Cargando…

Circulating Tumour Cells Indicate the Presence of Residual Disease Post-Castration in Prostate Cancer Patient-Derived Xenograft Models

Castrate-resistant prostate cancer (CRPC) is the lethal form of prostate cancer. Epithelial mesenchymal plasticity (EMP) has been associated with disease progression to CRPC, and prostate cancer therapies targeting the androgen signalling axis, including androgen deprivation therapy (ADT), promote E...

Descripción completa

Detalles Bibliográficos
Autores principales: Hassan, Sara, Blick, Tony, Wood, Jack, Thompson, Erik W., Williams, Elizabeth D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9043137/
https://www.ncbi.nlm.nih.gov/pubmed/35493092
http://dx.doi.org/10.3389/fcell.2022.858013
_version_ 1784694814133977088
author Hassan, Sara
Blick, Tony
Wood, Jack
Thompson, Erik W.
Williams, Elizabeth D.
author_facet Hassan, Sara
Blick, Tony
Wood, Jack
Thompson, Erik W.
Williams, Elizabeth D.
author_sort Hassan, Sara
collection PubMed
description Castrate-resistant prostate cancer (CRPC) is the lethal form of prostate cancer. Epithelial mesenchymal plasticity (EMP) has been associated with disease progression to CRPC, and prostate cancer therapies targeting the androgen signalling axis, including androgen deprivation therapy (ADT), promote EMP. We explored effects of castration on EMP in the tumours and circulating tumour cells (CTCs) of patient-derived xenograft (PDX)-bearing castrated mice using human-specific RT-qPCR assays and immunocytochemistry. Expression of prostate epithelial cell marker KLK3 was below detection in most tumours from castrated mice (62%, 23/37 mice), consistent with its known up-regulation by androgens. Endpoint tumour size after castration varied significantly in a PDX model-specific pattern; while most tumours were castration-sensitive (BM18, LuCaP70), the majority of LuCaP105 tumours continued to grow following castration. By contrast, LuCaP96 PDX showed a mixed response to castration. CTCs were detected in 33% of LuCaP105, 43% of BM18, 47% of LuCaP70, and 54% of LuCaP96 castrated mice using RPL32 mRNA measurement in plasma. When present, CTC numbers estimated using human RPL32 expression ranged from 1 to 458 CTCs per ml blood, similar to our previous observations in non-castrated mice. In contrast to their non-castrated counterparts, there was no relationship between tumour size and CTC burden in castrated mice. Unsupervised hierarchical clustering of the gene expression profiles of CTCs collected from castrated and non-castrated mice revealed distinct CTC sub-groups within the pooled population that were classified as having mesenchymal, epithelial, or EMP hybrid gene expression profiles. The epithelial signature was only found in CTCs from non-castrated mice. Hybrid and mesenchymal signatures were detected in CTCs from both castrated and non-castrated mice, with an emphasis towards mesenchymal phenotypes in castrated mice. Post-castration serum PSA levels were either below detection or very low for all the CTC positive samples highlighting the potential usefulness of CTCs for disease monitoring after androgen ablation therapy. In summary, our study of castration effects on prostate cancer PDX CTCs showed that CTCs were often detected in the castrate setting, even in mice with no palpable tumours, and demonstrated the superior ability of CTCs to reveal residual disease over the conventional clinical biomarker serum PSA.
format Online
Article
Text
id pubmed-9043137
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-90431372022-04-28 Circulating Tumour Cells Indicate the Presence of Residual Disease Post-Castration in Prostate Cancer Patient-Derived Xenograft Models Hassan, Sara Blick, Tony Wood, Jack Thompson, Erik W. Williams, Elizabeth D. Front Cell Dev Biol Cell and Developmental Biology Castrate-resistant prostate cancer (CRPC) is the lethal form of prostate cancer. Epithelial mesenchymal plasticity (EMP) has been associated with disease progression to CRPC, and prostate cancer therapies targeting the androgen signalling axis, including androgen deprivation therapy (ADT), promote EMP. We explored effects of castration on EMP in the tumours and circulating tumour cells (CTCs) of patient-derived xenograft (PDX)-bearing castrated mice using human-specific RT-qPCR assays and immunocytochemistry. Expression of prostate epithelial cell marker KLK3 was below detection in most tumours from castrated mice (62%, 23/37 mice), consistent with its known up-regulation by androgens. Endpoint tumour size after castration varied significantly in a PDX model-specific pattern; while most tumours were castration-sensitive (BM18, LuCaP70), the majority of LuCaP105 tumours continued to grow following castration. By contrast, LuCaP96 PDX showed a mixed response to castration. CTCs were detected in 33% of LuCaP105, 43% of BM18, 47% of LuCaP70, and 54% of LuCaP96 castrated mice using RPL32 mRNA measurement in plasma. When present, CTC numbers estimated using human RPL32 expression ranged from 1 to 458 CTCs per ml blood, similar to our previous observations in non-castrated mice. In contrast to their non-castrated counterparts, there was no relationship between tumour size and CTC burden in castrated mice. Unsupervised hierarchical clustering of the gene expression profiles of CTCs collected from castrated and non-castrated mice revealed distinct CTC sub-groups within the pooled population that were classified as having mesenchymal, epithelial, or EMP hybrid gene expression profiles. The epithelial signature was only found in CTCs from non-castrated mice. Hybrid and mesenchymal signatures were detected in CTCs from both castrated and non-castrated mice, with an emphasis towards mesenchymal phenotypes in castrated mice. Post-castration serum PSA levels were either below detection or very low for all the CTC positive samples highlighting the potential usefulness of CTCs for disease monitoring after androgen ablation therapy. In summary, our study of castration effects on prostate cancer PDX CTCs showed that CTCs were often detected in the castrate setting, even in mice with no palpable tumours, and demonstrated the superior ability of CTCs to reveal residual disease over the conventional clinical biomarker serum PSA. Frontiers Media S.A. 2022-04-13 /pmc/articles/PMC9043137/ /pubmed/35493092 http://dx.doi.org/10.3389/fcell.2022.858013 Text en Copyright © 2022 Hassan, Blick, Wood, Thompson and Williams. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Hassan, Sara
Blick, Tony
Wood, Jack
Thompson, Erik W.
Williams, Elizabeth D.
Circulating Tumour Cells Indicate the Presence of Residual Disease Post-Castration in Prostate Cancer Patient-Derived Xenograft Models
title Circulating Tumour Cells Indicate the Presence of Residual Disease Post-Castration in Prostate Cancer Patient-Derived Xenograft Models
title_full Circulating Tumour Cells Indicate the Presence of Residual Disease Post-Castration in Prostate Cancer Patient-Derived Xenograft Models
title_fullStr Circulating Tumour Cells Indicate the Presence of Residual Disease Post-Castration in Prostate Cancer Patient-Derived Xenograft Models
title_full_unstemmed Circulating Tumour Cells Indicate the Presence of Residual Disease Post-Castration in Prostate Cancer Patient-Derived Xenograft Models
title_short Circulating Tumour Cells Indicate the Presence of Residual Disease Post-Castration in Prostate Cancer Patient-Derived Xenograft Models
title_sort circulating tumour cells indicate the presence of residual disease post-castration in prostate cancer patient-derived xenograft models
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9043137/
https://www.ncbi.nlm.nih.gov/pubmed/35493092
http://dx.doi.org/10.3389/fcell.2022.858013
work_keys_str_mv AT hassansara circulatingtumourcellsindicatethepresenceofresidualdiseasepostcastrationinprostatecancerpatientderivedxenograftmodels
AT blicktony circulatingtumourcellsindicatethepresenceofresidualdiseasepostcastrationinprostatecancerpatientderivedxenograftmodels
AT woodjack circulatingtumourcellsindicatethepresenceofresidualdiseasepostcastrationinprostatecancerpatientderivedxenograftmodels
AT thompsonerikw circulatingtumourcellsindicatethepresenceofresidualdiseasepostcastrationinprostatecancerpatientderivedxenograftmodels
AT williamselizabethd circulatingtumourcellsindicatethepresenceofresidualdiseasepostcastrationinprostatecancerpatientderivedxenograftmodels