To our knowledge there has been no previous report of any genetic mutation or expression change that occurs with such high frequency among patients in a variety of cancers. The regularity of this change suggests that low levels of MAO-A might serve as a biomarker for cancer. In addition, it is possible that the lack of significant differences in thyroid and gastric cancer could be a result of an overall decrease in MAO-A levels in both normal and cancerous tissue. Unfortunately, datasets that compared cancerous thyroid and gastric tissues to those of healthy individuals were not available at the time of this study.
In higher species there are two isoforms of Monoamine Oxidase (MAO): MAO-A and MAO-B. In humans MAO-A preferentially metabolizes serotonin and the dopamine derivatives epinephrine, and norepinephrine; specifically MAO-A is responsible for catalyzing the inactivation of serotonin by removal of a terminal amine group. MAO-B metabolizes phenethylamine, and both MAO-A and MAO-B metabolize dopamine. There is a significant amount of literature regarding the role of dopamine in carcinogenesis [10
], and several studies have indicated that it may have an antiproliferative effect [25
]. The dopamine derivatives epinephrine and norepinephrine have also been implicated in carcinogenesis [26
]. These hormones are released in response to stress and are also metabolized by MOA-A. Both epinephrine and norepinephrine are capable of increasing cell growth in tumor cells [28
] and drugs that prevent norepinephrine signaling can reduce cancer risk [29
]. In contrast the role of serotonin is less clear, while drugs that increase serotonin seem to have a protective effect in leukemias/lymphoms [20
] as well as other cancers [12
], increased serotonin appears to promote mitosis in vitro
]. However our findings of a consistent change in MAO-A, but not MAO-B, in conjunction with the literature provide some support for our premise that the critical role of MAO-A in cancer occurs via the serotonergic system rather than the dopaminergic or catecholamine system.
MAO-A is the target of monoamine oxidase inhibitors (MAOIs), a class of antidepressants. There have been several epidemiologic studies that examine the risk between antidepressants and cancer[15
]. While certain studies link the use of MAOIs with an increase risk for cancer[30
] the literature remains inconclusive about the exact risk [15
]. Given the downregulation of MAO-A observed in cancerous tissue here, one might expect that MAO-A-specific inhibitors may increase cancer risk. Indeed, MAO-AIs and other antidepressants increase cell proliferation in animal models [34
]. If the same is true for humans, then MAO-AI's may be particularly likely to increase cancer risk.
SSRIs, another class of antidepressants, have recently been shown to be effective in vitro
at inducing apoptosis in biopsy-like Burkitt's lymphoma cells, and have been shown in vivo
to reduce the risk of colon cancer [9
]. Visual inspection of data from precancerous tissue in MMTV-Neu and Patched heterozygote transgenic mice suggests that there is more severe downregulation in MAO-A expression in cancer than in the pre-cancerous condition. This study adds to the evidence that SSRIs may be a safer alternative than other antidepressants for treatment of depression in patients with a precancerous condition (such as Atypical Ductal Hyperplasia or Barrett's Esophagus) or cancer [16
Since genechips measure mRNA levels within a complex sample we were unable to discriminate between actively dividing cells and those at rest. It is possible the downregulation of MAO-A observed occurs in the resting cells. Although the presence of downregulation in many cancers is compelling, this evidence is not adequate to establish causation, and further clinical studies are needed to determine whether MAOIs and specifically MAO-AIs cause an increase in cancer risk.