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The role of STEAP2 in aggressive prostate cancer traits and androgen responses / LEIA JONES

Swansea University Author: LEIA JONES

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DOI (Published version): 10.23889/SUthesis.57522

Abstract

The prognosis of localised prostate cancer is generally promising, as many tumours remain dormant and therefore do not require immediate intervention. In contrast, once metastasised, the prognosis for aggressive prostate cancer is often poor, highlighting the need for novel, effective treatment appr...

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Published: Swansea 2021
Institution: Swansea University
Degree level: Doctoral
Degree name: Ph.D
Supervisor: Doak, Shareen H. ; Jenkins, Gareth J.
URI: https://cronfa.swan.ac.uk/Record/cronfa57522
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first_indexed 2021-08-05T09:54:37Z
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fullrecord <?xml version="1.0"?><rfc1807><datestamp>2021-08-05T11:26:12.6054594</datestamp><bib-version>v2</bib-version><id>57522</id><entry>2021-08-05</entry><title>The role of STEAP2 in aggressive prostate cancer traits and androgen responses</title><swanseaauthors><author><sid>418ef94cecc3687c69241cb6b2155a22</sid><firstname>LEIA</firstname><surname>JONES</surname><name>LEIA JONES</name><active>true</active><ethesisStudent>false</ethesisStudent></author></swanseaauthors><date>2021-08-05</date><abstract>The prognosis of localised prostate cancer is generally promising, as many tumours remain dormant and therefore do not require immediate intervention. In contrast, once metastasised, the prognosis for aggressive prostate cancer is often poor, highlighting the need for novel, effective treatment approaches. The expression of the six transmembrane epithelial antigen of the prostate2 (STEAP2) cell surface protein is increased in aggressive prostate cancer compared to normal prostate tissue. In vitro studies have shown STEAP2 to aid in prostate cancer progression, and as such this molecule shows promise as a potential novel therapeutic target in the treatment of advanced disease. The aim of this thesis was to develop a comprehensive understanding of the mechanistic role of STEAP2 in promoting aggressive prostate cancer traits and evaluate if its knock-out has the capacity to reduce the invasive potential of prostate cancer cells in vitro. As prostate cancer is a largely androgen dependent disease, this thesis also aimed to evaluate the effects of STEAP2 inhibition on the expression of the androgen receptor and androgen-regulated genes. This study developed and optimised a protocol for generating a set of 3D prostate cancer spheroids to provide more representative models of the in vivo prostate cancer environment. In this thesis, one commercial anti-STEAP2 polyclonal antibody and a panel of anti-STEAP2 monoclonal antibodies were selected for proof-of-concept studies where their effects on reducing prostate cancer cell viability were assessed. Receptor internalisation of STEAP2 was evaluated upon anti-STEAP2 monoclonal antibody binding to determine its suitability for use with antibody-drug conjugate technology. STEAP2 expression was knocked out using CRISPR/Cas9 genome engineering technology in two prostate cancer cell lines to evaluate its impact on cell proliferation, migration and invasion. Furthermore, gene expression profiling was conducted to explore interactions between STEAP2, the androgen receptor and a panel of androgen-regulated genes (PSA, FKBP5, GPRC6A and TMPRSS2) following: 1) anti-STEAP2 antibody treatment, 2) STEAP2-knockout and 3) the growth of prostate cancer cells in androgen-depleted conditions. The data presented in this thesis demonstrate that inhibition of STEAP2 by both the polyclonal anti-STEAP2 antibody and lead anti-STEAP2 monoclonal antibody significantly reduced prostate cancer cell viability. STEAP2 receptor internalisation was triggered following treatment of prostate cancer cells with the anti-STEAP2 monoclonal antibody, demonstrating its potential utility with antibody-drug conjugate technology in the future. STEAP2 knockout prostate cancer cells exhibited decreased cell proliferation, migration and invasion in comparison to wild-type cells. These promising findings highlight the therapeutic value of STEAP2-knockout in inhibiting invasive tumour cell traits. Gene expression data from both STEAP2-knockout cells and androgen-depleted cells suggest that STEAP2 may be involved in crosstalk between the androgen receptor and androgen-regulated genes. STEAP2 could therefore provide a novel target in conjunction with current conventional androgen deprivation therapy. In conclusion, the in vitro findings presented herein suggest STEAP2 as a viable target for the development of more tailored and personalised therapeutic agents to improve the clinical management of men with aggressive prostate cancer.