There is evidence that endometriosis as well as drugs used in the process of in vitro fertilisation appear to associate with increased risk for gynaecological cancer. In this review, we attempt to describe this relationship according to the most recent epidemiologic data and to present the possible mechanisms on the molecular level that could potentially explain this correlation.
There are data to support that ovarian endometriosis could have the potential for malignant transformation. Epidemiologic and genetic studies support this notion. It seems that endometriosis is associated with specific types of ovarian cancer (endometrioid and clear cell). There is no clear association between endometriosis and breast or endometrial cancer. More studies are needed to establish the risk factors that may lead to malignant transformation of this condition and to identify predisposed individuals who may require closer surveillance. Currently, there is no proven relationship between any type of gynaecological cancer and drugs used for infertility treatment. In principle, infertile women have increased risk for gynaecologic malignancies. Nulligravidas who received treatment are at increased risk for malignancy compared with women who had conceived after treatment. There is limited evidence that clomiphene citrate use for more than six cycles or 900 mg or treatment of women over the age of 40 could increase their risk for ovarian and breast cancer. More studies with the appropriate statistical power and follow-up time are required to evaluate accurately the long-term effects of these drugs and procedures.
Introduction
Endometriosis is a disorder of the reproductive age defined as the presence of endometrial-like tissue (e.g., glands and stroma) outside of the endometrial cavity. Endometriosis is uncommon before menarche and it frequently regresses after menopause. The prevalence of endometriosis reaches 7–15% among women of reproductive age, but can increase up to 25–30% in women with infertility and to 40–70% in women with pelvic pain. Although endometriosis is considered to be a benign condition, it shares characteristics often encountered in malignancy, such as development of local and distant metastases, attachment, invasion and subsequent damage of adjacent tissues. Endometriosis, however, does not cause metabolic disturbance, does not have catabolic consequences and does not lead to death.
Studies that have investigated the overall risk of cancer in women with endometriosis have failed to demonstrate an increased risk for cancer in those women compared with population controls. In a study involving 64 492 Swedish patients hospitalised with the diagnosis of endometriosis, with an average follow-up of 12.7 years, the overall risk of cancer was similar to the general population (standardised incidence ratio (SIR) 1.04, 95% confidence interval (CI): 1.00–1.07). Similarly, no overall increased risk of cancer (age-adjusted relative risk (RR) 0.9, 95% CI: 0.7–1.2) was found after 13 years of follow-up in an epidemiological study of 1392 postmenopausal women with a self-reported history of endometriosis.
Although endometriosis does not appear to be associated with an increased risk of cancer in general, evidence is accumulating suggesting a relation between endometriosis and specific types of cancer. To date, the main scientific interest has been focussed on the relationship between endometriosis and gynaecological cancer, with special emphasis on ovarian cancer.
Endometriosis and ovarian cancer
Sampson was the first to describe, back in 1925, a malignancy (ovarian carcinoma) derived by an endometriotic lesion. Since then, several studies have indicated a relation between endometriosis and ovarian cancer.
In a Swedish study involving 20 686 patients with endometriosis with an average follow-up of 11.4 years, the risk for developing ovarian cancer was about 2 times higher than in the general population (standardised incidence ratio (SIR) 1.9, 95% confidence interval (CI): 1.3–2.8). Furthermore, for women with long-standing endometriosis involving the ovaries, the risk was even higher (SIR 4.2, 95% CI 2.0–7.7). A more recent study from Scandinavia, which included 28 163 women with endometriosis, had also showed that these women had a 30% increase in the possibility of developing ovarian cancer.
In the study by Melin et al., with an average follow-up period of 12.7 years, an increased risk for ovarian cancer was documented in women with endometriosis compared with the general population (SIR 1.43, 95% CI: 1.19–1.71). Women with early diagnosed and long-standing endometriosis had a higher risk of ovarian cancer, with SIR of 2.01 and 2.23, respectively. Women who had a hysterectomy before or at the time of the endometriosis diagnosis did not show an increased risk of ovarian cancer, suggesting that hysterectomy or possibly tubal occlusion (ligation) may offer some protection. Both these studies, however, have been criticised that they have overestimated the risk of ovarian cancer in women with endometriosis, due to the fact that the cohorts were hospitalised patients with more advanced stages of endometriosis.
