Abstract
The extracellular matrix (ECM) plays an active role in tumor progression. Increasing evidence points out a permissive tumor microenvironment that enhances malignancy and makes drug targeting a more difficult task. Protein-based materials as a substrate for cell culture hydrogels offer the advantage of having the presence of cell-responsive sequences as opposed to synthetic polymer-based hydrogels. This is important for cancer research to evaluate different aspects of tumor proliferation, such as cell growth, cell adhesion, and cell invasion. The gold standard for protein-based hydrogels has been Matrigel. However, its ill-defined nature, low reproducibility, and weak mechanical properties do not make it an ideal scaffold for more rigorous cancer research – especially in the mechanotransduction field. Therefore, alternatives are very much in need. Herein, it is presented the main proteinaceous materials used as scaffolds to model tumor development: collagen, gelatin, fibrin, and silk fibroin.
This is a preview of subscription content, log in via an institution to check access.
References
Ahn JB, Ha TK, Kwon SJ. Bone metastasis in gastric cancer patients. J Gastric Cancer. 2011;11(1):38–45. https://doi.org/10.5230/jgc.2011.11.1.38.
Ahn J, Lim J, Jusoh N, Lee J, Park TE, Kim YT, Kim J, Jeon NL. 3D microfluidic bone tumor microenvironment comprised of hydroxyapatite/fibrin composite. Front Bioeng Biotechnol. 2019;7(Jul):1–13. https://doi.org/10.3389/fbioe.2019.00168.
Augustine R, Zahid AA, Mraiche F, Alam K, Al Moustafa AE, Hasan A. Gelatin-methacryloyl hydrogel based in vitro blood–brain barrier model for studying breast cancer-associated brain metastasis. Pharm Dev Technol. 2021;26(4):490–500. https://doi.org/10.1080/10837450.2021.1872624.
Baek SJ, Hur H, Min BS, Baik SH, Lee KY, Kim NK. The characteristics of bone metastasis in patients with colorectal cancer: a long-term report from a single institution. World J Surg. 2016;40(4):982–6. https://doi.org/10.1007/s00268-015-3296-x.
Berger AJ, Renner CM, Hale I, Yang X, Ponik SM, Weisman PS, Masters KS, Kreeger PK. Scaffold stiffness influences breast cancer cell invasion via EGFR-linked Mena upregulation and matrix remodeling. Matrix Biol. 2020;85–86(3):80–93. https://doi.org/10.1016/j.matbio.2019.07.006.
Bhattacharjee S, Hamberger F, Ravichandra A, Miller M, Nair A, Affo S, Filliol A, et al. Tumor restriction by type I collagen opposes tumor-promoting effects of cancer-associated fibroblasts. J Clin Investig. 2021;131(11):1–17. https://doi.org/10.1172/JCI146987.
Broders-Bondon F, Ho-Bouldoires THN, Fernandez-Sanchez ME, Farge E. Mechanotransduction in tumor progression: the dark side of the force. J Cell Biol. 2018;217(5):1571–87. https://doi.org/10.1083/jcb.201701039.
Carvalho MR, Maia FR, Vieira S, Reis RL, Oliveira JM. Tuning enzymatically crosslinked silk fibroin hydrogel properties for the development of a colorectal cancer extravasation 3D model on a Chip. Global Chall. 2018;2(5–6):1700100. https://doi.org/10.1002/gch2.201700100.
Chen JWE, Lumibao J, Leary S, Sarkaria JN, Steelman AJ, Gaskins HR, Harley BAC. Crosstalk between microglia and patient-derived glioblastoma cells inhibit invasion in a three-dimensional gelatin hydrogel model. J Neuroinflammation. 2020;17(1):1–15. https://doi.org/10.1186/s12974-020-02026-6.
Cox TR. The matrix in cancer. Nat Rev Cancer. 2021;21(4):217–38. https://doi.org/10.1038/s41568-020-00329-7.
Curtis KJ, Schiavi J, Mc Garrigle MJ, Kumar V, McNamara LM, Niebur GL. Mechanical stimuli and matrix properties modulate cancer spheroid growth in three-dimensional gelatin culture. J R Soc Interface. 2020;17(173):20200568. https://doi.org/10.1098/rsif.2020.0568.
Curvello R, Kast V, Abuwarwar MH, Fletcher AL, Garnier G, Loessner D. 3D collagen-nanocellulose matrices model the tumour microenvironment of pancreatic cancer. Front Digit Health. 2021;3(Jul):1–13. https://doi.org/10.3389/fdgth.2021.704584.
