INCREASED SUSCEPTIBILITY TO METASTASIS DURING PRO-OESTRUS OESTRUS IN RATS - POSSIBLE ROLE OF ESTRADIOL AND NATURAL-KILLER-CELLS/

It has been suggested that tumour development and immunocompetence are affected by the menstrual and the oestrous cycle, and sex hormones ha ve been shown to modulate lymphokine production, neuroendocrine activi ty and immunity. In this study, we assessed natural killer cell activi ty and host susceptibility to metastasis during the oestrous cycle in the Fisher 344 inbred rat strain. Females were inoculated intravenousl y with MADB106 tumour cells, a syngeneic mammary adenocarcinoma cell l ine that metastasises only to the lungs. The susceptibility to metasta tic development of this tumour was found to be significantly higher du ring pro-oestrus and oestrus than during metoestrus and dioestrus. Two days of exposure to oestradiol benzoate caused similar effects in ova riectomised females, and a single administration of progesterone reduc ed 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 progest erone, suggesting that the effects of sex hormones on the metastatic p rocess are not attributable to a direct effect on tumour cells. Becaus e the metastatic process of MADB106 tumour cells is known, and confirm ed 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 circ ulating blood LG/NK cells (NKR-Pl(+) bright) were studied. Findings in dicated oestrous-dependent alterations in the number of LGL/NK cells a nd suggested a diminished NK activity per LGL/NK cell during pro-oestr us/oestrus, the same phases that were characterised by higher suscepti bility to metastatic development. These findings provide the first emp irical evidence for a causal relationship between a short-term exposur e to elevated oestradiol/low progesterone levels and decreased resista nce to tumour metastasis, and it is hypothesised that an alteration in LGL/NK cell activity underlies these effects. Homologies and relevanc e to clinical phenomena are discussed.