Developing a biomaterial model of the glioblastoma perivascular niche to investigate the effects of angiocrine signals on disease progression

Brain and other central nervous system cancers affect tens of thousands of people every year and remain a challenging class of diseases to treat. Glioblastoma (GBM) is the most common primary malignant form of brain cancer and accounts for nearly 50% of all malignant brain tumors. Prognosis for GBM is grim, as the median survival time is approximately 15 months and the five-year survival rate is 10%. The challenge in treating GBM is a product of intratumoral heterogeneity and a pro-tumorigenic microenvironment. Specifically, the perivascular niche (PVN) of GBM has been shown to facilitate tumor cell invasion and harbor a subpopulation of cancer stem cells, which are implicated in tumorigenesis and disease recurrence. However, the mechanisms by which the PVN promotes disease progression are unclear. Angiocrine cues are signals derived from vascular cells and have been shown to influence tumor cell behavior in metastatic cancers. Identifying angiocrine cues in GBM will provide an improved understanding of how the microenvironment contributes to disease progression and enable the development of new therapeutics. Currently, in vitro platforms that recapitulate the architecture and cellular interactions found in the in-vivo PVN are lacking and limit the exploration and discovery of angiocrine cues. Thus, this dissertation focuses on the development of biomaterial platforms to recapitulate the tumor-vascular cellular interactions that occur in GBM, as well as the utilization of these platforms to identify the effects of angiocrine signals on tumor cell behavior and potential mechanisms of tumor cell infiltration and therapeutic resistance. We establish design principles for developing vascularized tumor models in gelatin hydrogels and workflows for evaluating heterotypic cell-cell interactions. Furthermore, we demonstrate the ability to establish and utilized vascularized biomaterial platforms to investigate the role of angiocrine cues beyond tumor biology. Collectively, the work in this dissertation provides a methodology for developing physiologically relevant benchtop models of perivascular niche environments to investigate the role of angiocrine cues in homeostasis, regeneration, and disease.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Chemical Engineering

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2021

Author dc:creator

• Ngo, Mai T.

Contributors dc:contributor

• Harley, Brendan AC
• Bhargava, Rohit
• Kong, Hyunjoon
• Gaskins, H. Rex

• biomaterials
• tissue engineering
• cancer
• glioblastoma
• vascularization
• angiogenesis
• angiocrine

Statement dc:rights

• Copyright 2021 Mai Ngo

Language dc:language

en

Handle dc:identifier

http://hdl.handle.net/2142/110622

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/110622