Murdock, Mark
(2022)
Non-Neoplastic Extracellular Matrix Components
As A Therapeutic For Glioblastoma Multiforme.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Glioblastoma multiforme (GBM), a type of glioma arising in the central nervous system, is one of the most aggressive and lethal types of cancer with a two-year survival rate of ~15%, and a five-year survival rate of just ~5%. The current standard of care for GBM is aggressive surgical resection followed by radiotherapy with concomitant daily temozolomide, both of which are associated with morbidity and decreased quality of life. In 2005 clinical testing for this approach showed an increase in median survival of only 2.5 months. New methods of treating GBM are desperately needed.
Suppressive and/or lethal effects of non-neoplastic mammalian extracellular matrix (ECM) biomaterials upon various cancer cell types including breast, urinary bladder, prostate, esophageal, melanoma, and colon cancer have been reported. Though the mechanisms of action are unclear, ECM biomaterials purportedly exert their anti-cancer effects both directly through multiple effector molecules existent in the ECM microenvironment and indirectly by modulating the immune system. The present dissertation shows that there is potential therapeutic value for GBM in the saline-soluble fraction of non-neoplastic mammalian ECM biomaterials.
The type of source tissue from which ECM biomaterials were isolated was a determinant factor in the anti-cancer potency of the resultant microenvironment as evidenced by in vitro viability assays of primary and cancer cell lines. Saline-soluble fractions of these ECM biomaterials were sufficient to reproduce the cancer-killing effect enacted by whole pepsin-digested ECM with porcine urinary bladder matrix being the most potent. The saline-soluble fraction of urinary bladder matrix (UBM-ECM-SF) induced apoptosis in primary GBM cells in vitro, showed neurosupportive function with astrocytes and neurons in vitro, showed low toxicity with non-neoplastic cells in vitro, and good biocompatibility intravenously and intracranially in rodents. Furthermore, treatment with UBM-ECM-SF decreased intracranial tumor growth rate leading to smaller final tumor volumes while doubling the median survival in the commonly used C6-Wistar rat glioma model. The proteomic composition of UBM-ECM-SF was explored though specific effector molecules remain unknown.
The findings from this work show that non-neoplastic ECM components have potent anti-glioma effects and may represent an alternative or complementary approach to conventional therapy for GBM.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
| Creators | Email | Pitt Username | ORCID  |
|---|
| Murdock, Mark | | | |
|
| ETD Committee: |
| Title | Member | Email Address | Pitt Username | ORCID |
|---|
| Committee Chair | Mars, Wendy | | | | | Thesis Advisor | Badylak, Stephen | | | | | Committee Member | Amankulor, Nduka | | | | | Committee Member | Ambrosio, Fabrisia | | | | | Committee Member | Murdoch, Geoffrey | | | | | Committee Member | Piganelli, Jon | | | |
|
| Date: |
17 May 2022 |
| Date Type: |
Completion |
| Defense Date: |
14 September 2021 |
| Approval Date: |
31 August 2022 |
| Submission Date: |
18 May 2022 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
183 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Pathology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
glioma, cancer, extracellular matrix, ECM, tissue engineering, regenerative medicine, oncology, therapy, dynamic reciprocity |
| Date Deposited: |
31 Aug 2022 17:34 |
| Last Modified: |
31 Aug 2022 17:34 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/43006 |
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