Oncofetal protein glypican‐3 is a biomarker and critical regulator of function for neuroendocrine cells in prostate cancer

Neuroendocrine (NE) cells comprise ~1% of epithelial cells in benign prostate and prostatic adenocarcinoma (PCa). However, they become enriched in hormonally treated and castration‐resistant PCa (CRPC). In addition, close to 20% of hormonally treated tumors recur as small cell NE carcinoma (SCNC), c...

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Published inThe Journal of pathology Vol. 260; no. 1; pp. 43 - 55
Main Authors Butler, William, Xu, Lingfan, Zhou, Yinglu, Cheng, Qing, Hauck, J. Spencer, He, Yiping, Marek, Robert, Hartman, Zachary, Cheng, Liang, Yang, Qing, Wang, Mu‐En, Chen, Ming, Zhang, Hong, Armstrong, Andrew J, Huang, Jiaoti
Format Journal Article
LanguageEnglish
Published Chichester, UK John Wiley & Sons, Ltd 01.05.2023
Wiley Subscription Services, Inc
Subjects
Adenocarcinoma
Adenocarcinoma - pathology
Androgen receptors
biomarkers
Biomarkers - metabolism
Calcium homeostasis
Calcium signalling
Castration
Cell differentiation
Cell surface
cellular heterogeneity
Epithelial cells
genitourinary oncology
Glypicans - metabolism
Heparan sulfate proteoglycans
Homeostasis
Humans
immunotherapy
Liver cancer
Male
Neoplasm Recurrence, Local - pathology
neuroendocrine
Neuroendocrine Cells - metabolism
Neuroendocrine Cells - pathology
Precision medicine
precision oncology
Prostate cancer
Prostatic Neoplasms - pathology
Toxicity
Tumor cells
Tumors
precision oncology
prostate cancer
neuroendocrine
biomarkers
immunotherapy
cellular heterogeneity
genitourinary oncology
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Abstract Neuroendocrine (NE) cells comprise ~1% of epithelial cells in benign prostate and prostatic adenocarcinoma (PCa). However, they become enriched in hormonally treated and castration‐resistant PCa (CRPC). In addition, close to 20% of hormonally treated tumors recur as small cell NE carcinoma (SCNC), composed entirely of NE cells, which may be the result of clonal expansion or lineage plasticity. Since NE cells do not express androgen receptors (ARs), they are resistant to hormonal therapy and contribute to therapy failure. Here, we describe the identification of glypican‐3 (GPC3) as an oncofetal cell surface protein specific to NE cells in prostate cancer. Functional studies revealed that GPC3 is critical to the viability of NE tumor cells and tumors displaying NE differentiation and that it regulates calcium homeostasis and signaling. Since our results demonstrate that GPC3 is specifically expressed by NE cells, patients with confirmed SCNC may qualify for GPC3‐targeted therapy which has been developed in the context of liver cancer and displays minimal toxicity due to its tumor‐specific expression. © 2023 The Pathological Society of Great Britain and Ireland.
AbstractList Neuroendocrine (NE) cells comprise ~1% of epithelial cells in benign prostate and prostatic adenocarcinoma (PCa). However, they become enriched in hormonally treated and castration‐resistant PCa (CRPC). In addition, close to 20% of hormonally treated tumors recur as small cell NE carcinoma (SCNC), composed entirely of NE cells, which may be the result of clonal expansion or lineage plasticity. Since NE cells do not express androgen receptors (ARs), they are resistant to hormonal therapy and contribute to therapy failure. Here, we describe the identification of glypican‐3 (GPC3) as an oncofetal cell surface protein specific to NE cells in prostate cancer. Functional studies revealed that GPC3 is critical to the viability of NE tumor cells and tumors displaying NE differentiation and that it regulates calcium homeostasis and signaling. Since our results demonstrate that GPC3 is specifically expressed by NE cells, patients with confirmed SCNC may qualify for GPC3‐targeted therapy which has been developed in the context of liver cancer and displays minimal toxicity due to its tumor‐specific expression. © 2023 The Pathological Society of Great Britain and Ireland.
