Endometriosis and cancer - Future Medicine

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Endometriosis and cancer

Endometriosis is manifested by the presence of both endometrial glandular and stromal cells outside the uterine cavity. It is characterized by ectopic implantation of endometrial cells with elevated proliferation and migration. Endometriosis is the leading cause of morbidity among premenopausal women and the complex pathogenesis of this disease remains controversial despite extensive research. This rather complex disease has a significant impact on quality of life of many women as none of the current treatments represent a cure. Based on the current knowledge, one can conclude that the histological and genetic alterations in endometriosis might explain why and how endometriosis can change into several types of cancer. However, the exact mechanisms of this conversion are still not fully established. Keywords: cancer • endometriosis • markers • ovarian cancer • stem cells

Endometriosis, often defined as the presence of endometrium or endometrial-like tissue outside the uterus, is manifested by the presence of both endometrial glandular and stromal cells outside the uterine cavity, mainly in the pelvis. This disease is characterized by ectopic implantation of endometrial cells with elevated proliferation and migration. It is the leading cause of morbidity among premenopausal women and the complex pathogenesis of this enigmatic disorder remains controversial despite extensive research [1] . This disease represents one of the most common gynecological problems and affects approximately 10–15% of all women in reproductive age [2] . It is generally believed that this disease is due primarily to retrograde menstruation and/or transplantation of shed endometrium. However, despite significant research, the exact mechanisms leading to the development of endometriosis are still unknown. Among existing theories on the cell origin of endometriosis, one should mention retrograde menstruation and implantation, coelomic metaplasia [3] , embryonic cell rest theory or stem cell theory (for review see [4]). The coelomic metaplasia

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possibility seems to be particularly attractive in cases of endometriosis in the absence of menstruation [5] . This theory is based on the fact that ovary and the Müllerian ducts (progenitors of the endometrium) are both derived from the coelomic epithelium, therefore the metaplasia might explain the development of ovarian endometriosis. Despite the fact that postmenopausal endometrioisis is rare, there is a risk in patients taking hormone therapy [6] . This rather complex disease has a significant impact on quality of life of many women. There are several optional treatments, including hormonal and/or surgical treatment, but none of those represent a cure. Despite the fact that endometriosis is a benign disease, more and more studies support the notion that it represents the initial stages of neoplastic processes. Atypical endometriosis most probably represents a transitional form from benign disease to cancer. The common features shared by endometriosis and cancer include the ability to evade apoptosis, the adult stem cell-like dysregulation, neovascularization, progressive course, implantation at distant sites, creation of a

Womens Health (2014) 10(6), 591–597

Milena Králíčková1,2,3, Petr Losan1,2,3 & Vaclav Vetvicka*,4 1 Department of Histology & Embryology, Faculty of Medicine, Charles University, Karlovarska 48, Plzen, Czech Republic 2 Department of Obstetrics & Gynecology, University Hospital, Faculty of Medicine, Charles University, Alej Svobody 80, Plzen, Czech Republic 3 Biomedical Centre, Faculty of Medicine, Charles University, Plzen, Czech Republic 4 Department of Pathology, University of Louisville, 511 S Floyd, Louisville, KY 40202, USA *Author for correspondence: vaclav.vetvicka@ louisville.edu

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Review Králíčková, Losan & Vetvicka microenvironment that renders its course independent and mobilization of the immune system. Some studies suggested that changes in characteristics of eutopic endometrium of women with endometriosis (unusual formation of various cytokines, growth factors and/or angiogenic factors can serve as an example) might play a role in the establishment and maintenance of this disease. Another possibility might be changes in expression of specific cancer-related genes. Women with endometriosis appear to be more likely to develop certain types of cancer, such as ovarian, hematopoietic (primarily non-Hodgkin’s lymphoma) and brain tumors [2,7–9] . In addition to these clearly established connections, the results of studies examining the association between endometriosis and breast cancer are often contradictory [8] and the newest population-based cohort studies showed no overall association [10] . In fact, the connection between endometriosis and ovarian cancer was mentioned for the first time almost 90 years ago [11] . Many of the risk factors associated with both ovarian cancer and endometriosis are similar, including more regular periods, lower parity and earlier menarche. However, it is quite possible that endometrosis itself is a risk factor for ovarian cancer [1,12] . Endometriosis and ovarian cancer are linked, but the relationship is not clear cut. A 2002 pooled case–control study demonstrated that the lifetime chance of ovarian cancer was 50% higher among women suffering from endometriosis. Factors such as duration of oral contraception use or the number of births played no significant role in these statistics. Subsequent case–control study revealed up to 3.5-fold higher development of endometrioid and clear cell tumors among these women [13] . On the other hand, a systematic review of all abstracts between 1985 and 2010 showed only modest effects, ranging between 1.3 and 1.9 [2] . Both endometriosis and ovarian cancer are progressive and depend on estrogen for their growth (endometrial tissue shows elevated activity of aromatase, an enzyme used for a key step in the biosynthesis of estrogens). Further support for the theory of estrogen importance is the fact that women with synchronous primary cancers of the ovary and the endometrium have distinct clinical characteristics [14] . A study comparing patients having typical epithelial ovarian cancer with ovarian cancer associated with endometriosis showed that the patients with the latter disease strongly differ in both biological and histological characteristics, including serum levels of Ca125 and distribution of histological subtypes [15] . Endometriosis-related ovarian neoplasms (ERONs) are a group of tumors commonly associated with endometriosis. This is particularly true for endometriosis manifested as an ovarian endometriotic cyst.

