Molecular aspects of development and regulation of endometriosis

Abstract

Endometriosis is a common and painful condition affecting women of reproductive age. While the underlying pathophysiology is still largely unknown, much advancement has been made in understanding the progression of the disease. In recent years, a great deal of research has focused on non-invasive diagnostic tools, such as biomarkers, as well as identification of potential therapeutic targets. In this article, we will review the etiology and cellular mechanisms associated with endometriosis as well as the current diagnostic tools and therapies. We will then discuss the more recent genomic and proteomic studies and how these data may guide development of novel diagnostics and therapeutics. The current diagnostic tools are invasive and current therapies primarily treat the symptoms of endometriosis. Optimally, the advancement of "-omic" data will facilitate the development of non-invasive diagnostic biomarkers as well as therapeutics that target the pathophysiology of the disease and halt, or even reverse, progression. However, the amount of data generated by these types of studies is vast and bioinformatics analysis, such as we present here, will be critical to identification of appropriate targets for further study.

Figure 1

Transcriptional regulation of proliferation’s factors. NF-kB, STAT and SMADs are the main regulators of such factors as MMP-2, MMP-9, MMP-7, leptin, HGF, TNF-alpha, which can stimulate proliferation of endometriotic lesions.

Figure 2

VEGF and angiopoietin – two main regulators of angiogenesis. Angiogenesis of lesions is essential for endometriotic cell survival and development. Signaling pathways of VEGF and angiopoietin intersect at PI3K.

Figure 3

MicroRNA involved in endometriosis. MicroRNAs (miRNAs) are naturally occurring posttranscriptional regulatory molecules that potentially play a role in endometriotic lesion development. A number of miRNAs are regulated by 17β-estradiol in the endometrial epithelial and stromal cells, including miR-21, miR-23a, miR-26a-1, miR-203, miR-181a, miR-424, and miR-34c. MicroRNA-15b, miR-126 have been predicted to target the expression of VEGF-A; miR-34c-5p – the expression of EGF.

Figure 4

Intracellular regulation of TNF-alpha, VEGF-A, sICAM1 and annexin V. VEGF-A may activate annexin V, a marker of apoptosis, through VEGFR-2. TNF-alpha is regulated by such transcriptional factors as VDR, GATA-3, and NF-kB and is involved in signaling pathways of many growth factors. sICAM1, one of the adhesion molecules involved in the implantation and development of endometriotic lesions, is activated by NF-kB. There are a lot of drugs that have an effect on TNF-alpha, annexin V, VEGF-A and might be potentially used in the treatment of endometriosis.

Figure 5

STAT1 as an integral factor of IGF, HGF, EGF, IL-6, and PDGF signaling pathways. STAT1, 3, and 5 are primarily activated by growth factors and regulate proliferation and apoptosis. A number of growth factors are known to contribute to the increased proliferative potential of cells derived from endometriotic lesions. The effects of such factors as EGF, PDGF, FGFR, IL-6, HGF and VEGF are all primarily achieved through STAT activation.

Figure 6

Intracellular interactions of estradiol, androgens and prolactin. Estradiol, androgens and prolactin signaling pathways also pass through the STATs. STAT1 and STAT3 contribute to the implementation of their effects.

Figure 7

JAK/STAT signaling pathway in endometriosis. The effects of PDGF, FGF, IL-6, HGF, and VEGF are all primarily achieved through STAT activation. The JAK/STAT pathway is a tempting target for novel therapeutics because it is relatively simple mechanistically, providing a direct translation of extracellular signals into a transcriptional response. Of the pathways identified, perhaps the most viable as a biomarker are the STATs. Among the small molecule inhibitors of this pathway are Leflunomide (a JAK inhibitor) and Atiprimod (a STAT3 inhibitor).

Figure 8

TGF-β/SMAD signaling pathway. The SMAD proteins are the only family of transcription factors known to propagate TGF-β signals. Lerdelimumab (a recombinant human IgG4 targeting TGF- β2) and Metelimumab (a human monoclonal IgG4 against TGF- β1) can inhibit TGF-β signaling.

Figure 9

Interactions between MEK, c-Myc, c-Fos and growth factors. The effects of EGF and TNF-alpha are mediate via the MEK-pathway. Selumetinib and other MEK/ERK inhibitors are being primarily developed and studied for cancer treatment. However, the role of the MEK/ERK-pathway in endometriosis suggests that these therapeutic strategies may lend themselves equally well to this disease.