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The greater frequency and aggressiveness of hepatocellular carcinoma (HCC) in men than in women might be attributable to greater synthesis and accumulation of serotonin in males, according to a report published online in Cellular and Molecular Gastroenterology and Hepatology (2017 May. doi: 10.1016/j.jcmgh.2017.01.002).
HCC is nearly five times more common in men than in women, and several molecular studies “have shown a more robust and active HCC tumor microenvironment” in men as well. For example, the density of infiltrating, tumor-associated macrophages is higher among males in a mouse model of the cancer, and human men have substantially higher amounts of intratumoral cluster-of-differentiation cells and neutrophils that indicate a poor prognosis, said Qiqi Yang, PhD, of the department of biological sciences at the National University of Singapore, and her associates.
The investigators developed several zebrafish models of HCC in which the cancer could be induced by transgenic expression of an oncogene in the animals’ hepatocytes. These models “allow the oncogene to be activated at a given and controlled timing in both sexes, providing an excellent platform to study the sex disparity in HCC initiation and progression,” they noted.
They also confirmed the zebrafish findings in human lab studies by analyzing tissue samples from 5 normal livers, 7 inflamed livers, 16 cirrhotic livers, and 30 livers affected with HCC.
The investigators found an increased level of serotonin production in male, compared with female, livers. They demonstrated that serotonin was necessary for the survival of hepatic stellate cells, which also are more abundant in males than in females and have recently been shown to promote tumorigenesis. Serotonin also was crucial for activating hepatic stellate cells during HCC carcinogenesis.
In addition, serotonin levels were significantly elevated in inflamed, cirrhotic, and cancerous livers, compared with normal livers, among men but not among women. “This is in line with the prevailing knowledge that men have a significantly higher rate of serotonin synthesis than do women,” Dr. Yang and her associates said.
Serotonin is a small molecule neurotransmitter with diverse functions such as modulation of mood, appetite, wound healing, gastrointestinal motility, and blood coagulation. It was shown that serotonin can promote liver regeneration in mice via a direct action on hepatocytes, the main building blocks of liver. However, other cell types such as liver stellate cells, the main liver fibrogenic cells, can also be influenced by serotonin. Serotonin action on liver stellate cells results in production of transforming growth factor–beta1 (TGF-beta1), a multifunctional cytokine. TGF-beta1 can then inhibit regeneration of hepatocytes and promote fibrosis. In a new study, scientists have shown that the same pathway is active during hepatic carcinogenesis and promotes development of cancer in a zebrafish model. They also discovered that hepatocytes can produce serotonin and increase TGF-beta1 synthesis in stellate cells. Interestingly, they uncovered a significant sexual dimorphism in both human and fish samples in components of this pathway (for example, more serotonin and TGF-beta1 in males). This study unravels underlying mechanisms of sex differences in liver cancer. Importantly, it can provide a therapeutic opportunity to treat human liver cancer by modulation of serotonin signaling. This approach is attractive since potent and selective pharmacologic agents for serotonin signaling are already available for other purposes such as modulation of gut motility or neurological disorders. Future studies using human cells or samples will pave the path toward clinical translation of these findings.
Mo Ebrahimkhani, MD, is an assistant professor in the school of biological and health systems engineering, Arizona State University, Tempe. He has no conflicts of interest.
Serotonin is a small molecule neurotransmitter with diverse functions such as modulation of mood, appetite, wound healing, gastrointestinal motility, and blood coagulation. It was shown that serotonin can promote liver regeneration in mice via a direct action on hepatocytes, the main building blocks of liver. However, other cell types such as liver stellate cells, the main liver fibrogenic cells, can also be influenced by serotonin. Serotonin action on liver stellate cells results in production of transforming growth factor–beta1 (TGF-beta1), a multifunctional cytokine. TGF-beta1 can then inhibit regeneration of hepatocytes and promote fibrosis. In a new study, scientists have shown that the same pathway is active during hepatic carcinogenesis and promotes development of cancer in a zebrafish model. They also discovered that hepatocytes can produce serotonin and increase TGF-beta1 synthesis in stellate cells. Interestingly, they uncovered a significant sexual dimorphism in both human and fish samples in components of this pathway (for example, more serotonin and TGF-beta1 in males). This study unravels underlying mechanisms of sex differences in liver cancer. Importantly, it can provide a therapeutic opportunity to treat human liver cancer by modulation of serotonin signaling. This approach is attractive since potent and selective pharmacologic agents for serotonin signaling are already available for other purposes such as modulation of gut motility or neurological disorders. Future studies using human cells or samples will pave the path toward clinical translation of these findings.
Mo Ebrahimkhani, MD, is an assistant professor in the school of biological and health systems engineering, Arizona State University, Tempe. He has no conflicts of interest.