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These ERONs represent heterogeneous types of cancer including clear cell carcinoma, endometrioid carcinoma and seromucinous borderline tumor [16] . Endometrioid adenocarcinoma being predominantly positive for estrogen receptors, while the clear cell carcinoma exhibit lower estrogen receptor (ER) expression [17] . Besides these more common types of cancer, the less common types include endometrial stromal sarcoma. These cancers are rare with only 79 cases being reported since 1977 (for review see [18]). Ovarian cancers are in general, described as type I and type II. The major differences are based on histological grade, molecular phenotype and genotype. Type I ovarian cancers are mostly low grade, serous, endometroid or clear cell cancer, whereas the more common type II cancers are high grade of serous, endometroid or undifferentiated histotype (for review see [19]). Our review is focused on the complex connections between endometriosis and cancer – mainly on common molecular mechanisms underlying endometriosis as well as cancer. Evasion of apoptosis Based on numerous studies, it is clear that the euthopic endometrium is the place where primary defect in endometriosis can be located [20] . As endometriums of healthy women do not have abnormalities inherent to the eutopic endometrium, the primary defects might participate in the ectopic growth outside the uterine cavity [21] . Evidence for a relationship between cancer and endometriosis are substantial, especially in endometriotic and clear cell ovarian carcinomas. Thus, many hypothesize that changes in the expression of tumor suppressor genes and oncogenes occurring in the eutopic endometrium might lead to overgrowth of endometrial foci outside the uterus [22,23] . As endometriosis is characterized by genetic instability, it is not surprising that mutations in genes known to suppress tumors, such as PTEN, p53, bcl, ARID1A and TP53, have been found in both ovarian tumors and endometriotic lesions [24,25] . However, the exact mechanisms remain unknown. Genome-wide association studies and as well as transcriptome sequencing have shown that genes from the 1p36 region might be important in both endometriosis and endometriosisassociated cancer development [26] . Additional studies found KRAS, PTEN, LOH, PIK3CA and BRAF mutations [19] . Endometriosis is a multifactorial disease and new data suggest that severe dysregulations of microRNA expression might be one of the causes. MicroRNA plays an important role of regulatory molecules (both suppressor and oncogenes) in cancer development.

