Increased susceptibility to metastasis during pro-oestrus/oestrus in rats: possible role of oestradiol and natural killer cells

Abstract

Summary It has been suggested that tumour development and immunocompetence are affected by the menstrual and the oestrous cycle, and sex hormones have been shown to modulate lymphokine production, neuroendocrine activity and immunity. In this study, we assessed natural killer cell activity and host susceptibility to metastasis during the oestrous cycle in the Fischer 344 inbred rat strain. Females were inoculated intravenously with MADB106 tumour cells, a syngeneic mammary adenocarcinoma cell line that metastasises only to the lungs. The susceptibility to metastatic development of this tumour was found to be significantly higher during pro-oestrus and oestrus than during metoestrus and dioestrus. Two days of exposure to oestradiol benzoate caused similar effects in ovariectomised females, and a single administration of progesterone reduced this effect of oestradiol to a statistically non-significant level. The tumour was found to be negative for oestradiol receptors, and its in vitro proliferation rate was not affected by oestradiol or progesterone, suggesting that the effects of sex hormones on the metastatic process are not attributable to a direct effect on tumour cells. Because the metastatic process of MADB106 tumour cells is known, and confirmed here, to be highly controlled by large granular lymphocyte/natural killer (LGL/NK) cell activity, we assessed their role in mediating the effects of the oestrous cycle. The number and activity levels of circulating blood LG/NK cells (NKR-Pl+bright) were studied. Findings indicated oestrous-dependent alterations in the number of LGL/NK cells and suggested a diminished NK activity per LGL/NK cell during pro-oestrus/ oestrus, the same phases that were characterised by higher susceptibility to metastatic development. These findings provide the first empirical evidence for a causal relationship between a short-term exposure to elevated oestradiol/low progesterone levels and decreased resistance to tumour metastasis, and it is hypothesised that an alteration in LGL/NK cell activity underlies these effects. Homologies and relevance to clinical phenomena are discussed.

Timing within the menstrual cycle, sex, and the use of oral contraceptives determine adrenergic suppression of NK cell activity

“…Some reported a decrease in NK activity during the follicular phase (White et al, 1982), some a significant reduction around the periovulatory period (Sulke et al, 1985), and others reported no differences (Thyss et al, 1984). Animal studies are also inconsistent in this respect (Hrushesky et al, 1988;Ben-Eliyahu et al, 1996). It is our hypothesis that whereas baseline levels of NK activity may not be affected by the ovulatory cycle, the suppressive effects of stress, specifically those induced by catecholamines, are modulated by the ovulatory cycle.…”

Timing within the oestrous cycle modulates adrenergic suppression of NK activity and resistance to metastasis: possible clinical implications

“…Secondly, in a previous study, we have shown that the infusion of physiological levels of oestradiol, but not progesterone, to ovariectomized F344 females, increased susceptibility to MADB106 metastasis. This effect was evident only 24 h after the infusion of oestradiol (Ben-Eliyahu et al, 1996), as was also the case in the current study in which the effects were evident only 24 h after the rise in oestradiol levels. Thirdly, expression of β-adrenergic receptors on women's lymphocytes was found to be higher during days of elevated oestradiol levels (days 21-23 vs. days 2-4) (Wheeldon et al, 1994), although in humans this period is also characterized by high levels of progesterone.…”

“…Rats did not synchronize their oestrous cycle within or between cages in any of the experiments, as was the case in our previous studies (Ben-Eliyahu et al, 1996). About half of the rats had a cycle of 4 days and half of 5 days.…”

“…Additionally, in order to avoid unplanned exposure of leukocytes to catecholamines secreted upon blood withdrawal, plasma was rapidly replaced by an artificial medium (see Methods). Such measures were not taken in previous studies, in which we and others found oestrous cycle effects on NKA and resistance to metastasis without deliberately exposing rats to stress hormones (White et al, 1982(White et al, , 1997Sulke et al, 1985;Ratajczak et al, 1988;Ben-Eliyahu et al, 1996;Page and Ben-Eliyahu, 1997). Based on the findings of the current study, in which the effects of the oestrous cycle are shown to be limited to conditions of stress or adrenoceptor stimulation, we suggest that the previous findings are attributable to unintended procedural stress and the systemic release of catecholamines.…”

“…It reduces the time between blood withdrawal and assessment of cytotoxicity, and lessens the potential interference with NK cell function. Our previous studies (Page et al, 1994;Ben-Eliyahu et al, 1996) indicate that cytotoxicity in this assay depends on NK cells, since their selective depletion nullified all specific killing.…”