Serotonin is a small molecule neurotransmitter with diverse functions such as modulation of mood, appetite, wound healing, gastrointestinal motility, and blood coagulation. It was shown that serotonin can promote liver regeneration in mice via a direct action on hepatocytes, the main building blocks of liver. However, other cell types such as liver stellate cells, the main liver fibrogenic cells, can also be influenced by serotonin. Serotonin action on liver stellate cells results in production of transforming growth factor–beta1 (TGF-beta1), a multifunctional cytokine. TGF-beta1 can then inhibit regeneration of hepatocytes and promote fibrosis. In a new study, scientists have shown that the same pathway is active during hepatic carcinogenesis and promotes development of cancer in a zebrafish model. They also discovered that hepatocytes can produce serotonin and increase TGF-beta1 synthesis in stellate cells. Interestingly, they uncovered a significant sexual dimorphism in both human and fish samples in components of this pathway (for example, more serotonin and TGF-beta1 in males). This study unravels underlying mechanisms of sex differences in liver cancer. Importantly, it can provide a therapeutic opportunity to treat human liver cancer by modulation of serotonin signaling. This approach is attractive since potent and selective pharmacologic agents for serotonin signaling are already available for other purposes such as modulation of gut motility or neurological disorders. Future studies using human cells or samples will pave the path toward clinical translation of these findings.
Mo Ebrahimkhani, MD, is an assistant professor in the school of biological and health systems engineering, Arizona State University, Tempe. He has no conflicts of interest.
The greater frequency and aggressiveness of hepatocellular carcinoma (HCC) in men than in women might be attributable to greater synthesis and accumulation of serotonin in males, according to a report published online in Cellular and Molecular Gastroenterology and Hepatology (2017 May. doi: 10.1016/j.jcmgh.2017.01.002).
HCC is nearly five times more common in men than in women, and several molecular studies “have shown a more robust and active HCC tumor microenvironment” in men as well. For example, the density of infiltrating, tumor-associated macrophages is higher among males in a mouse model of the cancer, and human men have substantially higher amounts of intratumoral cluster-of-differentiation cells and neutrophils that indicate a poor prognosis, said Qiqi Yang, PhD, of the department of biological sciences at the National University of Singapore, and her associates.
The investigators developed several zebrafish models of HCC in which the cancer could be induced by transgenic expression of an oncogene in the animals’ hepatocytes. These models “allow the oncogene to be activated at a given and controlled timing in both sexes, providing an excellent platform to study the sex disparity in HCC initiation and progression,” they noted.
They also confirmed the zebrafish findings in human lab studies by analyzing tissue samples from 5 normal livers, 7 inflamed livers, 16 cirrhotic livers, and 30 livers affected with HCC.
The investigators found an increased level of serotonin production in male, compared with female, livers. They demonstrated that serotonin was necessary for the survival of hepatic stellate cells, which also are more abundant in males than in females and have recently been shown to promote tumorigenesis. Serotonin also was crucial for activating hepatic stellate cells during HCC carcinogenesis.
In addition, serotonin levels were significantly elevated in inflamed, cirrhotic, and cancerous livers, compared with normal livers, among men but not among women. “This is in line with the prevailing knowledge that men have a significantly higher rate of serotonin synthesis than do women,” Dr. Yang and her associates said.
The greater frequency and aggressiveness of hepatocellular carcinoma (HCC) in men than in women might be attributable to greater synthesis and accumulation of serotonin in males, according to a report published online in Cellular and Molecular Gastroenterology and Hepatology (2017 May. doi: 10.1016/j.jcmgh.2017.01.002).
HCC is nearly five times more common in men than in women, and several molecular studies “have shown a more robust and active HCC tumor microenvironment” in men as well. For example, the density of infiltrating, tumor-associated macrophages is higher among males in a mouse model of the cancer, and human men have substantially higher amounts of intratumoral cluster-of-differentiation cells and neutrophils that indicate a poor prognosis, said Qiqi Yang, PhD, of the department of biological sciences at the National University of Singapore, and her associates.
The investigators developed several zebrafish models of HCC in which the cancer could be induced by transgenic expression of an oncogene in the animals’ hepatocytes. These models “allow the oncogene to be activated at a given and controlled timing in both sexes, providing an excellent platform to study the sex disparity in HCC initiation and progression,” they noted.
They also confirmed the zebrafish findings in human lab studies by analyzing tissue samples from 5 normal livers, 7 inflamed livers, 16 cirrhotic livers, and 30 livers affected with HCC.
The investigators found an increased level of serotonin production in male, compared with female, livers. They demonstrated that serotonin was necessary for the survival of hepatic stellate cells, which also are more abundant in males than in females and have recently been shown to promote tumorigenesis. Serotonin also was crucial for activating hepatic stellate cells during HCC carcinogenesis.
In addition, serotonin levels were significantly elevated in inflamed, cirrhotic, and cancerous livers, compared with normal livers, among men but not among women. “This is in line with the prevailing knowledge that men have a significantly higher rate of serotonin synthesis than do women,” Dr. Yang and her associates said.
FROM CELLULAR & MOLECULAR GASTROENTEROLOGY & HEPATOLOGY
Key clinical point: The greater frequency and aggressiveness of hepatocellular carcinoma in men than in women might be attributable to greater synthesis and accumulation of serotonin in males.
Major finding: Serotonin levels were significantly elevated in 7 inflamed, 16 cirrhotic, and 30 cancerous livers, compared with 5 normal livers, among men but not among women.
Data source: Laboratory studies involving a zebrafish model of HCC and tissue samples from 60 human livers.
Disclosures: This study was supported by the National Medical Research Council and the Ministry of Education of Singapore. Dr. Yang and her associates reported no relevant financial disclosures.