Researchers at the University of Cincinnati have documented that the brain hormone serotonin is made in human breast cancer cells and functions abnormally, contributing to malignant growth.

Wednesday, 16/03/2011  |   Breast Cancer, Herb or Compound, Prostate Cancer  |  no comments

Researchers at the University of Cincinnati have documented that the brain hormone serotonin is made in human breast cancer cells and functions abnormally, contributing to malignant growth.
Researchers in the lab of Nelson Horseman, PhD, a professor in the department of molecular and cellular physiology, published their findings this month in Breast Cancer Research, a peer-reviewed online journal. The study represents the first report of direct involvement of serotonin in human breast cancer.
Horseman’s team has previously shown that serotonin, a neurotransmitter best known for its involvement in mood regulation, plays a role in mammary gland development. Armed with that knowledge, researchers analyzed human breast tumors from patients and in a laboratory setting to determine if serotonin played a role in breast cancer.
In a normal mammary gland, serotonin acts as a physiological regulator of lactation and involution (shrinkage of the milk-making system when it’s not needed), in part by favoring growth arrest and cell death. Researchers found that the serotonin system was subverted in two important ways in human breast cancers.
“First, the amount of serotonin that the breast cancer cells synthesize changes abnormally,” Horseman says. “And second, breast cancer cells have receptors for serotonin that are different from normal breast cells, so they receive the serotonin signal in a different way—and that contributes to abnormal growth.”
The findings open a possible new avenue for diagnosis and prognosis of human breast cancer, Horseman says, and could provide valuable new therapeutic targets for managing the disease, the second-leading cause of cancer death (behind only lung cancer) among American women.
Horseman points out that a number of drugs are in use that affect serotonin levels, including selective serotonin reuptake inhibitors (SSRIs) such as the antidepressants Prozac, Zoloft and Paxil. Further study is needed, he says, to explore their potential anti-cancer benefits.
Accessed 16 Mar 2011 (PhysOrg.com)

Serotonin synthesis and metabolism-related molecules in a human prostate cancer cell line
Prostate cancer is one of the most common tumors in males and its incidence is steadily increasing worldwide. Serotonin or 5-hydroxytryptamine (5-HT) is a well-known neurotransmitter that mediates a wide variety of physiological effects. An increase in the number of 5-HT-releasing neuroendocrine (NE) cells has been correlated with tumor progression. However, it is particularly unclear whether released 5-HT or the release of 5-HT has a role in tumor cell growth. We hypothesized that 5-HT synthesis and metabolism in NE cells regulate the growth of prostate cancer cells. In the present study, 5-HT was found to play a role as a cell growth factor in prostate cancer cells. Moreover, the pharmacological inhibition of 5-HT synthesis and metabolism interrupted the growth of prostate cancer cells. To confirm the existence of 5-HT in prostate cancer cells, we performed ELISA, HPLC, RT-PCR and immunohistochemical analyses. A high expression of tryptophan hydroxylase (TPH-1), dopa decarboxylase (DDC) and monoamine oxidase A (MAO-A) was noted in the prostate cancer cells when compared with normal prostate cells. Previous studies showed that 5-HT stimulated the proliferation of prostate cancer cells mediated by 5-HT receptors 5-HTR1A and R1B. However, cell proliferation was significantly inhibited when siRNA for both DDC and TPH-1 was transfected to the cells. Consequently, we propose that the secretion system of prostate NE cells capable of 5-HT synthesis and metabolism plays a significant role in prostate tumor generation and progression. These findings provide crucial clues for the development of potential pharmacotherapeutics to slow prostate tumor progression.
Source:
Shinka T, Onodera D, Tanaka T, Shoji N, Miyazaki T, Moriuchi T, Fukumoto T. Oncology Letters. March-April 2011, Volume 2 Number 2. Doi: 10.3892/ol.2011.244

Altered serotonin physiology in human breast cancers favors paradoxical growth and cell survival
Introduction