There is sufficient evidence to support that endometriosis is related to specific histological types of ovarian cancer. In a pathology review of 1000 consecutive cases, there was a strong correlation between endometriosis and endometrioid and clear cell ovarian carcinomas, whereas extraovarian endometriosis was associated with adenocarcinomas and adenosarcomas. In a review of 556 patients with ovarian cancer, the frequency of endometriosis was significantly higher in patients with endometrioid, clear-cell and mixed-types tumours (26.3%, 21.1% and 22.2% respectively) compared with those with mucous or serous carcinomas.
In another study, pathology slides from 79 patients with stage I epithelial cancer of the ovary were evaluated. Endometriosis was evident in 22 out of the 79 cases (28%). Ovarian tumours of endometriod, clear cell and mixed type were associated with endometriosis in 39%, 41% and 50%, respectively. Thirty-two percent of the ovarian tumours developed in areas of endometriosis, with evidence of progression from benign to atypical endometriosis (characterised by cytologic atypia and architectural proliferation) to cancer.
These findings were confirmed by Ogawa et al., who in 127 patients with primary ovarian carcinoma documented 37 patients with endometriosis. Out of 43 patients with clear-cell carcinoma 30 had endometriosis (70%), and out of seven patients with endometrioid carcinoma three had endometriosis (43%). By contrast, endometriosis was documented in only four out of 60 (7%) patients with serous carcinoma and in none out of 17 with mucinous carcinoma. Twenty-nine cases had atypical endometriosis and the transition from atypical endometriosis to carcinoma was evident in 23 cases. The authors concluded that atypical endometriosis could be a precancerous condition for ovarian carcinoma.
Others, however, do not support this notion. Olson et al., in a group of 37 434 postmenopausal women, which included a cohort of 1392 patients with a self-reported diagnosis of endometriosis, failed to document any increased risk of ovarian carcinoma (RR 0.8, 95% CI: 0.2–2.4). This study had an acceptable follow-up period of 13 years, but has been criticised by the fact that the cohort was small and included only three ovarian cancer cases. Other limitations of this study were the inclusion of only postmenopausal women and the fact that the diagnosis of endometriosis was not surgically confirmed.
The relationship between endometriosis and ovarian cancer was further explored in terms of causality by Vigano et al. by employing the nine criteria proposed by Austin Bradford Hill, which still stand as fundamental of causal inference. The criterion of strength was not fulfilled, and there were mixed or insufficient data for four criteria (i.e., biological gradient, biological plausibility, analogy and coherence). The other four criteria (i.e., consistency, temporality, specificity and experimental evidence in animal model) were fulfilled, and the authors concluded that a causal relationship between endometriosis and ovarian cancer should be recognised, but that the low magnitude of the risk observed could be associated with the fact that ectopic and eutopic endometrium undergo malignant transformation with the same frequency.
Molecular and genetic aspects linking endometriosis to ovarian cancer
During the past several years, a significant amount of research on molecular and genetic factors that may connect endometriosis to ovarian cancer has been conducted. There is significant evidence to support the presence of common molecular pathways for the development of both conditions. On the other hand, the existing data highlight the possibility of endometriosis being a benign disease that may transform into a malignant one.
Both endometriosis and ovarian cancer share common pathogenetic factors such as familiar predisposition, genetic instability and a similar reaction to immunologic, angiogenetic and hormonal factors. Similar alterations in the immune response cascade and in the mechanism of inflammation have been observed in women with ovarian cancer and endometriosis.
Mechanisms that lead to both ovarian cancer and endometriosis due to genetic instability include deactivation of one or two alleles of tumour-suppressive genes, changes of the enzymes that act in DNA repair and higher oncogenic activity. The most commonly affected chromosome loci include 9p, 11q and 22q.
