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SP0127 Transition from Chronic Inflammation to Cancer: Immune Endocrine Synergies
  1. M. Cutolo
  1. Division of Rheumatology Internal Medicine, University of Genova, Genova, Italy

Abstract

The complex role of chronic inflammation in carcinogenesis has been extensively investigated and documented over the last decades. Generally, when the acute inflammatory process is unregulated and become chronic, concomitant factors might induce malignant cell transformation in the surrounding tissue (1). Epigenetic perturbations together with important steroid hormone metabolic changes, have been found closely linked to the risk and severity in several chronic inflammatory rheumatic diseases conditions, as well as in cancer. Among the mechanisms involved, are already recognized the cell proliferation that is also induced by endocrine mechanisms such as increase of specific peripheral estrogen metabolites or the increased angiogenesis and increased endothelin 1 (ET-1), that acts in synergism with various growth factors, such as tranforming growth factor beta (TGFbeta) or epidermal growth factor (EGF) to potentiate cellular transformation or replication. In particular. aromatase, is frequently highly expressed in the tumour-bearing breast of women diagnosed as having estrogen receptor (ER) positive tumours, and resulting in dramatically increased local estrogen production to drive tumour progression. On the other hand, it is now evident that prostate is an estrogen target tissue, and estrogens directly and indirectly affect growth and differentiation of prostate (2). Indeed, the formation of catecholestrogen metabolites, that are capable of forming either stable or depurinating DNA adducts, can cause extensive DNA damage and finally disease-specific and cancer autoantibodies. In addition, an important role in both estrogen-driven immune response and cancer, seems to be related to the selection of microRNAs (miRNA), single-stranded non-coding RNAs. In fact, the recently detected selective regulation of miRNA expression in immune cells by estrogen, is indicative of an important role of miRNAs in estrogen-mediated immune diseases in particular in systemic lupus erythematosus (SLE) (3). As consequence of their promoting effects on disease progression, the use of estrogens (oral contraception, estrogens replacement therapy, treatment of infertility etc.) should be avoided in patients with active chronic autoimmune disorders, in order to reduce the risk to potentiate the immune response and even to induce possible carcinogenesis.

A prominent endocrine role for 1,25(OH)D3 (vitamin D) in peripheral estrogen metabolism and related cell proliferative activities was recently discovered. Calcitriol decreases the expression of aromatase, the enzyme that generally catalyzes the peripheral estrogen synthesis from androgens, both in normal and inflammatory conditions, as well as in cancer tissues (i.e. breast and prostate cancer), where the estrogen intracrine synthesis is increased (4).

On the other hands, Inflammatory cytokines (IL-6, IL-1, TNFa) are also strong enhancers of aromatase activity, as reported in chronic inflammatory conditions such as rheumatoid arthritis synovitis. Conversely, vitamin D deficiency seems to play a role in increasing autoantibody production by B cells, and seasonal vitamin D declines may trigger flares in RA patients, as recently shown. Calcitriol seems to exert an inhibitory effect of aromatase transcription by a direct repression via promoter II, as well as to exert an indirect effect, due to a reduction in the levels and biological activity of prostaglandins, especially PGE2, which seems a major stimulator of aromatase transcription. Recently, an enhanced growth inhibitory effect by combining calcitriol and aromatase inhibitors in breast cancer cell cultures was revealed. In addition, it was recently shown that calcitriol down-regulates the expression of estrogen receptors and thereby further reduces estrogen signaling in breast cancer cells, including the cell proliferative stimulus provided by estrogens. All together, these important new achievements suggest that the inhibition of estrogen synthesis and signaling by 1,25(OH)D3 and its anti-inflammatory actions might play an important role in the use of calcitriol for the prevention and/or treatment of breast cancer at least (5). From the clinical side, the negative consequences of low serum 25(OH)D levels seem to support the vitamin D protective role in cancer.

References

  1. Cutolo M et al. Expert Rev Clin Immunol. 2014;10:31-9.

  2. Cutolo M et al. Clin Exp Rheumatol. 2014;32:839-47.

  3. Di Leva et al. PLoS Genet. 2013;9:e1003311.

  4. Feldman D et al. Nat Rev Cancer. 2014;14:342-57.

  5. Byers SW et al. Rev Endocr Metab Disord. 2012;13:31-8

Disclosure of Interest None declared

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