The breast microenvironment can either retard or accelerate the events associated with progression of latent cancers. However, the actions of local physiological mediators in the context of breast cancers are poorly understood. Serotonin (5-HT) is a critical local regulator of epithelial homeostasis in the breast and other organs. Herein, we report complex alterations in the intrinsic mammary gland serotonin system of human breast cancers.
Methods
Serotonin biosynthetic capacity was analyzed in human breast tumor tissue microarrays using immunohistochemistry for tryptophan hydroxylase 1 (TPH1). Serotonin receptors (5-HT1-7) were analyzed in human breast tumors using the Oncomine database. Serotonin receptor expression, signal transduction, and 5-HT effects on breast cancer cell phenotype were compared in non-transformed and transformed human breast cells.
Results
In the context of the normal mammary gland, 5-HT acts as a physiological regulator of lactation and involution, in part by favoring growth arrest and cell death. This tightly regulated 5-HT system is subverted in multiple ways in human breast cancers. Specifically, TPH1 expression undergoes a non-linear change during progression, with increased expression during malignant progression. Correspondingly, the tightly regulated pattern of 5-HT receptors becomes dysregulated in human breast cancer cells, resulting in both ectopic expression of some isoforms and suppression of others. The receptor expression change is accompanied by altered downstream signaling of 5-HT receptors in human breast cancer cells, resulting in resistance to 5-HT-induced apoptosis, and stimulated proliferation.
Conclusions
Our data constitutes the first report of direct involvement of 5-HT in human breast cancer. Increased 5-HT biosynthetic capacity accompanied by multiple changes in 5-HT receptor expression and signaling favor malignant progression of human breast cancer cells (for example, stimulated proliferation, inappropriate cell survival). This occurs through uncoupling of serotonin from the homeostatic regulatory mechanisms of the normal mammary epithelium. The findings open a new avenue for identification of diagnostic and prognostic markers, and valuable new therapeutic targets for managing breast cancer.
Source:
Pai VP, Marshall AM, Hernandez LL, Buckley AR & and Horseman N. Breast Cancer Research 2009, 11:R81 doi:10.1186/bcr2448

Serotonin regulates macrophage-mediated angiogenesis in a mouse model of colon cancer allografts.
Abstract

Serotonin, a neurotransmitter with numerous functions in the central nervous system (CNS), is emerging as an important signaling molecule in biological processes outside of the CNS. Recent advances have implicated serotonin as a regulator of inflammation, proliferation, regeneration, and repair. The role of serotonin in tumor biology in vivo has not been elucidated. Using a genetic model of serotonin deficiency (Tph1(-/-)) in mice, we show serotonin to be crucial for the growth of s.c. colon cancer allografts in vivo. Serotonin does not enhance tumor cell proliferation but acts as a regulator of angiogenesis by reducing the expression of matrix metalloproteinase 12 (MMP-12) in tumor-infiltrating macrophages, entailing lower levels of angiostatin-an endogenous inhibitor of angiogenesis. Accordingly, serotonin deficiency causes slower growth of s.c. tumors by reducing vascularity, thus increasing hypoxia and spontaneous necrosis. The biological relevance of these effects is underscored by the reconstitution of serotonin synthesis in Tph1(-/-) mice, which restores allograft phenotype in all aspects. In conclusion, we show how serotonin regulates angiogenesis in s.c. colon cancer allografts by influencing MMP-12 expression in tumor-infiltrating macrophages, thereby affecting the production of circulating angiostatin.
Source:
Nocito A, Dahm F, Jochum W, Jang JH, Georgiev P, Bader M, Graf R, Clavien PA. Cancer Res. 2008 Jul 1;68(13):5152-8.

Selective serotonin reuptake inhibitors and breast cancer mortality in women receiving tamoxifen: a population based cohort study
Objective

To characterise whether some selective serotonin reuptake inhibitor (SSRI) antidepressants reduce tamoxifen’s effectiveness by inhibiting its bioactivation by cytochrome P450 2D6 (CYP2D6).
Participants Women living in Ontario aged 66 years or older treated with tamoxifen for breast cancer between 1993 and 2005 who had overlapping treatment with a single SSRI.
Main outcome measures Risk of death from breast cancer after completion of tamoxifen treatment, as a function of the proportion of time on tamoxifen during which each SSRI had been co-prescribed.
Results
Of 2430 women treated with tamoxifen and a single SSRI, 374 (15.4%) died of breast cancer during follow-up (mean follow-up 2.38 years, SD 2.59). After adjustment for age, duration of tamoxifen treatment, and other potential confounders, absolute increases of 25%, 50%, and 75% in the proportion of time on tamoxifen with overlapping use of paroxetine (an irreversible inhibitor of CYP2D6) were associated with 24%, 54%, and 91% increases in the risk of death from breast cancer, respectively (P<0.05 for each comparison). By contrast, no such risk was seen with other antidepressants. We estimate that use of paroxetine for 41% of tamoxifen treatment (the median overlap in our sample) would result in one additional breast cancer death within five years of cessation of tamoxifen for every 19.7 (95% confidence interval 12.5 to 46.3) patients so treated; the risk with more extensive overlap would be greater.
Conclusion
Paroxetine use during tamoxifen treatment is associated with an increased risk of death from breast cancer, supporting the hypothesis that paroxetine can reduce or abolish the benefit of tamoxifen in women with breast cancer.
Source:
Kelly CM, Juurlink DN, Gomes T, et al. BMJ 2010; 340:c693 doi: 10.1136/bmj.c693