Mutations in the genes that encode metabolic and detoxification enzymes, like GALT and GSTM, have been implicated in the pathogenesis of endometriosis as well as in development of ovarian cancer. Mutations in PTEN, a tumour-suppressive gene, have been documented in endometriosis as well as in certain histologic types of ovarian carcinomas. PTEN mutations as well as loss of heterozygosity (LOH) at locus 10q23.3 are quite common in ovarian endometriomas, in atypical endometriosis as well as in endometrioid and clear-cell ovarian cancers. K-ras is an oncogene that has been related to endometriosis and ovarian cancer. Mutations of K-ras are found in clear-cell ovarian carcinomas in women with endometriosis. K-ras mutations were found in cancerous cells, but not in the neighbouring cells with endometriosis or atypical endometriosis. According to the investigators, K-ras mutations are associated with malignant transformation of benign endometriosis to clear-cell carcinoma of the ovaries. In a rodent model, activation of the oncogenic K-ras or conditional PTEN deletion within the ovarian surface epithelium gave rise to pre-neoplastic ovarian lesions with an endometrioid glandular morphology. The authors were able to demonstrate that a combination of the two mutations in the ovary leads to the induction of invasive and widely metastatic endometrioid ovarian adenocarcinomas.
The p-53 and c-erbB-2 genes have also been found to associate with endometriosis-related ovarian cancer. The expression of these two oncogenes was significantly higher in the endometriosis-associated clear-cell tumours compared with those patients without endometriosis. These findings were in agreement with the report by Sainz de la Cuesta et al. In their study, 17 out of 410 (4.1%) women with epithelial ovarian cancer had endometriosis, whereas six out of 521 (1.2%) women with endometriosis had atypical lesions. Of the 17 patients, 14 (82.4%) with endometriosis-associated ovarian cancer and six out of six (100%) women with atypical endometriosis had an over-expression of the p-53 gene. Only two out of 17 (11.8%) women with endometriosis had a mutation of the p-53 gene, and this difference was statistically significant.
Endometriosis and ovarian cancer: response to oestrogen stimulation
Oestrogens have been linked to the pathogenesis and growth of three common women’s cancers (i.e., breast, endometrium and ovary). The key enzyme for oestrogen biosynthesis or, in fact, conversion of androgens to oestrogens is aromatase. Tissue-specific aromatase expression is regulated by tissue-specific promoters located upstream of a common coding region. Aromatase gene expression in malignant tumours of the breast, endometrium and ovary is primarily regulated by a promoter located in the 1.3/II region. These promoters are stimulated by PGE2 via a cAMP/PKA-dependent pathway. Thus, inflammatory substances such as PGE2 may play an important role in inducing local production of oestrogens that promote tumour growth.
Agents that block the function of this enzyme, ‘aromatase inhibitors’, have been used successfully in the treatment of breast cancer, whereas their roles in endometrial and ovarian cancers are less clear. Aromatase inhibitors have also been used in the treatment of endometriosis.
Oestrogen-induced triggering is similar in both endometriosis and oestrogen-dependent neoplasms. Normally, oestradiol is being metabolised to oestrone, a weak oestrogen, by the action of the enzyme 17-β-hydroxysteroid dehydrogenase (17-β-HSD) type-2, which is being induced by progesterone in the endometrium. In endometriosis, a local increase in oestradiol concentration has been described, attributed to an increased expression of cytochromal-P450 aromatase and a simultaneous insufficient expression of 17-β-HSD type-2, which has been attributed to a resistance of the endometriotic lesions to progesterone.
Ovarian cancer seems to be connected to oestrogen action as well. Seeger et al. concluded that oestradiol and its derivatives may have a variable impact on the survival and growth of ovarian cell lines and the quantification of these derivatives may be of prognostic value of the risk women have for the development of ovarian cancer. O’Donnell et al. have shown that the potential carcinogenic action of oestrogen are mediated through oestrogen receptor (ER-α). In ovarian cancer cell lines, genes controlled through ER-α-mediated transcription had a threefold increase in their expression, whereas there was no change in the expression of genes controlled by ER-β-mediated transcription.
