Serotonin Metabolism Is Dysregulated in Cholangiocarcinoma, which Has Implications for Tumor Growth

Abstract

Cholangiocarcinoma is a devastating cancer of biliary origin with limited treatment options. Symptoms are usually evident after blockage of the bile duct by the tumor, and at this late stage, they are relatively resistant to chemotherapy and radiation therapy. Therefore, it is imperative that alternative treatment options are explored. We present novel data indicating that the metabolism of serotonin is dysregulated in cholangiocarcinoma cell lines, compared with normal cholangiocytes, and tissue and bile from cholangiocarcinoma patients. Specifically, there was an increased expression of tryptophan hydroxylase 1 and a suppression of monoamine oxidase A expression (enzymes responsible for the synthesis and degradation of serotonin, respectively) in cholangiocarcinoma. This resulted in an increased secretion of serotonin from cholangiocarcinoma and increased serotonin in the bile from cholangiocarcinoma patients. Increased local serotonin release may have implications on cholangiocarcinoma cell growth. Serotonin administration increased cholangiocarcinoma cell growth in vitro, whereas inhibition of serotonin synthesis decreases tumor cell growth both in vitro and in vivo. The data presented here represent the first evidence that serotonin metabolism is dysregulated in cholangiocarcinoma and that modulation of serotonin synthesis may represent an alternative target for the development of therapeutic strategies. [Cancer Res 2008;68(22):9184-93]

Monoamine oxidase A mediates prostate tumorigenesis and cancer metastasis

“…These regulations, particularly the induction of androgen by MAOA, may be an important underlying clue for the expression and function of MAOA in PCa distinct from other types of cancer. Moreover, serotonin, a monoamine neurotransmitter degraded preferentially by MAOA, has been shown to act as a growth factor for several types of cancer (47,48), including melanoma (49) and cholangiocarcinoma (50). Inhibition of MAOA by clorgyline, which elevated serotonin levels, showed protection of melanoma cells against cell death (51).…”

Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA)

“…Bile Interestingly, some of those mediators, such as sero tonin or endogenous opioid peptides, limit cholangiocyte hyperplasia in response to damage 99,102,105 However, such a function is lost in the course of CCA development, in which they stimulate cell growth and survival 99,102,105 . Among neuroendocrine factors that either inhibit proliferation or induce apoptosis secretin, gastrin, γ-aminobutyric acid, endothelin-1 and the endocannabinoid anandamide have been described 103,104,[106][107][108][109][110][111] .…”

“…Examples of factors promoting proliferative effects in CCA cells include serotonin, dopamine, leptin, opioids and the endocannabinoid 2-arachidonoylglycerol [99][100][101][102][103][104] .…”

Secretin inhibits cholangiocarcinoma growth via dysregulation of the cAMP‐dependent signaling mechanisms of secretin receptor

“…Cholangiocarcinoma tissue array analysis. Immunoreactivity for SCTR and the cholangiocyte marker CK-19 were assessed in commercially available Accumax tissue arrays (Isu Abxis Co.) by immunohistochemistry, as described, 25 using specific antibodies. These tissue arrays contain 48 well-characterized cholangiocarcinoma biopsy samples from a variety of tumordifferentiation grades, as well as 4 control liver biopsy samples.…”