Geiger F, Rüdiger D, Zahler S, Engelke H. Fiber stiffness, pore size and adhesion control migratory phenotype of MDA-MB-231 cells in collagen gels. PLoS One. 2019;14(11):1–13. https://doi.org/10.1371/journal.pone.0225215.
Gong X, Kulwatno J, Mills KL. Rapid fabrication of collagen bundles mimicking tumor-associated collagen architectures. Acta Biomater. 2020;108:128–41. https://doi.org/10.1016/j.actbio.2020.03.019.
Huang W, Hu H, Zhang Q, Wu X, Wei F, Yang F, Gan L, Wang N, Yang X, Guo AY. Regulatory networks in mechanotransduction reveal key genes in promoting cancer cell stemness and proliferation. Oncogene. 2019;38(42):6818–34. https://doi.org/10.1038/s41388-019-0925-0.
James-Bhasin M, Siegel PM, Nazhat SN. A three-dimensional dense collagen hydrogel to model cancer cell/osteoblast interactions. J Funct Biomater. 2018;9(4):72. https://doi.org/10.3390/jfb9040072.
Khoo AS, Valentin TM, Leggett SE, Bhaskar D, Bye EM, Benmelech S, Ip BC, Wong IY. Breast cancer cells transition from mesenchymal to amoeboid migration in tunable three-dimensional silk–collagen hydrogels. ACS Biomater Sci Eng. 2019;5(9):4341–54. https://doi.org/10.1021/acsbiomaterials.9b00519.
Kim UJ, Park J, Li C, Jin HJ, Valluzzi R, Kaplan DL. Structure and properties of silk hydrogels. Biomacromolecules. 2004;5(3):786–92. https://doi.org/10.1021/bm0345460.
Kochhar D, DeBari MK, Abbott RD. The materiobiology of silk: exploring the biophysical influence of silk biomaterials on directing cellular behaviors. Front Bioeng Biotechnol. 2021;9(Jun):1–11. https://doi.org/10.3389/fbioe.2021.697981.
Kundu B, Bastos ARF, Brancato V, Cerqueira MT, Oliveira JM, Correlo VM, Reis RL, Kundu SC. Mechanical property of hydrogels and the presence of adipose stem cells in tumor stroma affect spheroid formation in the 3D osteosarcoma model. ACS Appl Mater Interfaces. 2019;11(16):14548–59. https://doi.org/10.1021/acsami.8b22724.
Kwaan HC, Lindholm PF. Fibrin and fibrinolysis in cancer. Semin Thromb Hemost. 2019;45(04):413–22. https://doi.org/10.1055/s-0039-1688495.
Kwak TJ, Lee E. In vitro modeling of solid tumor interactions with perfused blood vessels. Sci Rep. 2020;10(1):1–9. https://doi.org/10.1038/s41598-020-77180-1.
Le CC, Bennasroune A, Langlois B, Salesse S, Boulagnon-Rombi C, Morjani H, Dedieu S, Appert-Collin A. Functional interplay between collagen network and cell behavior within tumor microenvironment in colorectal cancer. Front Oncol. 2020;10(Apr):1–8. https://doi.org/10.3389/fonc.2020.00527.
Li ZL, Wang ZJ, Wei GH, Yang Y, Wang XW. Changes in extracellular matrix in different stages of colorectal cancer and their effects on proliferation of cancer cells. World J Gastrointest Oncol. 2020;12(3):267–75. https://doi.org/10.4251/WJGO.V12.I3.267.
Liaw CY, Ji S, Guvendiren M. Engineering 3D hydrogels for personalized in vitro human tissue models. Adv Healthc Mater. 2018;7(4):1–16. https://doi.org/10.1002/adhm.201701165.
Liu J, Tan Y, Zhang H, Zhang Y, Xu P, Chen J, Poh Y-C, Tang K, Wang N, Huang B. Soft fibrin gels promote selection and growth of tumorigenic cells. Nat Mater. 2012;11(8):734–41. https://doi.org/10.1038/nmat3361.
Lu P, Weaver VM, Werb Z. The extracellular matrix: A dynamic niche in cancer progression. J Cell Biol. 2012;196(4):395–406. https://doi.org/10.1083/jcb.201102147.
McGill M, Grant JM, Kaplan DL. Enzyme-mediated conjugation of peptides to silk fibroin for facile hydrogel functionalization. Ann Biomed Eng. 2020;48(7):1905–15. https://doi.org/10.1007/s10439-020-02503-2.