Neuroendocrine (NE) cells comprise ~1% of epithelial cells in benign prostate and prostatic adenocarcinoma (PCa). However, they become enriched in hormonally treated and castration-resistant PCa (CRPC). In addition, close to 20% of hormonally treated tumors recur as small cell NE carcinoma (SCNC), composed entirely of NE cells, which may be the result of clonal expansion or lineage plasticity. Since NE cells do not express androgen receptors (ARs), they are resistant to hormonal therapy and contribute to therapy failure. Here, we describe the identification of glypican-3 (GPC3) as an oncofetal cell surface protein specific to NE cells in prostate cancer. Functional studies revealed that GPC3 is critical to the viability of NE tumor cells and tumors displaying NE differentiation and that it regulates calcium homeostasis and signaling. Since our results demonstrate that GPC3 is specifically expressed by NE cells, patients with confirmed SCNC may qualify for GPC3-targeted therapy which has been developed in the context of liver cancer and displays minimal toxicity due to its tumor-specific expression. © 2023 The Pathological Society of Great Britain and Ireland.Neuroendocrine (NE) cells comprise ~1% of epithelial cells in benign prostate and prostatic adenocarcinoma (PCa). However, they become enriched in hormonally treated and castration-resistant PCa (CRPC). In addition, close to 20% of hormonally treated tumors recur as small cell NE carcinoma (SCNC), composed entirely of NE cells, which may be the result of clonal expansion or lineage plasticity. Since NE cells do not express androgen receptors (ARs), they are resistant to hormonal therapy and contribute to therapy failure. Here, we describe the identification of glypican-3 (GPC3) as an oncofetal cell surface protein specific to NE cells in prostate cancer. Functional studies revealed that GPC3 is critical to the viability of NE tumor cells and tumors displaying NE differentiation and that it regulates calcium homeostasis and signaling. Since our results demonstrate that GPC3 is specifically expressed by NE cells, patients with confirmed SCNC may qualify for GPC3-targeted therapy which has been developed in the context of liver cancer and displays minimal toxicity due to its tumor-specific expression. © 2023 The Pathological Society of Great Britain and Ireland.
Neuroendocrine (NE) cells comprise ~1% of epithelial cells in benign prostate and prostatic adenocarcinoma (PCa). However, they become enriched in hormonally-treated and castration-resistant PCa (CRPC). In addition, close to 20% of hormonally-treated tumors recur as small cell neuroendocrine carcinoma (SCNC), composed entirely of NE cells, which may be the result of clonal expansion or lineage plasticity. Since NE cells do not express androgen receptor (AR), they are resistant to hormonal therapy and contribute to therapy failure. Here, we describe the identification of glypican-3 (GPC3) as an oncofetal cell surface protein specific to NE cells in prostate cancer. Functional studies revealed that GPC3 is critical to the viability of NE tumor cells and tumors displaying NE differentiation and that it regulates calcium homeostasis and signaling. Since our results demonstrate that GPC3 is specifically expressed by NE cells, patients with confirmed SCNC may qualify for GPC3-targeted therapy which has been developed in the context of liver cancer and displays minimal toxicity due to its tumor-specific expression.