</abstract><type>E-Thesis</type><journal/><volume/><journalNumber/><paginationStart/><paginationEnd/><publisher/><placeOfPublication>Swansea</placeOfPublication><isbnPrint/><isbnElectronic/><issnPrint/><issnElectronic/><keywords>prostate cancer, CRISPR, STEAP2</keywords><publishedDay>21</publishedDay><publishedMonth>7</publishedMonth><publishedYear>2021</publishedYear><publishedDate>2021-07-21</publishedDate><doi>10.23889/SUthesis.57522</doi><url/><notes>ORCiD identifier https://orcid.org/0000-0003-0554-0041</notes><college>COLLEGE NANME</college><CollegeCode>COLLEGE CODE</CollegeCode><institution>Swansea University</institution><supervisor>Doak, Shareen H. ; Jenkins, Gareth J.</supervisor><degreelevel>Doctoral</degreelevel><degreename>Ph.D</degreename><apcterm/><lastEdited>2021-08-05T11:26:12.6054594</lastEdited><Created>2021-08-05T10:17:53.1701934</Created><path><level id="1">Faculty of Medicine, Health and Life Sciences</level><level id="2">Swansea University Medical School - Medicine</level></path><authors><author><firstname>LEIA</firstname><surname>JONES</surname><order>1</order></author></authors><documents><document><filename>57522__20549__a4250c5d20a0437b869ed5eced987603.pdf</filename><originalFilename>Jones_Leia_PhD_thesis_Final_Redacted_Signature.pdf</originalFilename><uploaded>2021-08-05T11:18:28.3527718</uploaded><type>Output</type><contentLength>79590799</contentLength><contentType>application/pdf</contentType><version>E-Thesis &#x2013; open access</version><cronfaStatus>true</cronfaStatus><documentNotes>Copyright: The author, Leia Ashleigh Jones, 2021.</documentNotes><copyrightCorrect>true</copyrightCorrect><language>eng</language></document></documents><OutputDurs/></rfc1807>
spelling 2021-08-05T11:26:12.6054594 v2 57522 2021-08-05 The role of STEAP2 in aggressive prostate cancer traits and androgen responses 418ef94cecc3687c69241cb6b2155a22 LEIA JONES LEIA JONES true false 2021-08-05 The prognosis of localised prostate cancer is generally promising, as many tumours remain dormant and therefore do not require immediate intervention. In contrast, once metastasised, the prognosis for aggressive prostate cancer is often poor, highlighting the need for novel, effective treatment approaches. The expression of the six transmembrane epithelial antigen of the prostate2 (STEAP2) cell surface protein is increased in aggressive prostate cancer compared to normal prostate tissue. In vitro studies have shown STEAP2 to aid in prostate cancer progression, and as such this molecule shows promise as a potential novel therapeutic target in the treatment of advanced disease. The aim of this thesis was to develop a comprehensive understanding of the mechanistic role of STEAP2 in promoting aggressive prostate cancer traits and evaluate if its knock-out has the capacity to reduce the invasive potential of prostate cancer cells in vitro. As prostate cancer is a largely androgen dependent disease, this thesis also aimed to evaluate the effects of STEAP2 inhibition on the expression of the androgen receptor and androgen-regulated genes. This study developed and optimised a protocol for generating a set of 3D prostate cancer spheroids to provide more representative models of the in vivo prostate cancer environment. In this thesis, one commercial anti-STEAP2 polyclonal antibody and a panel of anti-STEAP2 monoclonal antibodies were selected for proof-of-concept studies where their effects on reducing prostate cancer cell viability were assessed. Receptor internalisation of STEAP2 was evaluated upon anti-STEAP2 monoclonal antibody binding to determine its suitability for use with antibody-drug conjugate technology. STEAP2 expression was knocked out using CRISPR/Cas9 genome engineering technology in two prostate cancer cell lines to evaluate its impact on cell proliferation, migration and invasion. Furthermore, gene expression profiling was conducted to explore interactions between STEAP2, the androgen receptor and a panel of androgen-regulated genes (PSA, FKBP5, GPRC6A and TMPRSS2) following: 1) anti-STEAP2 antibody treatment, 2) STEAP2-knockout and 3) the growth of prostate cancer cells in androgen-depleted conditions. The data presented in this thesis demonstrate that inhibition of STEAP2 by both the polyclonal anti-STEAP2 antibody and lead anti-STEAP2 monoclonal antibody significantly reduced prostate cancer cell viability. STEAP2 receptor internalisation was triggered following treatment of prostate cancer cells with the anti-STEAP2 monoclonal antibody, demonstrating its potential utility with antibody-drug conjugate technology in the future. STEAP2 knockout prostate cancer cells exhibited decreased cell proliferation, migration and invasion in comparison to wild-type cells. These promising findings highlight the therapeutic value of STEAP2-knockout in inhibiting invasive tumour cell traits. Gene expression data from both STEAP2-knockout cells and androgen-depleted cells suggest that STEAP2 may be involved in crosstalk between the androgen receptor and androgen-regulated genes. STEAP2 could therefore provide a novel target in conjunction with current conventional androgen deprivation therapy. In conclusion, the in vitro findings presented herein suggest STEAP2 as a viable target for the development of more tailored and personalised therapeutic agents to improve the clinical management of men with aggressive prostate cancer. E-Thesis Swansea prostate cancer, CRISPR, STEAP2 21 7 2021 2021-07-21 10.23889/SUthesis.57522 ORCiD identifier https://orcid.org/0000-0003-0554-0041 COLLEGE NANME COLLEGE CODE Swansea University Doak, Shareen H. ; Jenkins, Gareth J. Doctoral Ph.D 2021-08-05T11:26:12.6054594 2021-08-05T10:17:53.1701934 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine LEIA JONES 1 57522__20549__a4250c5d20a0437b869ed5eced987603.pdf Jones_Leia_PhD_thesis_Final_Redacted_Signature.pdf 2021-08-05T11:18:28.3527718 Output 79590799 application/pdf E-Thesis – open access true Copyright: The author, Leia Ashleigh Jones, 2021. true eng