Increased expression of ER-α has also been shown in active endometriosis. Samples from 33 peritoneal and 37 ovarian endometriotic lesions were examined and analysed, using polymerase chain reaction (PCR) and in situ hybridisation (ISH). In active endometriosis lesions, higher ER-α than ER-β levels have been observed, a finding that is in contrast to what happens in the non-active lesions. These findings support the role of the increased expression of oestrogen receptors (especially ER-α) in the pathogenesis of endometriosis.
Growth factors such as TGF-a and IGF-I have also been implicated in the development of endometriosis as well as of ovarian cancer. Women with severe endometriosis have significantly higher IGF-I levels in their plasma compared with controls. Moreover, menopausal and premenopausal women with high-IGF-I serum levels are at increased risk of developing ovarian, endometrial and cervical cancer.
Resistance to apoptotic mechanisms: Bcl-2 over-expression, Bax down-regulation
Over-expression of anti-apoptotic (Bcl-2) genes and under-expression of pre-apoptotic (Bax) factors, as well as deactivation of the p53 tumour-suppressive gene, through gene mutations are often involved in the pathogenesis of malignancy. Spontaneous apoptosis is significantly decreased in the eutopic endometrium of women with endometriosis compared with healthy controls. In addition, increased expression of the anti-apoptotic gene Bcl-2 and suppression of the pre-apoptotic gene Bax has also been noted during the proliferative-phase endometrium of those women.
Local tissue invasion and metastatic potential
Both endometriosis and ovarian cancer have the ability to invade and spread to neighbouring structures as well as in remote locations. The mechanism of tumour invasion involves the secretion of matrix metalloproteinases (MMPs) to penetrate the basal membrane and stroma. In endometriosis, a similarly increased action of MMPs is observed. The expression and localisation of several MMPs were evaluated by immunohistochemistry in women with endometriomas. MMP-1, -2 and -9 were strongly detected in both stromal and epithelial cells, whereas MMP-3 was mainly expressed in macrophages containing haemosiderin. Based on these results, the authors suggested that the destruction of the surrounding matrix by endometriosis might be caused by various MMPs, which are mainly produced in stromal cells.
In the study conducted by Ueda et al., the expression of E-cadherin, a- and b-katenin, MMP-2, MMP-9 and membrane-type-1-MMP (MT1-MMP) were evaluated in 35 women with endometriosis and in 12 normal controls. The expression of MMP-2, MMP-9 and MT1-MMP in coloured lesions was significantly higher in comparison to normal endometrium, whereas the expression of E-cadherin, a- and b-katenin was not suppressed in the endometriosis lesions. B-katenin, E-cadherin and P-cadherin in combination with increased expression of MMPs probably play a role in the pathogenesis of endometriosis and in the development of several malignant conditions, including ovarian cancer.
Endometriosis and ovarian cancer
Sampson was the first to describe, back in 1925, a malignancy (ovarian carcinoma) derived by an endometriotic lesion. Since then, several studies have indicated a relation between endometriosis and ovarian cancer.
In a Swedish study involving 20 686 patients with endometriosis with an average follow-up of 11.4 years, the risk for developing ovarian cancer was about 2 times higher than in the general population (standardised incidence ratio (SIR) 1.9, 95% confidence interval (CI): 1.3–2.8). Furthermore, for women with long-standing endometriosis involving the ovaries, the risk was even higher (SIR 4.2, 95% CI 2.0–7.7). A more recent study from Scandinavia, which included 28 163 women with endometriosis, had also showed that these women had a 30% increase in the possibility of developing ovarian cancer.
In the study by Melin et al., with an average follow-up period of 12.7 years, an increased risk for ovarian cancer was documented in women with endometriosis compared with the general population (SIR 1.43, 95% CI: 1.19–1.71). Women with early diagnosed and long-standing endometriosis had a higher risk of ovarian cancer, with SIR of 2.01 and 2.23, respectively. Women who had a hysterectomy before or at the time of the endometriosis diagnosis did not show an increased risk of ovarian cancer, suggesting that hysterectomy or possibly tubal occlusion (ligation) may offer some protection. Both these studies, however, have been criticised that they have overestimated the risk of ovarian cancer in women with endometriosis, due to the fact that the cohorts were hospitalised patients with more advanced stages of endometriosis.