Author Hartman, Zachary
Huang, Jiaoti
Zhang, Hong
Zhou, Yinglu
Hauck, J. Spencer
Cheng, Qing
He, Yiping
Marek, Robert
Armstrong, Andrew J
Butler, William
Chen, Ming
Xu, Lingfan
Cheng, Liang
Yang, Qing
Wang, Mu‐En
AuthorAffiliation 2 Department of Surgery, Duke University School of Medicine, Durham NC, USA
3 Department of Medicine, Duke University School of Medicine, Durham NC 27710, USA
6 Department of Data Science, Dana-Farber Cancer Institute, Boston MA, USA
5 Department of Pathology and Laboratory Medicine, Warren Alpert Medical School of Brown University, Providence RI, USA
4 School of Nursing, Duke University School of Medicine, Durham NC 27710, USA
1 Department of Pathology, Duke University School of Medicine, Durham NC, USA
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Keywords precision oncology
prostate cancer
neuroendocrine
biomarkers
immunotherapy
cellular heterogeneity
genitourinary oncology
Language English
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Notes Conflict of interest statement: JH is a consultant for or owns shares in the following companies: Amgen, Artera, Kingmed Diagnostics, Teddy Clinical Research Laboratories, MoreHealth, OptraScan, Genetron, Omnitura, Vetonco, York Biotechnology, Genecode, VIVA Biotech, and Sisu Pharma and received grants from Zenith Epigenetics, BioXcel Therapeutics, Inc., Dracen Pharmaceuticals, and Fortis Therapeutics. AJA is a consultant or advisor for the following companies: Astellas, Epic Sciences, Pfizer, Bayer, Janssen, Dendreon, BMS, AstraZeneca, Merck, Forma, Celgene, Clovis, Exact Sciences, Myovant, Exelixis, GoodRx, and Novartis. AJA received research support/grants from the National Institutes of Health/National Cancer Institute, Prostate Cancer Foundation/Movember, Department of Defense, Astellas, Pfizer, Bayer, Janssen, Dendreon, Bristol Myers Squibb, AstraZeneca, Merck, Forma, Celgene, Amgen, and Novartis. No other conflicts of interest were declared.
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WB and JH conceived this project. WB, JH and LX designed experiments. WB performed all experiments. LX, SH, LC, RM, ZH, MW, MC, HZ, AA and Y.H. assisted with some experiments. LX, YZ, QY and QC provided genomic sequencing analysis and statistical support. WB and JH wrote the manuscript. JH supervised the study. All authors discussed results and contributed to the manuscript.
Author contributions statement
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Hussain A (e_1_2_8_5_1) 2000; 14
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National Research Council, Division on Earth and Life Studies, Institute for Laboratory Animal Research, Committee for the Update of the Guide for the Care and Use of Laboratory Animals (e_1_2_8_25_1) 2011
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37409446 - J Pathol. 2023 Aug;260(4):493
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Snippet Neuroendocrine (NE) cells comprise ~1% of epithelial cells in benign prostate and prostatic adenocarcinoma (PCa). However, they become enriched in hormonally...
Neuroendocrine (NE) cells comprise ~1% of epithelial cells in benign prostate and prostatic adenocarcinoma (PCa). However, they become enriched in...
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StartPage 43
SubjectTerms Adenocarcinoma
Adenocarcinoma - pathology
Androgen receptors
biomarkers
Biomarkers - metabolism
Calcium homeostasis
Calcium signalling
Castration
Cell differentiation
Cell surface
cellular heterogeneity
Epithelial cells
genitourinary oncology
Glypicans - metabolism
Heparan sulfate proteoglycans
Homeostasis
Humans
immunotherapy
Liver cancer
Male
Neoplasm Recurrence, Local - pathology
neuroendocrine
Neuroendocrine Cells - metabolism
Neuroendocrine Cells - pathology
Precision medicine
precision oncology
Prostate cancer
Prostatic Neoplasms - pathology
Toxicity
Tumor cells
Tumors
Title Oncofetal protein glypican‐3 is a biomarker and critical regulator of function for neuroendocrine cells in prostate cancer
URI https://onlinelibrary.wiley.com/doi/abs/10.1002%2Fpath.6063
https://www.ncbi.nlm.nih.gov/pubmed/36752189
https://www.proquest.com/docview/2795123624
https://www.proquest.com/docview/2774497118
https://pubmed.ncbi.nlm.nih.gov/PMC10273879
Volume 260
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