Abstract
Cancer is the leading cause of death worldwide and its incidence is expected to rise. Despite overwhelming efforts to design innovative preclinical models that faithfully replicate disease ex vivo, some of them still lack central players in the tumor microenvironment (TME). The extracellular matrix (ECM), a major component of the TME, has a profound impact on cancer cells’ behavior and overall disease progression. Hydrogels hold great promise as tools for the in vitro modeling of tumors, as their versatility allows for the design of 3D cellular microenvironments with tunable biochemical/physical properties that mimic important features of the ECM. Thus, the use of engineered ECM-like hydrogels has been successfully translated into cancer research, providing improved 3D models to study tumor biology and response to therapy. This chapter provides an overview of 3D in vitro models for cancer research, with a focus on the use of polysaccharide-based bioengineered hydrogels as artificial ECMs.
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Akhtar MF, Hanif M, Ranjha NM. Methods of synthesis of hydrogels … A review. Saudi Pharm J. 2016; https://doi.org/10.1016/j.jsps.2015.03.022.
Augst AD, Kong HJ, Mooney DJ. Alginate hydrogels as biomaterials. Macromol Biosci. 2006; https://doi.org/10.1002/mabi.200600069.
Azouz AB, Vázquez M, Brabazon D. Developments of laser fabrication methods for lab-on-a-chip microfluidic multisensing devices. In: Hashmi S, Batalha GF, Van Tyne CJ, Yilbas B, editors. Comprehensive materials processing. Oxford: Elsevier; 2014. p. 447–58.
Bahcecioglu G, Basara G, Ellis BW, Ren X, Zorlutuna P. Breast cancer models: Engineering the tumor microenvironment. Acta Biomater. 2020; https://doi.org/10.1016/j.actbio.2020.02.006.
Bialkowska K, Komorowski P, Bryszewska M, Milowska K. Spheroids as a type of three-dimensional cell cultures-examples of methods of preparation and the most important application. Int J Mol Sci. 2020; https://doi.org/10.3390/ijms21176225.
Bidarra SJ, Barrias CC, Fonseca KB, Barbosa MA, Soares RA, Granja PL. Injectable in situ crosslinkable RGD-modified alginate matrix for endothelial cells delivery. Biomaterials. 2011; https://doi.org/10.1016/j.biomaterials.2011.07.013.
Bidarra SJ, Barrias CC, Granja PL. Injectable alginate hydrogels for cell delivery in tissue engineering. Acta Biomater. 2014; https://doi.org/10.1016/j.actbio.2013.12.006.
Bidarra SJ, Oliveira P, Rocha S, Saraiva DP, Oliveira C, Barrias CC. A 3D in vitro model to explore the inter-conversion between epithelial and mesenchymal states during EMT and its reversion. Sci Rep. 2016; https://doi.org/10.1038/srep27072.
Bombaldi de Souza RF, Bombaldi de Souza FC, Rodrigues C, Drouin B, Popat KC, Mantovani D, et al. Mechanically-enhanced polysaccharide-based scaffolds for tissue engineering of soft tissues. Mater Sci Eng C Mater Biol Appl. 2019; https://doi.org/10.1016/j.msec.2018.09.045.
Boucher Y, Baxter LT, Jain RK. Interstitial pressure gradients in tissue-isolated and subcutaneous tumors: implications for therapy. Cancer Res. 1990;50(15):4478–84.
Bray LJ, Werner C. Evaluation of three-dimensional in vitro models to study tumor angiogenesis. ACS Biomater Sci Eng. 2018; https://doi.org/10.1021/acsbiomaterials.7b00139.
Chan LW, Lee HY, Heng PWS. Mechanisms of external and internal gelation and their impact on the functions of alginate as a coat and delivery system. Carbohydr Polym. 2006; https://doi.org/10.1016/j.carbpol.2005.07.033.
Cui X, Hartanto Y, Zhang H. Advances in multicellular spheroids formation. J R Soc Interface. 2017; https://doi.org/10.1098/rsif.2016.0877.
David L, Dulong V, Le Cerf D, Chauzy C, Norris V, Delpech B, et al. Reticulated hyaluronan hydrogels: a model for examining cancer cell invasion in 3D. Matrix Biol. 2004; https://doi.org/10.1016/j.matbio.2004.05.005.
de Souza N. Organoids. Nat Methods. 2018; https://doi.org/10.1038/nmeth.4576.