Serotonin and Cancer Anorexia: Myths or Facts? Letter to the editor
In their excellent paper, Davis et al (1) review the relevant clinical issue of cancer-associated anorexia. Although the paper is very informative, detailed, and updated, we felt that the statement questioning the possible role of brain serotonin in the pathogenesis of human cancer anorexia, “there is no evidence to confirmthe central neurohumoral changes associated with [human] anorexia”, (1) could be misleading, and that a clarification was needed.
In humans, brain serotonergic activity cannot be easily measured in vivo, and therefore is inferred by CSF levels of tryptophan, the precursor of serotonin. In anorectic cancer patients, plasma and CSF concentrations of tryptophan in particular are increased when compared with controls and nonanorectic cancer patients. (2,3) Also, after tumor removal, plasma tryptophan normalizes and food intake improves. (4) The involvement of brain serotonin in cancer anorexia is also supported by data linking this monoamine with the anorexia characterizing other chronic diseases. In uremic patients, the presence of anorexia is associated with low circulating levels of branched-chain amino acids, (5) which compete with tryptophan for brain entry, therefore suggesting increased brain tryptophan levels. (6) Similarly, increased plasma tryptophan levels have been associated with the presence of anorexia in patients with liver cirrhosis. (7)
Finally, the therapeutic approach specifically designed to reduce brain tryptophan entry and serotonin synthesis, that is, administration of branched-chain amino acids, has been shown effective to improve anorexia not only in cancer patients, (8) but in uremic and cirrhotic patients as well. (5,9) We acknowledge that evidence we reported in the preceding paragraph reported could be considered circumstantial. However, we believe that their consistency demonstrated across different clinical settings indicates that serotonin is an important player in experimental and human anorexia.
Source:
A. Laviano and F. Rossi Fanelli & M.M. Meguid. American Society of Clinical Oncology. 2005 DOI: 10.1200/JCO.2005.05.240
References:
1. Davis MP, Dreicer R, Walsh D, et al: Appetite and cancer-associated anorexia: A review. J Clin Oncol 22:1510-1517, 2004
2. Rossi Fanelli F, Cangiano C, Ceci F, et al: Plasma tryptophan and anorexia in human cancer. Eur J Cancer Clin Oncol 22:89-95, 1986
3. Cangiano C, Cascino A, Ceci F, et al: Plasma and CSF tryptophan in cancer anorexia. J Neural Transm Gen Sect 81:225-233, 1990
4. Cangiano C, Testa U, Muscaritoli M, et al: Cytokines, tryptophan and anorexia in cancer patients before and after surgical tumor ablation. Anticancer Res 14:1451-1456, 1994
5. Hiroshige K, Sonta T, Suda T, et al: Oral supplementation of branchedchain amino acid improves nutritional status in elderly patients on chronic haemodialysis. Nephrol Dial Transplant 16:1856-1862, 2001
6. Aguilera A, Selgas R, Codoceo R, et al: Uremic anorexia: A consequence of persistently high brain serotonin levels? The tryptophan/serotonin disorder hypothesis. Perit Dial Int 20:810-816, 2000
7. Laviano A, Cangiano C, Preziosa I, et al: Plasma tryptophan and anorexia in liver cirrhosis. Int J Eat Disord 21:181-186, 1997
8. Cangiano C, Laviano A, Meguid MM, et al: Effects of administration of oral branched-chain amino acids on anorexia and caloric intake in cancer patients. J Natl Cancer Inst 88:550-552, 1996
9. Marchesini G, Bianchi G, Merli M, et al: Nutritional supplementation with brached-chain amino acids in advanced cirrhosis: A double-blind, randomized trial. Gastroenterology 124:1792-1801, 2003

Model of a working hypothesis for 5-HT influences on breast cancer progression. 5-HT is a tumor-suppressing signal in non-transformed breast cells and early stage breast cancers, so early tumor growth relies on reductions in tryptophan hydroxylase 1 (TPH1) expression. During tumor progression, cells acquire genetic or epigenetic alterations in 5-HT signaling which then make them resistant to suppressive 5-HT actions and favor tumor-promoting actions (e.g., dynamic cell junctions and cell shedding), as well as acquisition of new receptors and functions (e.g., stimulated proliferation and epithelial-mesenchymal transition)

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