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Endometriosis & cancer

Recent findings of aberrantly expressed miRNAs in ovarian and endometrial cancers suggest their role in gynecological pathology and cancers. Since these microRNAs can be found in serum and plasma, they might be utilized as possible biomarkers of these diseases or for development of therapeutic agents that block the expression or functions of these particular microRNAs (for review see [27]). Microsatellite analysis showed that loss of heterozygosity on p16(Ink4), p53, APOA 2 and GALT which occur often in ovarian cancer, occur also in endometriosis (for review see [1]). Recently, the endometriosis-associated ovarian carcinogenesis has been linked to oxidative stress-induced increased genomic instability, aberrant methylation and aberrant chromatin remodeling, as well as mutations of tumor suppressor genes [28] . Additional possibilities include the loss of estrogen functions resulting in strong changes in clear cell carcinoma progression and aggressiveness [17] . Molecular analyses of ERONs, most of all genomewide screens, have shown several molecular genetic alterations resulting in aberrant activation and/or inactivation of several pathways involving ARID1A, PI3K, Wnt and PP2A. So far, inactivating mutations of the ARID1A tumor suppressor gene are the most common in ERON [16] . Genome-wide studies identified a locus at 7p15.2 and changes in expression of genes such as heat-shock protein, S100 and Toll-like receptor 4 (for review see [7]). Stem cells dysregulation Adult stem cells that have been identified in the endometrium are involved in the regenerative ability of the endometrial cycle and also in the pathogenesis of proliferative gynecological diseases, such as endometriosis (for review see [29]). Mouse studies showed that endometriosis impaired bone marrow-derived stem cell recruitment to the uterus. The authors hypothesize that competition between the endometriosis and the eutopic endometrium for a limited supply of stem cells might be a novel mechanism by which endometriosis interferes with endometrial function and/or fertility [30] . In addition, evidence of endometrial regeneration by bone marrow-derived stem cells in patients receiving bone marrow transplantation suggest a possible new treatment and support a new hypothesis for the etiology of endometriosis [31] . Studies regarding endometrial stem cells lag behind the extensive research done on other tissues, therefore our knowledge of possible markers for endometrial adult stem cells needs both validation and analysis. More is known about cancer stem cells, where a CD133 is now considered to be a valid marker. Lately,


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this marker is even used as a prognostic factor in endometrial carcinoma (for review see [32]). With recent findings in stem cell biology offering new opportunities for both diagnosis and treatment of reproductive problems, the possibility of cultivating the ovarian stem cells into mature oocytes was presented. In addition, endometrial stem cells have been demonstrated to be useful in treatment of various medical problems (for review see [31]). Out of control angiogenesis Processes of angiogenesis play significant role in endometrial growth as well as in several gynecological disorders including endometriosis. Menstrual cycle phase has a significant effect on vessel segment length, within each region as well as within each of the uterus layers. In endometrial layers, vessel length and branch point densities were greater in the fundal than the isthmic regions, regardless of the phase of the menstrual cycle. At the same time, vessel segment lengths were the greatest in the isthmic region [33] . Angiogenesis is not the only process driving neovascularization of endometriotic lesions. Their formation also involves significant formation of microvessels originating from circulating endothelial progenitor cells [34] . This postnatal vasculogenesis is well-established in various pathogenic conditions including tumor growth and atherosclerosis. Typical manifestations involve activation, mobilization and recruitment of bone marrow-derived endothelial progenitor cells to the sites of tissue hypoxia [34] . Compared with healthy women, in secretory phase eutopic endometrium from women with endometriosis we can find higher microvessel density, expression of VEGF-A in glandular epithelium and VEGFR-2 in endometrial blood vessels. The same can be mentioned about endometriotic lesions with high proliferative activity. Severe dysregulation of angiogenic activity in the eutopic endometrium of women with endometriosis can be an important factor [35] . Results of animal studies are less clear. Estrogen can be either anti-angiogenic or pro-angiogenic. Progesterone increases angiogenesis. The findings showing that the basalis has approximately five-times as many lymphatic vessels than the functionalis cannot be currently explained [36] . Some studies suggest the role of VEGF-C or VEGF-D, but more studies are clearly needed. As the endometrium is known to be a major target tissue for progesterone and estrogen action, any serious disturbance in the hormone-tissue axis might significantly impair endometrial functions. More information regarding altered gene expression and progesterone resistance can be found in [37] , on clinical perspectives

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Review Králíčková, Losan & Vetvicka of effects of progesterone in women with endometriosis in [38] . In addition, progesterone resistance might be pronounced in patients with endometriosis [39] . The involvement of vasculogenesis in endometriosis may offer the exciting opportunity leading to the establishment of novel diagnostic and therapeutic strategies for this frequent gynecological disease. Failure of natural immunological mechanisms Alterations in both cell-mediated and humoral immunity contribute to the pathogenesis of endometriosis (for review see [21]). Activity of macrophages, T and B lymphocytes and natural killer (NK) cells in women with endometriosis promote immune tolerance to implanted tissue in the peritoneal environment. Several reports showed reduced activities of cytotoxic T cells and autoantibodies production in patients with endometriosis [40,41] . Increased KIR(+)NK cells in peripheral blood may represent a risk factor for endometriosis [42] . Increased number and activation of peritoneal macrophages, and decreased T-cell and NK-cell cytotoxic effects observed in endometriosis [43] represent significant changes in cellular immunity and might result in inadequate removal of ectopic endometrial cells from the peritoneal cavity. Among several immunological aspects, iron-induced oxidative stress, inflammation and hyperestrogenism have been suggested to form important links between endometriosis and cancer (for review see [25]). As mentioned above, both endometriosis and cancers are linked to inflammation. This disease was associated with increase in inflammatory markers such as CA-125 and C-reactive proteins. It is well documented that inflammation can in some cases cause cancer – for example, hepatitis can lead to liver carcinoma [44] and asbestosis might result in carcinoma of the lung [45] . Endometriosis is characterized by a chronic inflammatory state, which leads to the release of several cytokines. These cytokines may promote the growth of tumors by causing unregulated mitotic division, growth and differentiation. Readers seeking more information on the role of cytokines in endometriosis should see an excellent review by Nezhat et al. [46] . In addition, both diseases are related to early menarche and late menopause and also infertility [47] . In addition, repeated hemorrhage in endometriosis can contribute to carcinogenesis via increasing oxidative stress, promoting DNA methylation, activation of anti-apoptotic pathways and changed expression of stress signaling pathways [48] . Peritoneal cytokines, which are produced by mesothelial cells, leukocytes and ectopic endometrial cells, interwork locally and systemically in women with

