Low CD38 Identifies Progenitor-like Inflammation-Associated Luminal Cells that Can Initiate Human Prostate Cancer and Predict Poor Outcome

Xian Liu; Tristan R Grogan; Haley Hieronymus; Takao Hashimoto; Jack Mottahedeh; Donghui Cheng; Lijun Zhang; Kevin Huang; Tanya Stoyanova; Jung Wook Park; Ruzanna O Shkhyan; Behdokht Nowroozizadeh; Matthew B Rettig; Charles L Sawyers; David Elashoff; Steve Horvath; Jiaoti Huang; Owen N Witte; Andrew S Goldstein

doi:10.1016/j.celrep.2016.11.010

Low CD38 Identifies Progenitor-like Inflammation-Associated Luminal Cells that Can Initiate Human Prostate Cancer and Predict Poor Outcome

Cell Rep. 2016 Dec 6;17(10):2596-2606. doi: 10.1016/j.celrep.2016.11.010.

Authors

Xian Liu¹, Tristan R Grogan², Haley Hieronymus³, Takao Hashimoto¹, Jack Mottahedeh¹, Donghui Cheng⁴, Lijun Zhang⁵, Kevin Huang⁵, Tanya Stoyanova⁶, Jung Wook Park⁶, Ruzanna O Shkhyan¹, Behdokht Nowroozizadeh⁷, Matthew B Rettig⁸, Charles L Sawyers³, David Elashoff⁹, Steve Horvath¹⁰, Jiaoti Huang¹¹, Owen N Witte¹², Andrew S Goldstein¹³

Affiliations

¹ Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
² Department of Medicine Statistics Core, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
³ Programs in Human Oncology and Pathogenesis, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
⁴ Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁵ Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁶ Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁷ Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁸ Division of Hematology-Oncology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; VA Greater Los Angeles Healthcare System, Los Angeles, CA 90024, USA; Urology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁹ Department of Medicine Statistics Core, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹⁰ Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Biostatistics, UCLA Fielding School of Public Health, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹¹ Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹² Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA; Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹³ Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Urology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: agoldstein@mednet.ucla.edu.

Abstract

Inflammation is a risk factor for prostate cancer, but the mechanisms by which inflammation increases that risk are poorly understood. Here, we demonstrate that low expression of CD38 identifies a progenitor-like subset of luminal cells in the human prostate. CD38^lo luminal cells are enriched in glands adjacent to inflammatory cells and exhibit epithelial nuclear factor κB (NF-κB) signaling. In response to oncogenic transformation, CD38^lo luminal cells can initiate human prostate cancer in an in vivo tissue-regeneration assay. Finally, the CD38^lo luminal phenotype and gene signature are associated with disease progression and poor outcome in prostate cancer. Our results suggest that prostate inflammation expands the pool of progenitor-like target cells susceptible to tumorigenesis.

Keywords: CD38; cell of origin; inflammation; luminal; progenitor; prostate cancer; stem cells; transformation.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

ADP-ribosyl Cyclase 1 / genetics*
ADP-ribosyl Cyclase 1 / metabolism
Cell Differentiation / genetics
Cell Lineage / genetics
Cell Transformation, Neoplastic / genetics*
Cell Transformation, Neoplastic / pathology
Epithelial Cells / metabolism
Epithelial Cells / pathology
Humans
Inflammation / genetics*
Inflammation / metabolism
Inflammation / pathology
Male
NF-kappa B / genetics
Neoplastic Stem Cells / metabolism
Neoplastic Stem Cells / pathology
Prostate / metabolism
Prostate / pathology
Prostatic Neoplasms / genetics*
Prostatic Neoplasms / metabolism
Prostatic Neoplasms / pathology

Substances

NF-kappa B
ADP-ribosyl Cyclase 1

Abstract

Publication types

MeSH terms

Substances

Grants and funding