molecular characteristics correlated with glioblastoma sensitivity to EGFR kinase inhibition through use of an intracranial xenograft test panel. Mol. Cancer Ther. 6, 1167 (2007).Google Scholar
25.Sarkaria, J.N., Carlson, B.L., Schroeder, M.A., Grogan, P., Brown, P.D., Giannini, C., Ballman, K.V., Kitange, G.J., Guha, A., Pandita, A., and James, C.D.: Use of an orthotopic xenograft model for assessing the effect of epidermal growth factor receptor amplification on glioblastoma radiation response. Clin. Cancer Res. 12, 2264 (2006).Google Scholar
26.Giannini, C., Sarkaria, J.N., Saito, A., Uhm, J.H., Galanis, E., Carlson, B.L., Schroeder, M.A., and James, C.D.: Patient tumor EGFR and PDGFRA gene amplifications retained in an invasive intracranial xenograft model of glioblastoma multiforme. Neuro Oncol. 7, 164 (2005).Google Scholar
27.Pedron, S., Becka, E., and Harley, B.A.C.: Regulation of glioma cell phenotype in 3D matrices by hyaluronic acid. Biomaterials 34, 7408 (2013).Google Scholar
28.Mahadik, B.P., Wheeler, T.D., Skertich, L.J., Kenis, P.J., and Harley, B.A.: Microfluidic generation of gradient hydrogels to modulate hematopoietic stem cell culture environment. Adv. Healthc. Mater. 3, 449 (2014).Google Scholar
29.Mahadik, B.P., Pedron Haba, S., Skertich, L.J., and Harley, B.A.C.: The use of covalently immobilized stem cell factor to selectively affect hematopoietic stem cell activity within a gelatin hydrogel. Biomaterials 67, 297 (2015).Google Scholar
30.Mosmann, T.: Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J. Immunol. Methods 65, 55 (1983).Google Scholar
31.Duffy, G.P., McFadden, T.M., Byrne, E.M., Gill, S.L., Farrell, E., and O'Brien, F.J.: Towards in vitro vascularisation of collagen-GAG scaffolds. Eur. Cells Mater. 21, 15 (2011).Google Scholar
32.Livak, K.J. and Schmittgen, T.D.: Analysis of relative gene expression data using real-time quantitative PCR and the 2(T)(-Delta Delta C) method. Methods 25, 402 (2001).Google Scholar
33.Wiranowska, M.R. and Rojiani, M. V.: Extracellular matrix microenvironment in glioma progression, in Glioma—Exploring Its Biology and Practical Relevance, edited by Ghosh, A. (InTech, Rijeka, Croatia, 2011), p. 257.Google Scholar
34.Endersby, R. and Baker, S.J.: PTEN signaling in brain: neuropathology and tumorigenesis. Oncogene 27, 5416 (2008).Google Scholar
35.Perez, A., Neskey, D.M., Wen, J., Pereira, L., Reategui, E.P., Goodwin, W.J., Carraway, K.L., and Franzmann, E.J.: CD44 interacts with EGFR and promotes head and neck squamous cell carcinoma initiation and progression. Oral Oncol. 49, 306 (2013).Google Scholar
36.Cha, J., Kang, S.-G., and Kim, P.: Strategies of mesenchymal invasion of patient-derived brain tumors: microenvironmental adaptation. Sci. Rep. 6, 24912 (2016).Google Scholar
37.Toole, B.P.: Hyaluronan: from extracellular glue to pericellular cue. Nat. Rev. Cancer 4, 528 (2004).Google Scholar
38.Tsatas, D., Kanagasundaram, V., Kaye, A., and Novak, U.: EGF receptor modifies cellular responses to hyaluronan in glioblastoma cell lines. J. Clin. Neurosci. 9, 282 (2002).Google Scholar
39.Chen, J.-W., Pedron, S. and Harley, B.A.C.: The combined influence of hydrogel stiffness and matrix-bound hyaluronic acid content on glioblastoma invasion. Macromol. Biosci. 17, 1616 (2017).Google Scholar
40.Klank, R.L., Decker Grunke, S.A., Bangasser, B.L., Forster, C.L., Price, M.A., Odde, T.J., SantaCruz, K.S., Rosenfeld, S.S., Canoll, P., Turley, E.A., McCarthy, J.B., Ohlfest, J.R., and Odde, D.J.: Biphasic dependence of glioma survival and cell migration on CD44 expression level. Cell Rep. 18, 23.Google Scholar
41.Mendelsohn, J. and Baselga, J.: Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. J. Clin. Oncol. 21, 2787 (2003).Google Scholar
42.Akita, R.W. and Sliwkowski, M.X.: Preclinical studies with erlotinib (Tarceva). Semin. Oncol. 30, 15 (2003).Google Scholar
43.Wang, S.J. and Bourguignon, L.Y.W.: Role of hyaluronan-mediated CD44 signaling in head and neck squamous cell carcinoma progression and chemoresistance. Am. J. Pathol. 178, 956 (2011).Google Scholar
44.Holohan, C., Van Schaeybroeck, S., Longley, D.B., and Johnston, P.G.: Cancer drug resistance: an evolving paradigm. Nat. Rev. Cancer 13, 714 (2013).Google Scholar
45.Ohashi, R., Takahashi, F., Cui, R., Yoshioka, M., Gu, T., Sasaki, S., Tominaga, S., Nishio, K., Tanabe, K.K., and Takahashi, K.: Interaction between CD44 and hyaluronate induces chemoresistance in non-small cell lung cancer cell. Cancer Lett. 252, 225 (2007).Google Scholar
Supplementary material: PDF

Pedron et al supplementary material 1

Pedron et al supplementary material

Download Pedron et al supplementary material 1(PDF)
PDF 208.9 KB