Denton AE, Roberts EW, Fearon DT. Stromal cells in the tumor microenvironment. Adv Exp Med Biol. 2018; https://doi.org/10.1007/978-3-319-78127-3_6.
Dhand AP, Galarraga JH, Burdick JA. Enhancing biopolymer hydrogel functionality through interpenetrating networks. Trends Biotechnol. 2021; https://doi.org/10.1016/j.tibtech.2020.08.007.
Dovedytis M, Liu ZJ, Bartlett S. Hyaluronic acid and its biomedical applications: a review. Engineered Regeneration. 2020; https://doi.org/10.1016/j.engreg.2020.10.001.
Drost J, Clevers H. Organoids in cancer research. Nat Rev Cancer. 2018; https://doi.org/10.1038/s41568-018-0007-6.
Ermis M, Calamak S, Calibasi Kocal G, Guven S, Durmus NG, Rizvi I, et al. Hydrogels as a new platform to recapitulate the tumor microenvironment. In: Handbook of nanomaterials for cancer theranostics. Amsterdam: Elsevier; 2018. p. 463–94.
Fernández-Perianez R, Molina-Privado I, Rojo F, Guijarro-Munoz I, Alonso-Camino V, Zazo S, et al. Basement membrane-rich organoids with functional human blood vessels are permissive niches for human breast cancer metastasis. PLoS One. 2013; https://doi.org/10.1371/journal.pone.0072957.
Ferreira LP, Gaspar VM, Mano JF. Design of spherically structured 3D in vitro tumor models – advances and prospects. Acta Biomater. 2018; https://doi.org/10.1016/j.actbio.2018.05.034.
Fiorini GS, Chiu DT. Disposable microfluidic devices: fabrication, function, and application. BioTechniques. 2005; https://doi.org/10.2144/05383RV02.
Fong EL, Martinez M, Yang J, Mikos AG, Navone NM, Harrington DA, et al. Hydrogel-based 3D model of patient-derived prostate xenograft tumors suitable for drug screening. Mol Pharm. 2014; https://doi.org/10.1021/mp500085p.
Fontana F, Marzagalli M, Sommariva M, Gagliano N, Limonta P. In vitro 3D cultures to model the tumor microenvironment. Cancers. 2021; https://doi.org/10.3390/cancers13122970.
Goodarzi K, Rao SS. Hyaluronic acid-based hydrogels to study cancer cell behaviors. J Mater Chem B. 2021; https://doi.org/10.1039/d1tb00963j.
Gurski LA, Xu X, Labrada LN, Nguyen NT, Xiao L, van Golen KL, et al. Hyaluronan (HA) interacting proteins RHAMM and hyaluronidase impact prostate cancer cell behavior and invadopodia formation in 3D HA-based hydrogels. PLoS One. 2012; https://doi.org/10.1371/journal.pone.0050075.
Halldorsson S, Lucumi E, Gomez-Sjoberg R, Fleming RMT. Advantages and challenges of microfluidic cell culture in polydimethylsiloxane devices. Biosens Bioelectron. 2015; https://doi.org/10.1016/j.bios.2014.07.029.
Han SJ, Kwon S, Kim KS. Challenges of applying multicellular tumor spheroids in preclinical phase. Cancer Cell Int. 2021; https://doi.org/10.1186/s12935-021-01853-8.
Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000; https://doi.org/10.1016/s0092-8674(00)81683-9.
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011; https://doi.org/10.1016/j.cell.2011.02.013.
Hausman DM. What is cancer? Perspect Biol Med. 2019; https://doi.org/10.1353/pbm.2019.0046.
Hoarau-Vechot J, Rafii A, Touboul C, Pasquier J. Halfway between 2D and animal models: are 3D cultures the ideal tool to study cancer-microenvironment interactions? Int J Mol Sci. 2018; https://doi.org/10.3390/ijms19010181.
Hou G, Sun T, Qian J, Zhang Y, Guo M, Xu W, et al. Hydroxyethyl chitosan hydrogels for enhancing breast cancer cell tumorigenesis. Int J Biol Macromol. 2021; https://doi.org/10.1016/j.ijbiomac.2021.06.110.
Huerta-Reyes M, Aguilar-Rojas A. Three-dimensional models to study breast cancer (Review). Int J Oncol. 2021; https://doi.org/10.3892/ijo.2021.5176.
Hynes RO, Naba A. Overview of the matrisome--an inventory of extracellular matrix constituents and functions. Cold Spring Harb Perspect Biol. 2012; https://doi.org/10.1101/cshperspect.a004903.
