Role of SULF1 in the regulation of metastatic prostate cancer progression

Simple item page
dc.contributor.advisorCarson, Daniel Den_US
dc.contributor.advisorWarmflash, Aryehen_US
dc.creatorBrasil da Costa, Fabio Henriqueen_US
dc.date.accessioned2020-04-27T19:31:56Zen_US
dc.date.available2020-11-01T05:01:11Zen_US
dc.date.created2020-05en_US
dc.date.issued2020-04-24en_US
dc.date.submittedMay 2020en_US
dc.date.updated2020-04-27T19:31:56Zen_US
dc.description.abstractThe establishment of new prostate cancer (PCa) metastases in the bone marrow accompanies a classical stromal reaction orchestrated primarily by the bidirectional engagement of cancer cells and fibroblasts. As result, tumor-associated macrophages (TAMs) are recruited to the tumor and display a fluid spectrum of behaviors that may promote or suppress tumor progression. These stromal and immune reactions, although initially in place to constrain tumor growth, have been shown to ultimately benefit cancer cells, for example, due to increased bioavailability of growth factors and matrix remodeling. Also, deposition of the heparan sulfate (HS) proteoglycan perlecan (HSPG2) and secretion of HS-modifying enzymes are increased in the matrix as result of the Cancer-CAF-TAM trialogue. In this work, to investigate PCa bone metastases, we developed a novel, bone marrow mimetic hydrogel containing collagen type I, hyaluronic acid, and HS-decorated domain 1 of perlecan (COL1-HA-PlnDm1). Our goal was to use this model to study the prevalence and role of growth factor-releasing enzymes, like sulfatases 1 and 2 (SULF1/SULF2) and heparanase. We first demonstrated that PCa cells, bone marrow fibroblasts, and Mφs have excellent viability, show in vivo-like morphology, and exhibit classical phenotypic markers in COL1-HA-PlnDm1 hydrogels. Furthermore, we found that SULF1 is the major HS modifier and is predominantly expressed by activated fibroblasts both in vivo and in vitro. Then, we discovered that TAMs are highly prevalent in PCa bone marrow metastases, as indicated by CD163 and CD206 expression, and Mφs in 3D displayed similar phenotype. Additionally, alternatively activated macrophages induced upregulation of SULF1 and HSPG2 in fibroblasts in vitro. Finally, our 3D triculture data shows that when SULF1 is knocked out from fibroblasts, PCa cell proliferation and cluster volume are significantly increased in response to treatment with Wnt3a, even in the presence of Mφs. We conclude that 1) our 3D hydrogel model is a physiologically relevant in vitro system to discover fundamental aspects of HS signaling in the tumor microenvironment; and 2) the dynamics of SULF1 expression and activity suggest a tumor suppressing role in the context of Wnt3a signaling in PCa. Further studies are necessary to determine SULF1’s value as a prognostic marker or a candidate target for new therapies.en_US
dc.embargo.terms2020-11-01en_US
dc.format.mimetypeapplication/pdfen_US
dc.identifier.citationBrasil da Costa, Fabio Henrique. "Role of SULF1 in the regulation of metastatic prostate cancer progression." (2020) Diss., Rice University. <a href="https://hdl.handle.net/1911/108409">https://hdl.handle.net/1911/108409</a>.en_US
dc.identifier.urihttps://hdl.handle.net/1911/108409en_US
dc.language.isoengen_US
dc.rightsCopyright is held by the author, unless otherwise indicated. Permission to reuse, publish, or reproduce the work beyond the bounds of fair use or other exemptions to copyright law must be obtained from the copyright holder.en_US
dc.subjectProstate Canceren_US
dc.subjectSULF1en_US
dc.subjectHeparan sulfateen_US
dc.subjectPerlecanen_US
dc.subjectTAMsen_US
dc.subjectCAFsen_US
dc.subjectWnt3aen_US
dc.subjectBoneen_US
dc.subjectMetastasisen_US
dc.subject3D cultureen_US
dc.subjectBiomimeticen_US
dc.titleRole of SULF1 in the regulation of metastatic prostate cancer progressionen_US
dc.typeThesisen_US
dc.type.materialTexten_US
thesis.degree.departmentBiochemistry and Cell Biologyen_US
thesis.degree.disciplineNatural Sciencesen_US
thesis.degree.grantorRice Universityen_US
thesis.degree.levelDoctoralen_US
thesis.degree.majorLate Medieval and Early Modern Arten_US
thesis.degree.nameDoctor of Philosophyen_US
Files
Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
BRASILDACOSTA-DOCUMENT-2020.pdf
Size:
28.48 MB
Format:
Adobe Portable Document Format
Download
License bundle
Now showing 1 - 2 of 2
No Thumbnail Available
Name:
PROQUEST_LICENSE.txt
Size:
5.86 KB
Format:
Plain Text
Description:
Download
No Thumbnail Available
Name:
LICENSE.txt
Size:
2.62 KB
Format:
Plain Text
Description:
Download
Collections
Rice University Theses and Dissertations