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endometriosis [49] . Increased levels of several cytokines and growth factors which are secreted by immune or endometrial cells seem to promote implantation and growth of ectopic endometrium via induction of proliferation and angiogenesis. It is known that COX-2 and IL-1β can regulate the invasion of ectopic mesothelial cells. In future, these effects might be utilized in developing a new therapeutic strategy for endometriosis. Better characterization of mesothelial cells will need ex vivo invasion model [50] . Besides the diminished capacity of the immune cells to mediate removal of endometrial cells, inherent resistance of ectopic endometrial cells represents another exciting concept in the pathogenesis of endometriosis [51] . Endometriosis has also been considered to be an autoimmune disease, due to the often observed presence of autoantibodies [52] and additional autoimmune diseases [53] . On the other hand, the direct link between endometriosis and autoimmunity is still elusive (for review see [7]). Although immune cells are recruited into endometriotic lesions, their role is unclear. Tie2-expressing macrophages have no redundant functions in promoting angiogenesis and growth of experimental tumors. They are important for maintaining the viability of newly formed vessels and represent a potential therapeutic target in endometriosis [54] . Fertilization For women with severe endometriosis, IVF represents an effective option with prognosis identical to otherwise healthy patients [55] . Due to the potential problems with ovarian deficiency, the IFV treatment should be initiated as early as clinically possible. The possibility of the specific oocytes retrieval-related risk should be mentioned. No evidence of an increased risk of ovarian cancer following IVF in women who give birth exists. On the other hand, conflicting evidence regarding the effect of IVF in women who remain nulliparous. On one hand, parous women with endometriosis may have a slightly increased risk of ovarian cancer; on the other hand, nulliparous women have significant increase in risk of cancer [56] . Conclusion & future perspective Research in the field of endometriosis is limited due to the absence of a low-cost and reliable method for diagnosing endometriosis, especially in early stages. Based on the current knowledge, one can conclude that the histological and genetic alterations in endometriosis might explain why and how endometriosis can change into several types of cancer. However, the exact mechanisms of this conversion are still not fully established.



Clearly, there is an urgent need for new approaches in understanding and treatment of endometriosis. Financial & competing interests disclosure Supported by the project CZ.1.05/2.1.00/03.0076 from European Regional Development Fund. The authors have no

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other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Executive summary Evasion of apoptosis • Endometriosis is a multifactorial disease. • Genes located in the 1p36 region are important in both endometriosis and cancer development. • MicroRNAs might be utilized as possible biomarkers.

Stem cells dysregulation • Adult stem cells in the endometrium are involved in the pathogenesis of endometriosis. • CD133 might be a prognostic marker in endometrial carcinoma.

Out of control angiogenesis • Secretory phase eutopic endometrium from women with endometriosis has higher microvessel density. • Higher vascular expression of VEGFR-2.

Natural immunological mechanisms • Changes in both humoral and cellular immunity contribute to endometriosis. • Oxidative stress, inflammation and hyperestrogenism might form links between endometriosis and cancer.

Fertilization • IVF treatment should be initiated soon. • Parous women diagnosed with endometriosis may have slight risk of ovarian cancer.

Conclusion • Absence of simple and/or low-cost methods for diagnosis limits the research in this field. Histologic and genetic alterations in endometriosis might offer explanation how endometriosis progresses into several types of cancer.

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