Khan F, Ahmad SR. Polysaccharides and their derivatives for versatile tissue engineering application. Macromol Biosci. 2013; https://doi.org/10.1002/mabi.201200409.
Kim Y, Kumar S. CD44-mediated adhesion to hyaluronic acid contributes to mechanosensing and invasive motility. Mol Cancer Res. 2014; https://doi.org/10.1158/1541-7786.MCR-13-0629.
Kozlowski MT, Crook CJ, Ku HT. Towards organoid culture without Matrigel. Commun Biol. 2021; https://doi.org/10.1038/s42003-021-02910-8.
Kretzschmar K. Cancer research using organoid technology. J Mol Med (Berl). 2021; https://doi.org/10.1007/s00109-020-01990-z.
Kundu J, Pati F, Hun Jeong Y, Cho D-W. Chapter 2 – Biomaterials for biofabrication of 3D tissue scaffolds. In: Forgacs G, Sun W, editors. Biofabrication. Boston: William Andrew Publishing; 2013. p. 23–46.
Langhans SA. Three-dimensional in vitro cell culture models in drug discovery and drug repositioning. Front Pharmacol. 2018; https://doi.org/10.3389/fphar.2018.00006.
Lee KY, Mooney DJ. Alginate: properties and biomedical applications. Prog Polym Sci. 2012;37:106.
Lee J, Cuddihy MJ, Kotov NA. Three-dimensional cell culture matrices: state of the art. Tissue Eng Part B-Rev. 2008; https://doi.org/10.1089/teb.2007.0150.
Lewicki J, Bergman J, Kerins C, Hermanson O. Optimization of 3D bioprinting of human neuroblastoma cells using sodium alginate hydrogel. Bioprinting. 2019; https://doi.org/10.1016/j.bprint.2019.e00053.
Li YF, Kumacheva E. Hydrogel microenvironments for cancer spheroid growth and drug screening. Sci Adv. 2018; https://doi.org/10.1126/sciadv.aas8998.
Liaw CY, Ji S, Guvendiren M. Engineering 3D hydrogels for personalized in vitro human tissue models. Adv Healthc Mater. 2018; https://doi.org/10.1002/adhm.201701165.
Mak IWY, Evaniew N, Ghert M. Lost in translation: animal models and clinical trials in cancer treatment. Am J Transl Res. 2014;6(2):114–8.
Marrella A, Dondero A, Aiello M, Casu B, Olive D, Regis S, et al. Cell-laden hydrogel as a clinical-relevant 3D model for analyzing neuroblastoma growth, immunophenotype, and susceptibility to therapies. Front Immunol. 2019; https://doi.org/10.3389/fimmu.2019.01876.
Marrella A, Varani G, Aiello M, Vaccari I, Vitale C, Mojzisek M, et al. 3D fluid-dynamic ovarian cancer model resembling systemic drug administration for efficacy assay. ALTEX. 2021; https://doi.org/10.14573/altex.2003131.
Mehling M, Tay S. Microfluidic cell culture. Curr Opin Biotechnol. 2014; https://doi.org/10.1016/j.copbio.2013.10.005.
Moccia C, Haase K. Engineering breast cancer on-chip-moving toward subtype specific models. Front Bioeng Biotechnol. 2021; https://doi.org/10.3389/fbioe.2021.694218.
Morello G, Quarta A, Gaballo A, Moroni L, Gigli G, Polini A, et al. A thermo-sensitive chitosan/pectin hydrogel for long-term tumor spheroid culture. Carbohydr Polym. 2021; https://doi.org/10.1016/j.carbpol.2021.118633.
Nashimoto Y, Okada R, Hanada S, Arima Y, Nishiyama K, Miura T, et al. Vascularized cancer on a chip: the effect of perfusion on growth and drug delivery of tumor spheroid. Biomaterials. 2020; https://doi.org/10.1016/j.biomaterials.2019.119547.
Neves MI, Moroni L, Barrias CC. Modulating alginate hydrogels for improved biological performance as cellular 3D microenvironments. Front Bioeng Biotechnol. 2020; https://doi.org/10.3389/fbioe.2020.00665.
Nia HT, Munn LL, Jain RK. Physical traits of cancer. Science. 2020; https://doi.org/10.1126/science.aaz0868.
Nie M, Takeuchi S. Bottom-up biofabrication using microfluidic techniques. Biofabrication. 2018; https://doi.org/10.1088/1758-5090/aadef9.
