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Design and characterization of tunab...

Sawicki, Lisa A.

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Design and characterization of tunable hydrogels to examine microenvironmental regulation of breast cancer recurrence.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Design and characterization of tunable hydrogels to examine microenvironmental regulation of breast cancer recurrence./
作者:	Sawicki, Lisa A.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2017,
面頁冊數:	234 p.
附註:	Source: Dissertation Abstracts International, Volume: 78-08(E), Section: B.
Contained By:	Dissertation Abstracts International78-08B(E).
標題:	Materials science. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10256697
ISBN:	9781369681345

Design and characterization of tunable hydrogels to examine microenvironmental regulation of breast cancer recurrence.
Sawicki, Lisa A.

Design and characterization of tunable hydrogels to examine microenvironmental regulation of breast cancer recurrence. - Ann Arbor : ProQuest Dissertations & Theses, 2017 - 234 p.

Source: Dissertation Abstracts International, Volume: 78-08(E), Section: B.

Thesis (Ph.D.)--University of Delaware, 2017.

Late recurrence of breast cancer within distant metastatic tissue sites is often difficult to diagnose and treat, resulting in poor prognosis for patients. It is hypothesized that cells may go dormant by interactions with or lack of adhesion to the extracellular matrix (ECM) within these tissues, which differs from native breast tissue. The metastatic ECM is a complex microenvironment, containing a mixture of mechanical and chemical cues to which cells respond. To investigate how the ECM regulates cancer recurrence, two-dimensional (2D, plates) and three-dimensional (3D, naturally-derived scaffolds) in vitro culture models have been used. However, lack of complexity (2D), mechanical property control (2D, 3D), and chemical property control (3D) makes it challenging to identify key factors involved in regulating dormancy or activation in these systems. The development of synthetic polymer-based scaffolds in recent years provides an alternate route to investigating cellular response to the presentation of microenvironmental cues in 3D. Initially bioinert, these scaffolds may be modified with chemical ligands to permit cell-matrix interactions and their mechanical properties may be precisely tuned to mimic different tissue sites. The goal of this dissertation is to develop and characterize a novel synthetic material for cell culture applications and to examine how physical and chemical factors in this microenvironment regulate breast cancer activation.

ISBN: 9781369681345Subjects--Topical Terms:

543314
Materials science.

Design and characterization of tunable hydrogels to examine microenvironmental regulation of breast cancer recurrence.
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245 1 0 $a Design and characterization of tunable hydrogels to examine microenvironmental regulation of breast cancer recurrence.
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500 $a Source: Dissertation Abstracts International, Volume: 78-08(E), Section: B.
500 $a Adviser: April M. Kloxin.
502 $a Thesis (Ph.D.)--University of Delaware, 2017.
520 $a Late recurrence of breast cancer within distant metastatic tissue sites is often difficult to diagnose and treat, resulting in poor prognosis for patients. It is hypothesized that cells may go dormant by interactions with or lack of adhesion to the extracellular matrix (ECM) within these tissues, which differs from native breast tissue. The metastatic ECM is a complex microenvironment, containing a mixture of mechanical and chemical cues to which cells respond. To investigate how the ECM regulates cancer recurrence, two-dimensional (2D, plates) and three-dimensional (3D, naturally-derived scaffolds) in vitro culture models have been used. However, lack of complexity (2D), mechanical property control (2D, 3D), and chemical property control (3D) makes it challenging to identify key factors involved in regulating dormancy or activation in these systems. The development of synthetic polymer-based scaffolds in recent years provides an alternate route to investigating cellular response to the presentation of microenvironmental cues in 3D. Initially bioinert, these scaffolds may be modified with chemical ligands to permit cell-matrix interactions and their mechanical properties may be precisely tuned to mimic different tissue sites. The goal of this dissertation is to develop and characterize a novel synthetic material for cell culture applications and to examine how physical and chemical factors in this microenvironment regulate breast cancer activation.
520 $a Specifically, we have developed a novel poly(ethylene glycol) (PEG)-based hydrogel scaffold for in vitro cell culture. PEG modified with thiols and peptides containing alloxycarbonyl-protected lysines (containing a reactive vinyl) react rapidly upon the application of light in the presence of a photoinitiator, lithium acylphosphinate (~minutes). Scaffold mechanical properties are tuned by varying macromer concentration to mimic soft metastatic site tissue ECMs (Young's modulus ~ 600 -- 6000 Pa). These properties remain stable during long-term culture (~weeks). We also demonstrate the covalent attachment and spatial presentation of peptides mimicking proteins found within metastatic tissue ECMs in these scaffolds. All cell lines remain viable (>70%) after encapsulation, with many at greater than 90% viability, indicating minimal negative effects of light and radicals on cell survival post-polymerization.
520 $a While initially well-defined, the properties of synthetic hydrogel scaffolds change as cells secrete soluble factors that permit cell-cell signaling and synthesize new proteins that provide additional binding sites with which cells may interact. To investigate these chemical property changes, we developed a shotgun proteomics technique to isolate and identify large proteins secreted within synthetic, polymer-based hydrogel scaffolds. Metastatic niche cells (adult human mesenchymal stem cells, hMSCs) were cultured within hydrogel scaffolds and large proteins, including fibronectin and collagen VI were identified. Additionally, a bead-based multiplex assay identified several soluble factors secreted by hMSCs (VEGF, IL-8), which may play a role in regulating cell function and fate.
520 $a Finally, the response and activation of estrogen receptor negative (MDA-MB-231) and estrogen receptor positive (T-47D) breast cancer cells cultured within synthetic hydrogels with discrete mechanical and chemical properties was determined. The highly aggressive MDA-MB-231 cells demonstrated the greatest levels of activation and spread within these synthetic matrices, while T-47D cells, which have been associated with a dormant phenotype, exhibited only minimal response and formed multicellular spheroids. Specifically, hydrogels with high stiffness and matrix density restricted cancer cell growth, resulting in decreased spreading and smaller cell cluster volume. Individual and mixtures of peptides (GFOGER, RGDS, IKVAV) mimicking ECM proteins found within metastatic tissue sites and targeting cell surface receptors were also shown to affect response. GFOGER and RGDS, targeting integrin ?1, among others, resulted in the highest levels of activation observed within microenvironments. Collectively, this work describes the development of a novel material scaffold with well-defined chemical and physical properties that may be used to identify critical factors in metastatic microenvironments that regulate breast cancer activation toward development of new treatments for recurrent cancers.
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650 4 $a Biochemistry. $3 518028
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