Micek HM, Visetsouk MR, Masters KS, Kreeger PK. Engineering the extracellular matrix to model the evolving tumor microenvironment. iScience. 2020;23(11):101742. https://doi.org/10.1016/j.isci.2020.101742.
Mohseni Garakani M, Ahangar P, Watson S, Nisol B, Wertheimer MR, Rosenzweig DH, Ajji A. A novel 3D co-culture platform for integrating tissue interfaces for tumor growth, migration and therapeutic sensitivity: ‘PP-3D-S’. Mater Sci Eng C. 2021;Sept:112566. https://doi.org/10.1016/j.msec.2021.112566.
Moon S, Ok Y, Hwang S, Lim YS, Kim HY, Na YJ, Yoon S. A marine collagen-based biomimetic hydrogel recapitulates cancer stem cell niche and enhances progression and chemoresistance in human ovarian cancer. Mar Drugs. 2020;18(10):498. https://doi.org/10.3390/md18100498.
Ng S, Tan WJ, Pek MMX, Tan MH, Kurisawa M. Mechanically and chemically defined hydrogel matrices for patient-derived colorectal tumor organoid culture. Biomaterials. 2019;219(Jul):119400. https://doi.org/10.1016/j.biomaterials.2019.119400.
Nia HT, Munn LL, Jain RK. Physical traits of cancer. Science. 2020;370(1):6516. https://doi.org/10.1126/science.aaz0868.Physical.
Nissen NI, Karsdal M, Willumsen N. Collagens and cancer associated fibroblasts in the reactive stroma and its relation to cancer biology. J Exp Clin Cancer Res. 2019;38(1):1–12. https://doi.org/10.1186/s13046-019-1110-6.
Noori A, Ashrafi SJ, Vaez-Ghaemi R, Hatamian-Zaremi A, Webster TJ. A review of fibrin and fibrin composites for bone tissue engineering. Int J Nanomedicine. 2017;12:4937–61. https://doi.org/10.2147/IJN.S124671.
Pedron S, Wolter GL, Chen J-WE, Laken SE, Sarkaria JN, Harley BAC. Hyaluronic acid-functionalized gelatin hydrogels reveal extracellular matrix signals temper the efficacy of erlotinib against patient-derived glioblastoma specimens. Biomaterials. 2019;219(5):119371. https://doi.org/10.1016/j.biomaterials.2019.119371.
Peter M, Singh A, Mohankumar K, Jeenger R, Joge PA, Gatne MM, Tayalia P. Gelatin-based matrices as a tunable platform to study in vitro and in vivo 3D cell invasion. Research-article. ACS Appl Bio Mater. 2019;2(2):916–29. https://doi.org/10.1021/acsabm.8b00767.
Pierantoni L, Ribeiro VP, Costa L, Pina S, da Silva Morais A, Silva-Correia J, Kundu SC, Motta A, Reis RL, Oliveira JM. Horseradish peroxidase-crosslinked calcium-containing silk fibroin hydrogels as artificial matrices for bone cancer research. Macromol Biosci. 2021;21(4):1–7. https://doi.org/10.1002/mabi.202000425.
Quarta A, Gallo N, Vergara D, Salvatore L, Nobile C, Ragusa A, Gaballo A. Investigation on the composition of agarose–collagen I blended hydrogels as matrices for the growth of spheroids from breast cancer cell lines. Pharmaceutics. 2021;13(7):963. https://doi.org/10.3390/pharmaceutics13070963.
Reynolds DS, Bougher KM, Letendre JH, Fitzgerald SF, Gisladottir UO, Grinstaff MW, Zaman MH. Mechanical confinement via a PEG/collagen interpenetrating network inhibits behavior characteristic of malignant cells in the triple negative breast cancer cell line MDA.MB.231. Acta Biomater. 2018;77(1):85–95. https://doi.org/10.1016/j.actbio.2018.07.032.
Ribeiro VP, Silva-Correia J, Gonçalves C, Pina S, Radhouani H, Montonen T, Hyttinen J, et al. Rapidly responsive silk fibroin hydrogels as an artificial matrix for the programmed tumor cells death. PLoS One. 2018;13(4):1–21. https://doi.org/10.1371/journal.pone.0194441.
Salahuddin B, Wang S, Sangian D, Aziz S, Gu Q. Hybrid gelatin hydrogels in nanomedicine applications. ACS Appl Bio Mater. 2021;4(4):2886–906. https://doi.org/10.1021/acsabm.0c01630.