Northcott JM, Dean IS, Mouw JK, Weaver VM. Feeling stress: the mechanics of cancer progression and aggression. Front Cell Dev Biol. 2018; https://doi.org/10.3389/fcell.2018.00017.
Ohlund D, Elyada E, Tuveson D. Fibroblast heterogeneity in the cancer wound. J Exp Med. 2014; https://doi.org/10.1084/jem.20140692.
Pan T, Fong EL, Martinez M, Harrington DA, Lin SH, Farach-Carson MC, et al. Three-dimensional (3D) culture of bone-derived human 786-O renal cell carcinoma retains relevant clinical characteristics of bone metastases. Cancer Lett. 2015; https://doi.org/10.1016/j.canlet.2015.05.019.
Qiao SP, Zhao YF, Li CF, Yin YB, Meng QY, Lin FH, et al. An alginate-based platform for cancer stem cell research. Acta Biomater. 2016; https://doi.org/10.1016/j.actbio.2016.04.032.
Raeisdasteh Hokmabad V, Davaran S, Ramazani A, Salehi R. Design and fabrication of porous biodegradable scaffolds: a strategy for tissue engineering. J Biomater Sci Polym Ed. 2017;28(16):1797–825.
Rajabi M, McConnell M, Cabral J, Ali MA. Chitosan hydrogels in 3D printing for biomedical applications. Carbohydr Polym. 2021; https://doi.org/10.1016/j.carbpol.2021.117768.
Rezakhani L, Alizadeh M, Alizadeh A. A three dimensional in vivo model of breast cancer using a thermosensitive chitosan-based hydrogel and 4 T1 cell line in Balb/c. J Biomed Mater Res A. 2021; https://doi.org/10.1002/jbm.a.37121.
Rodrigues J, Heinrich MA, Teixeira LM, Prakash J. 3D in vitro model (r)evolution: unveiling tumor-stroma interactions. Trends Cancer. 2021; https://doi.org/10.1016/j.trecan.2020.10.009.
Ruedinger F, Lavrentieva A, Blume C, Pepelanova I, Scheper T. Hydrogels for 3D mammalian cell culture: a starting guide for laboratory practice. Appl Microbiol Biotechnol. 2015; https://doi.org/10.1007/s00253-014-6253-y.
Samimi H, Sohi AN, Irani S, Arefian E, Mahdiannasser M, Fallah P, et al. Alginate-based 3D cell culture technique to evaluate the half-maximal inhibitory concentration: an in vitro model of anticancer drug study for anaplastic thyroid carcinoma. Thyroid Res. 2021; https://doi.org/10.1186/s13044-021-00118-w.
Seliktar D. Designing cell-compatible hydrogels for biomedical applications. Science. 2012; https://doi.org/10.1126/science.1214804.
Singh S, Tran S, Putman J, Tavana H. Three-dimensional models of breast cancer-fibroblasts interactions. Exp Biol Med (Maywood). 2020; https://doi.org/10.1177/1535370220917366.
Sobierajska K, Ciszewski WM, Sacewicz-Hofman I, Niewiarowska J. Endothelial cells in the tumor microenvironment. Adv Exp Med Biol. 2020; https://doi.org/10.1007/978-3-030-37184-5_6.
Soysal SD, Tzankov A, Muenst SE. Role of the tumor microenvironment in breast cancer. Pathobiology. 2015; https://doi.org/10.1159/000430499.
Suo A, Xu W, Wang Y, Sun T, Ji L, Qian J. Dual-degradable and injectable hyaluronic acid hydrogel mimicking extracellular matrix for 3D culture of breast cancer MCF-7 cells. Carbohydr Polym. 2019; https://doi.org/10.1016/j.carbpol.2019.01.115.
Szekalska M, Pucitowska A, Szymanska E, Ciosek P, Winnicka K. Alginate: current use and future perspectives in pharmaceutical and biomedical applications. Int J Polym Sci. 2016; https://doi.org/10.1155/2016/7697031.
Tabriz AG, Hermida MA, Leslie NR, Shu W. Three-dimensional bioprinting of complex cell laden alginate hydrogel structures. Biofabrication. 2015; https://doi.org/10.1088/1758-5090/7/4/045012.
Tan H, Chu CR, Payne KA, Marra KG. Injectable in situ forming biodegradable chitosan- hyaluronic acid based hydrogels for cartilage tissue engineering. Biomaterials. 2009; https://doi.org/10.1016/j.biomaterials.2008.12.080.
