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A bioengineered 3D ovarian cancer model for the assessment of peptidase-mediated enhancement of spheroid growth and intraperitoneal spread

Citation

Loessner, D and Rizzi, SC and Stok, KS and Fuehrmann, T and Hollier, B and Magdolen, V and Hutmacher, DW and Clements, JA, A bioengineered 3D ovarian cancer model for the assessment of peptidase-mediated enhancement of spheroid growth and intraperitoneal spread, Biomaterials, 34, (30) pp. 7389-7400. ISSN 0142-9612 (2013) [Refereed Article]


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DOI: doi:10.1016/j.biomaterials.2013.06.009

Abstract

Cancer-associated proteases promote peritoneal dissemination and chemoresistance in malignant progression. In this study, kallikrein-related peptidases 4, 5, 6, and 7 (KLK4-7)-cotransfected OV-MZ-6 ovarian cancer cells were embedded in a bioengineered three-dimensional (3D) microenvironment that contains RGD motifs for integrin engagement to analyze their spheroid growth and survival after chemotreatment. KLK4-7-cotransfected cells formed larger spheroids and proliferated more than controls in 3D, particularly within RGD-functionalized matrices, which was reduced upon integrin inhibition. In contrast, KLK4-7-expressing cell monolayers proliferated less than controls, emphasizing the relevance of the 3D microenvironment and integrin engagement. In a spheroid-based animal model, KLK4-7-overexpression induced tumor growth after 4 weeks and intraperitoneal spread after 8 weeks. Upon paclitaxel administration, KLK4-7-expressing tumors declined in size by 91% (controls: 87%) and showed 90% less metastatic outgrowth (controls: 33%, P < 0.001). KLK4-7-expressing spheroids showed 53% survival upon paclitaxel treatment (controls: 51%), accompanied by enhanced chemoresistance-related factors, and their survival was further reduced by combination treatment of paclitaxel with KLK4/5/7 (22%, P = 0.007) or MAPK (6%, P = 0.006) inhibition. The concomitant presence of KLK4-7 in ovarian cancer cells together with integrin activation drives spheroid formation and proliferation. Combinatorial approaches of paclitaxel and KLK/MAPK inhibition may be more efficient for late-stage disease than chemotherapeutics alone as these inhibitory regimens reduced cancer spheroid growth to a greater extent than paclitaxel alone.

Item Details

Item Type:Refereed Article
Keywords:animal model, biomimetic material, cell encapsulation, cell viability, hydrogel, RGD peptide
Research Division:Engineering
Research Group:Biomedical Engineering
Research Field:Biomechanical Engineering
Objective Division:Expanding Knowledge
Objective Group:Expanding Knowledge
Objective Field:Expanding Knowledge in Engineering
UTAS Author:Stok, KS (Dr Kathryn Stok)
ID Code:133147
Year Published:2013
Web of Science® Times Cited:32
Deposited By:Menzies Institute for Medical Research
Deposited On:2019-06-13
Last Modified:2019-06-13
Downloads:0

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