Shang M, Soon RH, Lim CT, Khoo BL, Han J. Microfluidic modelling of the tumor microenvironment for anti-cancer drug development. Lab Chip. 2019;19(3):369–86. https://doi.org/10.1039/c8lc00970h.
Skardal A, Shupe T, Atala A. Organoid-on-a-chip and body-on-a-chip systems for drug screening and disease modeling. Drug Discov Today. 2016;21(9):1399–411. https://doi.org/10.1016/j.drudis.2016.07.003.
Tang X, Kuhlenschmidt TB, Li Q, Ali S, Lezmi S, Chen H, Pires-Alves M, Laegreid WW, Saif TA, Kuhlenschmidt MS. A mechanically-induced colon cancer cell population shows increased metastatic potential. Mol Cancer. 2014;13(1):1–15. https://doi.org/10.1186/1476-4598-13-131.
Unnikrishnan K, Thomas LV, Kumar RMR. Advancement of scaffold-based 3D cellular models in cancer tissue engineering: an update. Front Oncol. 2021;11(Oct):1–11. https://doi.org/10.3389/fonc.2021.733652.
Valente KP, Thind SS, Akbari M, Suleman A, Brolo AG. Collagen type I-gelatin methacryloyl composites: mimicking the tumor microenvironment. Research-article. ACS Biomat Sci Eng. 2019;5:2887–98. https://doi.org/10.1021/acsbiomaterials.9b00264.
Vepari C, Kaplan DL. Silk as a biomaterial. Prog Polym Sci. 2007;32(8–9):991–1007. https://doi.org/10.1016/j.progpolymsci.2007.05.013.
Vitale C, Fedi A, Marrella A, Varani G, Fato M, Scaglione S. 3D perfusable hydrogel recapitulating the cancer dynamic environment to in vitro investigate metastatic colonization. Polymers. 2020;12(11):1–19. https://doi.org/10.3390/polym12112467.
Weisel JW, Litvinov RI. Fibrin formation, structure and properties. In: Parry DAD, Squire JM, editors. Physiology & behavior, Subcellular biochemistry 82. Cham: Springer International Publishing; 2017. p. 405–56. https://doi.org/10.1007/978-3-319-49674-0_13.
Xu S, Xu H, Wang W, Li S, Li H, Li T, Zhang W, Yu X, Liu L. The role of collagen in cancer: from bench to bedside. J Transl Med. 2019;17(1):1–22. https://doi.org/10.1186/s12967-019-2058-1.
Yan LP, Silva-Correia J, Ribeiro VP, Miranda-Goncąlves V, Correia C, Morais ADS, Sousa RA, et al. Tumor growth suppression induced by biomimetic silk fibroin hydrogels. Sci Rep. 2016;6(Aug):1–11. https://doi.org/10.1038/srep31037.
Zhang M, Xu C, Wang H z, Peng Y n, Li H o, Zhou Y j, Liu S, et al. Soft fibrin matrix downregulates DAB2IP to promote Nanog-dependent growth of colon tumor-repopulating cells. Cell Death Dis. 2019;10(3):151. https://doi.org/10.1038/s41419-019-1309-7.
Acknowledgments
The authors thank Project “HEALTH-UNORTE: Setting-up biobanks and regenerative medicine strategies to boost research in cardiovascular, musculoskeletal, neurological, oncological, immunological and infectious diseases”, ref. NORTE-01-0145-FEDER-000039 funded under the program NORTE-45-2020-20 – Sistema de Apoio à Investigação Científica e Tecnológica – “Projetos Estruturados de I&D&I” UNorte. F. R. M. acknowledges FCT for her contract under Transitional Rule DL 57/2016 (CTTI-57/18-I3BS(5)). The authors also thank the funds provided under the IET A. F. Harvey Engineering Research Award 2018 (ENG ThE CANCER). The EU Framework Programme for Research and Innovation H2020 on FoReCaST (grant agreement no.668983) is also significantly acknowledged.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2023 Springer Nature Switzerland AG
About this entry
Cite this entry
Ramos, P., Maia, F.R., Reis, R.L., Oliveira, J.M. (2023). Protein-Based Materials as Cancer In Vitro 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_14-1
Download citation
DOI: https://doi.org/10.1007/978-3-030-92090-6_14-1
Received:
Accepted:
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-030-92090-6
Online ISBN: 978-3-030-92090-6
eBook Packages: Springer Reference Biomedicine and Life SciencesReference Module Biomedical and Life Sciences