MAOA-Dependent Activation of Shh-IL6-RANKL Signaling Network Promotes Prostate Cancer Metastasis by Engaging Tumor-Stromal Cell Interactions

Jason Boyang Wu; Lijuan Yin; Changhong Shi; Qinlong Li; Peng Duan; Jen-Ming Huang; Chunyan Liu; Fubo Wang; Michael Lewis; Yang Wang; Tzu-Ping Lin; Chin-Chen Pan; Edwin M Posadas; Haiyen E Zhau; Leland W K Chung

doi:10.1016/j.ccell.2017.02.003

MAOA-Dependent Activation of Shh-IL6-RANKL Signaling Network Promotes Prostate Cancer Metastasis by Engaging Tumor-Stromal Cell Interactions

Cancer Cell. 2017 Mar 13;31(3):368-382. doi: 10.1016/j.ccell.2017.02.003.

Authors

Jason Boyang Wu¹, Lijuan Yin², Changhong Shi², Qinlong Li³, Peng Duan², Jen-Ming Huang², Chunyan Liu², Fubo Wang⁴, Michael Lewis⁵, Yang Wang⁶, Tzu-Ping Lin⁷, Chin-Chen Pan⁸, Edwin M Posadas⁹, Haiyen E Zhau², Leland W K Chung¹⁰

Affiliations

¹ Uro-Oncology Research Program, Samuel Oschin Comprehensive Cancer Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Spokane, WA 99210, USA. Electronic address: boyang.wu@wsu.edu.
² Uro-Oncology Research Program, Samuel Oschin Comprehensive Cancer Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
³ Uro-Oncology Research Program, Samuel Oschin Comprehensive Cancer Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Department of Pathology, Xijing Hospital, the Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
⁴ Uro-Oncology Research Program, Samuel Oschin Comprehensive Cancer Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Department of Urology, Changhai Hospital, the Secondary Military Medical University, Shanghai 200433, China.
⁵ West Los Angeles VA Medical Center, Los Angeles, CA 90073, USA.
⁶ Department of Pathology, Changhai Hospital, the Secondary Military Medical University, Shanghai 200433, China.
⁷ Department of Urology, Taipei Veterans General Hospital, Taipei, Taiwan 11217, ROC; Department of Urology, School of Medicine and Shu-Tien Urological Research Center, National Yang-Ming University, Taipei, Taiwan 11217, ROC.
⁸ Department of Pathology, Taipei Veterans General Hospital, Taipei, Taiwan 11217, ROC.
⁹ Uro-Oncology Research Program, Samuel Oschin Comprehensive Cancer Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Division of Hematology/Oncology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
¹⁰ Uro-Oncology Research Program, Samuel Oschin Comprehensive Cancer Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. Electronic address: Leland.Chung@cshs.org.

PMID: 28292438
DOI: 10.1016/j.ccell.2017.02.003

Abstract

Metastasis is a predominant cause of death for prostate cancer (PCa) patients; however, the underlying mechanisms are poorly understood. We report that monoamine oxidase A (MAOA) is a clinically and functionally important mediator of PCa bone and visceral metastases, activating paracrine Shh signaling in tumor-stromal interactions. MAOA provides tumor cell growth advantages in the bone microenvironment by stimulating interleukin-6 (IL6) release from osteoblasts, and triggers skeletal colonization by activating osteoclastogenesis through osteoblast production of RANKL and IL6. MAOA inhibitor treatment effectively reduces metastasis and prolongs mouse survival by disengaging the Shh-IL6-RANKL signaling network in stromal cells in the tumor microenvironment. These findings provide a rationale for targeting MAOA and its associated molecules to treat PCa metastasis.

Keywords: bone metastasis; interleukin-6; monoamine oxidase A; osteoblast; osteoclast; prostate cancer; receptor activator of NF-kB ligand; sonic hedgehog signaling; tumor-stromal interactions; visceral metastasis.

Publication types

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

MeSH terms

Animals
Bone Neoplasms / secondary
Cell Communication*
Hedgehog Proteins / physiology*
Humans
Interleukin-6 / physiology*
Male
Mice
Mice, SCID
Monoamine Oxidase / analysis
Monoamine Oxidase / physiology*
Osteoblasts / physiology
Prostatic Neoplasms / pathology*
RANK Ligand / physiology*
Signal Transduction / physiology*
Stromal Cells / physiology
Tumor Microenvironment

Substances

Hedgehog Proteins
IL6 protein, human
Interleukin-6
RANK Ligand
SHH protein, human
TNFSF11 protein, human
Monoamine Oxidase