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

• Published in: Cancer cell Vol. 31; no. 3; pp. 368 - 382
• Main Authors: Wu, Jason Boyang, Yin, Lijuan, Shi, Changhong, Li, Qinlong, Duan, Peng, Huang, Jen-Ming, Liu, Chunyan, Wang, Fubo, Lewis, Michael, Wang, Yang, Lin, Tzu-Ping, Pan, Chin-Chen, Posadas, Edwin M., Zhau, Haiyen E., Chung, Leland W.K.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13.03.2017
• Subjects: Animals; bone metastasis; Bone Neoplasms - secondary; Cell Communication; Hedgehog Proteins - physiology; Humans; interleukin-6; Interleukin-6 - physiology; Male; Mice; Mice, SCID; Monoamine Oxidase - analysis; Monoamine Oxidase - physiology; monoamine oxidase A; osteoblast; Osteoblasts - physiology; osteoclast; prostate cancer; Prostatic Neoplasms - pathology; RANK Ligand - physiology; receptor activator of NF-kB ligand; Signal Transduction - physiology; sonic hedgehog signaling; Stromal Cells - physiology; Tumor Microenvironment; tumor-stromal interactions; visceral metastasis; prostate cancer; bone metastasis; visceral metastasis; tumor-stromal interactions; receptor activator of NF-kB ligand; sonic hedgehog signaling; osteoblast; osteoclast; monoamine oxidase A; interleukin-6
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccell.2017.02.003

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. [Display omitted] •MAOA is associated with prostate cancer metastasis in clinical specimens•MAOA promotes metastasis by activating the paracrine Shh-IL6-RANKL signaling•MAOA drives tumor-stromal cell interactions in a vicious-cycle manner•MAOA inhibitor treatment reduces metastasis and prolongs survival in mice Wu et al. show that monoamine oxidase A (MAOA) is an important mediator of prostate cancer bone and visceral metastases by activating paracrine Shh-IL6-RANKL signaling in tumor-stromal interactions. Pharmacological inhibition of MAOA restricts metastasis and extends survival in a mouse prostate cancer model.