Dim light during darkness stimulates tumor progression by enhancing tumor fatty acid uptake and metabolism

Abstract

Tumor linoleic acid uptake and metabolism, and growth are suppressed by melatonin, the synthesis of which is inhibited by light. Linoleic acid, via its mitogenic metabolite 13-hydroxyoctadecadienoic acid (13-HODE) is an important growth stimulant of rat hepatoma 7288CTC. Here we compared the effects of an alternating light:dark cycle (12L:12D), dim light (0.25 lux) present during the dark phase of a diurnal light cycle, and constant light on growth and fatty acid metabolism in hepatoma 7288CTC. Our results show that dim light suppressed melatonin release by the pineal gland, increased tumor linoleic acid uptake and 13-HODE production, and promoted tumor growth as effectively as did constant light.

Introduction

In recent years there has been a growing interest regarding the impact of both dietary and environmental factors on cancer growth. These factors include high fat diets [1] and increased exposure to artificial light at night [2]. Visible light influences circadian rhythms, a property of all eukaryotic organisms, and in turn affects parameters including the photobiologically-induced alterations in animal physiology and metabolism [3], [4], [5], [6]. Light-induced chronobiologic disruptions can occur in several behavioral and physiologic situations that encompass the sleep-wake cycle, food consumption and neuroendocrine secretions [6], [7], [8], [9], [10], [11]. In mammals entrained by a regular alternation in light and darkness, blood concentrations of melatonin during the light phase are low while levels during the dark phase are high [5]. Even low intensity light stimuli during the dark phase may alter normal circadian rhythms and suppress night time melatonin production by the pineal gland [7], [8], [12]. Concerning the acute suppressive effect of light on nocturnal melatonin, dose-response curves show that exposure to 1.2 lux (0.5 μW/cm²) of white light during the night is sufficient to suppress melatonin in rats [8] and hamsters [9]. Further studies in hamsters demonstrate that even lower illuminances at 0.05 lux (0.022 μW/cm²) of monochromatic (500 nm) green light can suppress pineal melatonin [10]. In fact, there is a wide range of sensitivity to light for melatonin suppression among different mammalian species [6], [7], [11].

With respect to neoplastic growth, physiological as well as pharmacological concentrations of melatonin possess oncostatic properties both in vivo and in vitro [13]. Like pinealectomy [14], [15], [16], constant light exposure increases the incidence of chemically-induced mammary cancers [16], [17], an effect presumed to be due to a suppression of melatonin production [3], [4], although the exact mechanism has never been elucidated. Based on these studies, Stevens postulated [2] that the melatonin-suppressive effects of ‘light-at-night’ in human populations may contribute to an increased risk of breast cancer. Supporting this hypothesis is recent evidence showing that blind individuals have a lower incidence of a variety of cancers, particularly breast cancer, as compared with sighted people [18], [19], [20], [21].

The growth of a variety of tumors, particularly rat hepatoma 7288CTC, is directly dependent upon ambient blood concentrations of linoleic acid, an ω-6 essential fatty acid (C18:2n9c12c). Linoleic acid is taken up by hepatoma 7288CTC and converted to 13-HODE [12], [22], a mitogenic metabolite [23] that is essential for the growth this tumor [22]. However, it is important to note that linoleate and 13-HODE also can have antiproliferative actions in hyperproliferative guinea pig epidermis [24] and mouse skin cancer [25]. Recent evidence from our laboratory indicates that melatonin inhibits hepatoma growth by blocking linoleic acid uptake and 13-HODE production in a circadian-dependent manner [26]. Furthermore, we recently reported [12] that a marked suppression in nocturnal plasma melatonin levels and a stimulation of hepatoma growth and linoleic acid uptake and metabolism was associated with the contamination of the animal quarters during the dark phase with as little as 0.2 lux (0.06 μW/cm²) of indirect, reflected fluorescent light leaking through the door from an adjacent room. This suggested that dim light during darkness may lead to an increase in cancer progression vis-à-vis the Stevens’ hypothesis [2]. In order to directly test this hypothesis, we examined the effects of carefully controlled direct illuminance with dim light (0.25 lux) from a dedicated light source present inside the animal room during the dark phase, on the growth of tissue-isolated hepatoma 7288CTC in male rats. The results of this investigation suggest a unique relationship between night time suppression of melatonin and enhanced tumor growth and linoleic acid metabolism.