Endometriosis Stem Cells as a Possible Main Target for Carcinogenesis of Endometriosis-Associated Ovarian Cancer (EAOC)

Abstract

Endometriosis is a serious recurrent disease impairing the quality of life and fertility, and being a risk for some histologic types of ovarian cancer defined as endometriosis-associated ovarian cancers (EAOC). The presence of stem cells in the endometriotic foci could account for the proliferative, migrative and angiogenic activity of the lesions. Their phenotype and sources have been described. The similarly disturbed expression of several genes, miRNAs, galectins and chaperones has been observed both in endometriotic lesions and in ovarian or endometrial cancer. The importance of stem cells for nascence and sustain of malignant tumors is commonly appreciated. Although the proposed mechanisms promoting carcinogenesis leading from endometriosis into the EAOC are not completely known, they have been discussed in several articles. However, the role of endometriosis stem cells (ESCs) has not been discussed in this context. Here, we postulate that ESCs may be a main target for the carcinogenesis of EAOC and present the possible sequence of events resulting finally in the development of EAOC.

Keywords: endometriosis; endometriosis stem cells; endometriosis-associated ovarian cancer; ovarian cancer; stem cells.

Figure 1

Niche for endometriosis epithelial stem cells Endometriosis epithelial stem cells (SCs) are regulated by several components of the endometriotic niche. Immune cells (natural killers (NK), Th1 and Th2 lymphocytes, Th17 lymphocytes, T regulatory cells (Tregs) and M1/M2 macrophages) are engaged in both elimination and supporting of endometrial lesions and their resultant action followed by secretion of cytokines and chemokines has a deep influence on survival of endometriosis epithelial SCs. Repeated injury and tissue repair (ReTRIAR) syndrome changes the ECM components and promotes fibrosis of implants. Fibrogenesis-mediated changes of gene expression, together with a pro-inflammatory environment could account for DNA damage in epithelial SCs. The mutational pressure of oxidative stress and heme metabolism products could depend on the fibrotic status of the endometriosis lesion. Oxidative stress, hypoxia and iron overload are highly mutagenic for epithelial SCs. Mesenchymal SCs are a relevant component of epithelial SCs niche. The participation of mesenchymal SCs in activin-A/ connective tissue growth factor (CTGF) pathway augments peritoneal inflammation and fibrosis in ectopic endometrial lesions. Disturbances in activin-A/CTGF pathway may be involved in carcinogenesis. Bone marrow-derived stem cells (BMDSCs) through cytokine secretion promote proliferation in endometriotic lesions. Estradiol is a hormonal mediator of mobilization of endothelial progenitor cells into endometrial implants, and in chemoattraction of BMDSCs into endometriosis implant’s stroma. Estradiol has also a stimulatory effect on inflammation and proliferation of implants. Finally, the components of diet and environmental toxins could modulate the function of endometriosis epithelial SCs.

Figure 2

A hypothetical sequence of events leading from beginning of endometriosis towards its malignant transformation. In women presenting with a genetic predisposition or having epigenetic transgenerational gene modification endometriosis could emerge inside the peritoneal cavity, tubes and ovaries. Disturbed hormonal function (estrogenic stimulation) and ineffective immunological response enhance the chances for progressive growth of endometriotic lesions. Endometriosis epithelial stem cells (ESCs) originating either from endometrial stem cells or from bone marrow-derived stem cells are present inside endometriotic lesions. The prolonged existence of endometriotic foci leads to changes that could push ESCs to increased proliferative and functional activity. The mechanisms that contribute to these changes involve the occurrence of driver mutations (ARID1A, PI3KCA, PTEN, KRAS), ReTRIAR syndrome, epigenetic regulation by miRNA and DNA methylation. All these changes support the proliferative activity and migration potential of ESCs. Moreover, the DNA of the endometriotic ESCs could be damaged by a hostile environment composed of oxidative chronic stress, hypoxia, products of heme metabolism and a pro-inflammatory setting. These are known stimuli sustaining the function and survival of stem cells. Finally, in the group of elderly patients with non-treated endometriosis the progression into endometriosis-associated ovarian cancer (EAOC) takes place. The origin of EAOC is probably dependent on several trigger mechanisms influencing ESCs cells. One of the most probable events is so-called “second hit” mutation which destabilizes genetically ESCs with previous ARID1A or other mutations. Other triggers could be disturbed chaperone and galectins functions. One of the most relevant stimuli originates in our opinion from disturbed mesenchymal SCs function. These cells present inside the stroma of endometriotic lesions support proliferative activity and probably stemness of epithelial ESCs. Exposition to environmental toxins or improper diet components could be the final step in changing the ESCs into cancer stem cells (CSCs), and endometriosis into atypical endometriosis or EAOC.