title The role of STEAP2 in aggressive prostate cancer traits and androgen responses
spellingShingle The role of STEAP2 in aggressive prostate cancer traits and androgen responses
LEIA JONES
title_short The role of STEAP2 in aggressive prostate cancer traits and androgen responses
title_full The role of STEAP2 in aggressive prostate cancer traits and androgen responses
title_fullStr The role of STEAP2 in aggressive prostate cancer traits and androgen responses
title_full_unstemmed The role of STEAP2 in aggressive prostate cancer traits and androgen responses
title_sort The role of STEAP2 in aggressive prostate cancer traits and androgen responses
author_id_str_mv 418ef94cecc3687c69241cb6b2155a22
author_id_fullname_str_mv 418ef94cecc3687c69241cb6b2155a22_***_LEIA JONES
author LEIA JONES
author2 LEIA JONES
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doi_str_mv 10.23889/SUthesis.57522
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hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
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description The prognosis of localised prostate cancer is generally promising, as many tumours remain dormant and therefore do not require immediate intervention. In contrast, once metastasised, the prognosis for aggressive prostate cancer is often poor, highlighting the need for novel, effective treatment approaches. The expression of the six transmembrane epithelial antigen of the prostate2 (STEAP2) cell surface protein is increased in aggressive prostate cancer compared to normal prostate tissue. In vitro studies have shown STEAP2 to aid in prostate cancer progression, and as such this molecule shows promise as a potential novel therapeutic target in the treatment of advanced disease. The aim of this thesis was to develop a comprehensive understanding of the mechanistic role of STEAP2 in promoting aggressive prostate cancer traits and evaluate if its knock-out has the capacity to reduce the invasive potential of prostate cancer cells in vitro. As prostate cancer is a largely androgen dependent disease, this thesis also aimed to evaluate the effects of STEAP2 inhibition on the expression of the androgen receptor and androgen-regulated genes. This study developed and optimised a protocol for generating a set of 3D prostate cancer spheroids to provide more representative models of the in vivo prostate cancer environment. In this thesis, one commercial anti-STEAP2 polyclonal antibody and a panel of anti-STEAP2 monoclonal antibodies were selected for proof-of-concept studies where their effects on reducing prostate cancer cell viability were assessed. Receptor internalisation of STEAP2 was evaluated upon anti-STEAP2 monoclonal antibody binding to determine its suitability for use with antibody-drug conjugate technology. STEAP2 expression was knocked out using CRISPR/Cas9 genome engineering technology in two prostate cancer cell lines to evaluate its impact on cell proliferation, migration and invasion. Furthermore, gene expression profiling was conducted to explore interactions between STEAP2, the androgen receptor and a panel of androgen-regulated genes (PSA, FKBP5, GPRC6A and TMPRSS2) following: 1) anti-STEAP2 antibody treatment, 2) STEAP2-knockout and 3) the growth of prostate cancer cells in androgen-depleted conditions. The data presented in this thesis demonstrate that inhibition of STEAP2 by both the polyclonal anti-STEAP2 antibody and lead anti-STEAP2 monoclonal antibody significantly reduced prostate cancer cell viability. STEAP2 receptor internalisation was triggered following treatment of prostate cancer cells with the anti-STEAP2 monoclonal antibody, demonstrating its potential utility with antibody-drug conjugate technology in the future. STEAP2 knockout prostate cancer cells exhibited decreased cell proliferation, migration and invasion in comparison to wild-type cells. These promising findings highlight the therapeutic value of STEAP2-knockout in inhibiting invasive tumour cell traits. Gene expression data from both STEAP2-knockout cells and androgen-depleted cells suggest that STEAP2 may be involved in crosstalk between the androgen receptor and androgen-regulated genes. STEAP2 could therefore provide a novel target in conjunction with current conventional androgen deprivation therapy. In conclusion, the in vitro findings presented herein suggest STEAP2 as a viable target for the development of more tailored and personalised therapeutic agents to improve the clinical management of men with aggressive prostate cancer.
published_date 2021-07-21T04:13:19Z
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