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A bioengineered 3D ovarian cancer model for the assessment of peptidase-mediated enhancement of spheroid growth and intraperitoneal spread.
Biomaterials 2013; 34(30):7389-400B

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.

Authors+Show Affiliations

Faculty of Health, Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, Brisbane, Queensland 4059, Australia. daniela.lossner@qut.edu.auNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23827191

Citation

Loessner, Daniela, et al. "A Bioengineered 3D Ovarian Cancer Model for the Assessment of Peptidase-mediated Enhancement of Spheroid Growth and Intraperitoneal Spread." Biomaterials, vol. 34, no. 30, 2013, pp. 7389-400.
Loessner D, Rizzi SC, Stok KS, et al. A bioengineered 3D ovarian cancer model for the assessment of peptidase-mediated enhancement of spheroid growth and intraperitoneal spread. Biomaterials. 2013;34(30):7389-400.
Loessner, D., Rizzi, S. C., Stok, K. S., Fuehrmann, T., Hollier, B., Magdolen, V., ... Clements, J. A. (2013). A bioengineered 3D ovarian cancer model for the assessment of peptidase-mediated enhancement of spheroid growth and intraperitoneal spread. Biomaterials, 34(30), pp. 7389-400. doi:10.1016/j.biomaterials.2013.06.009.
Loessner D, et al. A Bioengineered 3D Ovarian Cancer Model for the Assessment of Peptidase-mediated Enhancement of Spheroid Growth and Intraperitoneal Spread. Biomaterials. 2013;34(30):7389-400. PubMed PMID: 23827191.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A bioengineered 3D ovarian cancer model for the assessment of peptidase-mediated enhancement of spheroid growth and intraperitoneal spread. AU - Loessner,Daniela, AU - Rizzi,Simone C, AU - Stok,Kathryn S, AU - Fuehrmann,Tobias, AU - Hollier,Brett, AU - Magdolen,Viktor, AU - Hutmacher,Dietmar W, AU - Clements,Judith A, Y1 - 2013/07/01/ PY - 2013/04/11/received PY - 2013/06/07/accepted PY - 2013/7/6/entrez PY - 2013/7/6/pubmed PY - 2014/2/12/medline KW - Animal model KW - Biomimetic material KW - Cell encapsulation KW - Cell viability KW - Hydrogel KW - RGD peptide SP - 7389 EP - 400 JF - Biomaterials JO - Biomaterials VL - 34 IS - 30 N2 - 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. SN - 1878-5905 UR - https://www.unboundmedicine.com/medline/citation/23827191/A_bioengineered_3D_ovarian_cancer_model_for_the_assessment_of_peptidase_mediated_enhancement_of_spheroid_growth_and_intraperitoneal_spread_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0142-9612(13)00695-9 DB - PRIME DP - Unbound Medicine ER -