NK Cell Activity and Estrogen Hormone Levels during Normal Human Pregnancy

Gabrilovac, Jelka; J, Zadjelović; Osmak, Maja; Suchanek, Ernest; Županović, Željko; Boranić, Milivoj

doi:10.1159/000293766

Cited by 52 publications

(23 citation statements)

References 12 publications

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“…It is well established that NK cells are among the main effectors of innate antitumor immune surveillance, and their importance in controlling tumor dissemination is widely accepted (22). On the other hand, pregnancy is a state of dampened cellular immunity, and NK activity in particular has been suggested to be decreased during murine (34) as well as human (35)(36)(37) pregnancies. Accordingly, we found a decrease in NK cell proportions in blood, spleen, lungs, and liver of 16-day pregnant mice and greatly reduced NK cell cytotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Myeloid-derived suppressor cells are implicated in regulating permissiveness for tumor metastasis during mouse gestation

Mauti

Bitoux²,

Baumer³

et al. 2011

J. Clin. Invest.

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Metastasis depends on the ability of tumor cells to establish a relationship with the newly seeded tissue that is conducive to their survival and proliferation. However, the factors that render tissues permissive for metastatic tumor growth have yet to be fully elucidated. Breast tumors arising during pregnancy display early metastatic proclivity, raising the possibility that pregnancy may constitute a physiological condition of permissiveness for tumor dissemination. Here we have shown that during murine gestation, metastasis is enhanced regardless of tumor type, and that decreased NK cell activity is responsible for the observed increase in experimental metastasis. Gene expression changes in pregnant mouse lung and liver were shown to be similar to those detected in premetastatic sites and indicative of myeloid cell infiltration. Indeed, myeloid-derived suppressor cells (MDSCs) accumulated in pregnant mice and exerted an inhibitory effect on NK cell activity, providing a candidate mechanism for the enhanced metastatic tumor growth observed in gestant mice. Although the functions of MDSCs are not yet understood in the context of pregnancy, our observations suggest that they may represent a shared mechanism of immune suppression occurring during gestation and tumor growth.

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Section: Discussionmentioning

confidence: 99%

Myeloid-derived suppressor cells are implicated in regulating permissiveness for tumor metastasis during mouse gestation

Mauti

Bitoux²,

Baumer³

et al. 2011

J. Clin. Invest.

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“…Indeed, chronic exposure to oestradiol or progesterone under natural conditions (e.g. pregnancy) (Gabrilovac et al, 1988) or artificial conditions (e.g. some oral contraceptives, implants of oestradiol in ovariectomised rodents) (Baker et al, 1989;Hanna and Schneider, 1982;Seaman and Gindhart, 1979) was associated with suppressed NK activity, as were chronically elevated levels of prolactin (Hou and Zheng, 1988;Vidaller et al, 1992).…”

Section: Discussionmentioning

confidence: 99%

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

Ben‐Eliyahu

Page²,

Shakhar³

et al. 1996

Br J Cancer

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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.

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“…An interesting aspect of this systemic immunomodulation is that it simultaneously embraces cellular immunosuppression, immunotolerance to various antigens, and enhanced inflammatory response. In humans, it is specifically characterized by (a) an increase in WBC counts (23); (b) a suppression of NKCC that is strongest in the third trimester (33)(34)(35)(36); (c) a decrease in the ratio of Th1/Th2 cytokines, especially in the third trimester (23,24); (d) an increase in certain proinflammatory cytokines [e.g., interleukin-6 (IL-6), tumor necrosis factor-a], especially in the second half of pregnancy (21); (e) an increase in the number of regulatory T cells (37,38); (f) an increase in asymmetrical immunoglobulin G (IgG) antibodies, which can bind antigen but are unable to activate effector function (39,40); (g) a decrease in various breast cancer -related antibodies, such as anti-MUC1 IgM (41,42); and (h) an increased expression of various activation-associated adhesion molecules on granulocytes and monocytes (23).…”

Section: Immunomodulation Associated With Pregnancymentioning

confidence: 99%

Heightened Risk of Breast Cancer Following Pregnancy: Could Lasting Systemic Immune Alterations Contribute?

Shakhar

Valdimarsdottir

Bovbjerg

2007

Cancer Epidemiology, Biomarkers &Amp; Prevention

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The protective effect of having a first full-term pregnancy (FFTP) at a younger age on women's lifetime risk of breast cancer is well known. Less appreciated is the increased risk seen in the years immediately following pregnancy. This adverse effect is more pronounced and more prolonged in women with later age at FFTP. The mechanisms responsible for this increased risk are still poorly understood. In the present paper, we put forward the hypothesis that the marked peripheral immune changes induced by pregnancy may account for these effects. We highlight immune changes that characterize the unique immune state of pregnancy (a combination of cellular immunosuppression and enhanced inflammatory response), note the resemblance of these changes to cancer escape mechanisms, and discuss why such immune changes may be critical for the development of breast cancer following pregnancy. We further support this idea by initial findings from our own laboratory that the age at FFTP is negatively related to natural killer cell cytotoxicity many years later and propose possible models for the kinetics of the immune changes during and following pregnancy. The effect of age at FFTP on the immune function is currently understudied. Its potential relevance to the development of breast cancer stresses the need for further research. (Cancer Epidemiol Biomarkers Prev 2007;16(6):1082 -6) The widely known protective effect of having a first full-term pregnancy (FFTP) at an earlier age on women's lifetime risk of developing breast cancer has been extensively documented over the past 30 years and is included as a factor in the classic Gail model of breast cancer risk (1). Less widely appreciated are more recent data from large-scale studies indicating that this protective effect is preceded by a period of increased risk for breast cancer, especially among women with later age at FFTP (2-8). This increased risk of developing breast cancer is both more pronounced and more prolonged in women with later age at FFTP (3)(4)(5)8). Indeed, the crossover from increased to decreased risk of breast cancer following pregnancy, which occurs after about 10 years for women whose FFTP was before the age of 25, occurs only after about 20 years for women whose FFTP was between 25 and 29, and may never crossover for women whose FFTP occurred after the age of 35 (3, 10).The mechanisms underlying what has been termed the ''dual'' effect of pregnancy on breast cancer risk are largely unknown. Reduced susceptibility to carcinogenesis due to terminal differentiation of mammary gland stem cells is increasingly recognized as a likely mechanism for the longterm reduction of risk following an early pregnancy (2,11,12). To date, speculation concerning the mechanisms responsible for the initial increased risk of breast cancer following pregnancy has also centered on possible effects on breast tissues, including the extracellular matrix (2, 13). These effects are most commonly attributed to the high proliferative rate of breast cells during pregnancy and t...

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NK Cell Activity and Estrogen Hormone Levels during Normal Human Pregnancy

Cited by 52 publications

References 12 publications

Myeloid-derived suppressor cells are implicated in regulating permissiveness for tumor metastasis during mouse gestation

Myeloid-derived suppressor cells are implicated in regulating permissiveness for tumor metastasis during mouse gestation

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

Heightened Risk of Breast Cancer Following Pregnancy: Could Lasting Systemic Immune Alterations Contribute?

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