All ETDs from UAB

Advisory Committee Chair

Zhican Qu

Advisory Committee Members

Mary Ann Bjornsti

Andra Frost

Xu Feng

Document Type

Dissertation

Date of Award

2012

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Serotonin (5-hydroxytryptamine, 5-HT) is a well-known "happy" neurotransmitter. Selective serotonin reuptake inhibitors (SSRIs) are the most prescribed class of antidepressant medications to raise the serotonin level in the brain. However, the majority of serotonin in the human body is present outside of the brain and stored in platelets in blood circulation. Blood coagulation is a common feature of malignant solid tumors and leads to significant serotonin release from activated platelets into tumor environment. Due to the unique feature of platelet in lacking nucleus, the impact of platelet and serotonin on cancer progression has been overlooked by studies focusing on cancer genomic profiling. This research with in vitro and in vivo approaches has demonstrated serotonin angiogenesis promoting activities. Serotonin receptor 1B (HTR1B) has been identified for its high expression level in human endothelial cells and its role in mediating serotonin induced angiogenic signaling. Serotonin and the known angiogenic factor, vascular endothelial growth factor (VEGF) stimulate a same set of downstream signaling kinases, highlighting the overlapping angiogenic signalings activated by different angiogenic factors in tumor environment. These results suggest a potential mechanism underlying the resistance to the current VEGF-targeting anti-angiogenic therapy against cancer. Selective antagonists of HTR1B have demonstrated in vitro anti-angiogenic activities and inhibition of tumor angiogenesis in an ex vivo tumor angiogenesis model system. Systemic treatment of tumor-bearing mice with HTR1B antagonists has resulted in a significant inhibition against tumor growth and tumor microvessel density in a xenograft mouse model of human ovarian cancer. This study provides evidence that, under physiologically relevant conditions of tumor environment, serotonin functions as a potent angiokine with a higher angiogenic potential than that of VEGF and reveals a new molecular mechanism of tumor angiogenesis. This research has identified HTR1B and its downstream angiogenic-signaling pathway as novel targets for development of new cancer therapy. In addition, to understand the correlation between the antidepressants use and cancer risks as a critical public health issue, this study suggests a future investigation on possible effects of SSRIs in tumor angiogenesis through regulating serotonin levels in tumor environment and around dormant tumor.

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