Tang YD, Huang BX, Dong YQ, Wang WL, Zheng X, Zhou W, et al. Three-dimensional prostate tumor model based on a hyaluronic acid-alginate hydrogel for evaluation of anti-cancer drug efficacy. J Biomater Sci Polym Ed. 2017; https://doi.org/10.1080/09205063.2017.1338502.
Tanzi MC, Farè S, Candiani G. Chapter 1 – Organization, structure, and properties of materials. In: Tanzi MC, Farè S, Candiani G, editors. Foundations of biomaterials engineering. London: Academic; 2019. p. 3–103.
Teixeira FC, Chaves S, Torres AL, Barrias CC, Bidarra SJ. Engineering a vascularized 3D hybrid system to model tumor-stroma interactions in breast cancer. Front Bioeng Biotechnol. 2021; https://doi.org/10.3389/fbioe.2021.647031.
Tian L, George SC. Biomaterials to prevascularize engineered tissues. J Cardiovasc Transl Res. 2011; https://doi.org/10.1007/s12265-011-9301-3.
Truong DD, Kratz A, Park JG, Barrientos ES, Saini H, Nguyen T, et al. A human organotypic microfluidic tumor model permits investigation of the interplay between patient-derived fibroblasts and breast cancer cells. Cancer Res. 2019; https://doi.org/10.1158/0008-5472.CAN-18-2293.
Tuveson D, Clevers H. Cancer modeling meets human organoid technology. Science. 2019; https://doi.org/10.1126/science.aaw6985.
Varmus H. The new era in cancer research. Science. 2006; https://doi.org/10.1126/science.1126758.
Wang M, Guo L, Sun H. Manufacture of biomaterials. In: Narayan R, editor. Encyclopedia of biomedical engineering. Oxford: Elsevier; 2019. p. 116–34.
Wang Y, Tian F, Duan Y, Li Z, Chen Q, Chen J, et al. In vitro 3D cocultured tumor-vascular barrier model based on alginate hydrogel and Transwell system for anti-cancer drug evaluation. Tissue Cell. 2022; https://doi.org/10.1016/j.tice.2022.101796.
Xu X, Gurski LA, Zhang C, Harrington DA, Farach-Carson MC, Jia X. Recreating the tumor microenvironment in a bilayer, hyaluronic acid hydrogel construct for the growth of prostate cancer spheroids. Biomaterials. 2012; https://doi.org/10.1016/j.biomaterials.2012.08.061.
Yang L, Yang S, Li X, Li B, Li Y, Zhang X, et al. Tumor organoids: from inception to future in cancer research. Cancer Lett. 2019; https://doi.org/10.1016/j.canlet.2019.04.005.
Yilmaz O, Sakarya S. Is ‘Hanging Drop’ a useful method to form spheroids of Jimt, Mcf-7, T- 47d, Bt-474 that are breast cancer cell lines. Single Cell Biol. 2018; https://doi.org/10.4172/2168-9431.1000170.
Zanotelli MR, Reinhart-King CA. Mechanical forces in tumor angiogenesis. Adv Exp Med Biol. 2018; https://doi.org/10.1007/978-3-319-95294-9_6.
Zhao Q, Cui H, Wang Y, Du X. Microfluidic platforms toward rational material fabrication for biomedical applications. Small. 2020; https://doi.org/10.1002/smll.201903798.
Acknowledgments
The authors would like to acknowledge Fundo Europeu de Desenvolvimento Regional (FEDER) funds through the COMPETE 2020-Operational Programme for Competitiveness and Internationalization (POCI), Portugal 2020, and Portuguese funds through FCT-Fundação para a Ciência e a Tecnologia/Ministério da Ciência, Tecnologia e Ensino Superior, in the framework of Project ANGIONICHE (P0CI-01-0145-FEDER-028744 and PTDC/BTMMAT/28744/2017). The authors thank FCT for research contract DL 57/2016/CP1360/CT0006 (SJB) and scholarship Grant No. SFRH/BD/10184/2022 (MVM).
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Magalhães, M.V., Coutinho, I., Barrias, C.C., Bidarra, S.J. (2023). Polysaccharide-Based Hydrogels for Bioengineering 3D Tumor Models. In: Maia, F.R.A., Oliveira, J.M., Reis, R.L. (eds) Handbook of the Extracellular Matrix. Springer, Cham. https://doi.org/10.1007/978-3-030-92090-6_22-1
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