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Published on: July 12, 2018
Glypican 3 as target therapy to prevent cell migration and proliferation in rhabdomyosarcoma
Maira Bacchiega1,2, Stefania D'Agostino1,2, Antonella Grigoletto3
1Department of Women's and Children's Health, University of Padova, via Giustiniani 3, Padova, 35129, Italy.
Abstract:
Rhabdomyosarcoma (RMS) is a pediatric soft tissue sarcoma of mesenchymal origin with two main variants, the embryonal, less aggressive, and the alveolar RMS, more metastatic. The role of the extracellular matrix (ECM) in the growth and migration of RMS, as in other cancers, is becoming increasingly important. This work aims to study the RMS after the silencing of the proteoglycan Glypican 3, overexpressed in RMS. Using classical 2D cell culture with RMS cell lines and 3D hyaluronic acid-based hydrogel, the involvement of Glypican 3 in adhesion, proliferation, matrix degradation, and consequent cell motility was demonstrated. Functional assays were performed with the antineoplastic drug doxurubicin and the WNT3a inhibitor, ipafricept. Both in 2D and in 3D model, cell motility and proliferation were significantly impaired after Glypican 3 silencing and inhibition of the proteoglycan releasing the sulfatase enzyme SULF2. When the in vivo cell-ECM interactions were mimicked in the hyaluronic acid-based hydrogel, Doxorubicin and ipraficept were particularly effective against the GPC3-silenced RMS cells. This study lay the fundation for a different therapeutic approach against pediatric RMS that aim to dysregulate the protein microenvironment not only beat the cancer cells.
Insights
Silencing Glypican 3 in pediatric rhabdomyosarcoma (RMS) significantly reduced tumor cell growth and migration. Targeting the tumor microenvironment with drugs like Doxorubicin and ipraficept showed enhanced effectiveness against GPC3-silenced RMS cells.
Area of Science:
- Oncology
- Biochemistry
- Biomaterials Science
Background:
- Rhabdomyosarcoma (RMS) is a pediatric soft tissue sarcoma with distinct embryonal and alveolar variants.
- The extracellular matrix (ECM) plays a crucial role in cancer progression, including RMS growth and metastasis.
- Glypican 3 (GPC3) is a proteoglycan overexpressed in RMS, suggesting its potential as a therapeutic target.
Purpose of the Study:
- To investigate the role of Glypican 3 (GPC3) in pediatric rhabdomyosarcoma (RMS) progression.
- To evaluate the impact of GPC3 silencing on RMS cell adhesion, proliferation, matrix degradation, and motility.
- To assess the efficacy of combining GPC3 inhibition with standard therapies in a 3D microenvironment model.
Main Methods:
- Utilized classical 2D cell culture and a 3D hyaluronic acid-based hydrogel to mimic in vivo conditions.
- Employed gene silencing techniques to reduce GPC3 expression in RMS cell lines.
- Performed functional assays to measure cell adhesion, proliferation, matrix degradation, and motility.
- Tested the efficacy of Doxorubicin and the WNT3a inhibitor, ipraficept, in combination with GPC3 silencing.
Main Results:
- GPC3 silencing significantly impaired RMS cell motility and proliferation in both 2D and 3D models.
- Inhibition of GPC3, along with the sulfatase enzyme SULF2, further reduced cancer cell aggressiveness.
- In the 3D hydrogel model simulating in vivo cell-ECM interactions, Doxorubicin and ipraficept were more effective against GPC3-silenced RMS cells.
Conclusions:
- GPC3 is a critical mediator of RMS cell behavior and ECM interactions.
- Targeting GPC3 and the tumor microenvironment presents a novel therapeutic strategy for pediatric RMS.
- Combining GPC3 inhibition with existing chemotherapies may enhance treatment efficacy in pediatric RMS.