There is sufficient evidence to support that endometriosis is related to specific histological types of ovarian cancer. In a pathology review of 1000 consecutive cases, there was a strong correlation between endometriosis and endometrioid and clear cell ovarian carcinomas, whereas extraovarian endometriosis was associated with adenocarcinomas and adenosarcomas. In a review of 556 patients with ovarian cancer, the frequency of endometriosis was significantly higher in patients with endometrioid, clear-cell and mixed-types tumours (26.3%, 21.1% and 22.2% respectively) compared with those with mucous or serous carcinomas.
In another study, pathology slides from 79 patients with stage I epithelial cancer of the ovary were evaluated. Endometriosis was evident in 22 out of the 79 cases (28%). Ovarian tumours of endometriod, clear cell and mixed type were associated with endometriosis in 39%, 41% and 50%, respectively. Thirty-two percent of the ovarian tumours developed in areas of endometriosis, with evidence of progression from benign to atypical endometriosis (characterised by cytologic atypia and architectural proliferation) to cancer.
These findings were confirmed by Ogawa et al., who in 127 patients with primary ovarian carcinoma documented 37 patients with endometriosis. Out of 43 patients with clear-cell carcinoma 30 had endometriosis (70%), and out of seven patients with endometrioid carcinoma three had endometriosis (43%). By contrast, endometriosis was documented in only four out of 60 (7%) patients with serous carcinoma and in none out of 17 with mucinous carcinoma. Twenty-nine cases had atypical endometriosis and the transition from atypical endometriosis to carcinoma was evident in 23 cases. The authors concluded that atypical endometriosis could be a precancerous condition for ovarian carcinoma.
Others, however, do not support this notion. Olson et al., in a group of 37 434 postmenopausal women, which included a cohort of 1392 patients with a self-reported diagnosis of endometriosis, failed to document any increased risk of ovarian carcinoma (RR 0.8, 95% CI: 0.2–2.4). This study had an acceptable follow-up period of 13 years, but has been criticised by the fact that the cohort was small and included only three ovarian cancer cases. Other limitations of this study were the inclusion of only postmenopausal women and the fact that the diagnosis of endometriosis was not surgically confirmed.
The relationship between endometriosis and ovarian cancer was further explored in terms of causality by Vigano et al. by employing the nine criteria proposed by Austin Bradford Hill, which still stand as fundamental of causal inference. The criterion of strength was not fulfilled, and there were mixed or insufficient data for four criteria (i.e., biological gradient, biological plausibility, analogy and coherence). The other four criteria (i.e., consistency, temporality, specificity and experimental evidence in animal model) were fulfilled, and the authors concluded that a causal relationship between endometriosis and ovarian cancer should be recognised, but that the low magnitude of the risk observed could be associated with the fact that ectopic and eutopic endometrium undergo malignant transformation with the same frequency.
Molecular and genetic aspects linking endometriosis to ovarian cancer
During the past several years, a significant amount of research on molecular and genetic factors that may connect endometriosis to ovarian cancer has been conducted. There is significant evidence to support the presence of common molecular pathways for the development of both conditions. On the other hand, the existing data highlight the possibility of endometriosis being a benign disease that may transform into a malignant one.
Both endometriosis and ovarian cancer share common pathogenetic factors such as familiar predisposition, genetic instability and a similar reaction to immunologic, angiogenetic and hormonal factors. Similar alterations in the immune response cascade and in the mechanism of inflammation have been observed in women with ovarian cancer and endometriosis.
Mechanisms that lead to both ovarian cancer and endometriosis due to genetic instability include deactivation of one or two alleles of tumour-suppressive genes, changes of the enzymes that act in DNA repair and higher oncogenic activity. The most commonly affected chromosome loci include 9p, 11q and 22q.
Mutations in the genes that encode metabolic and detoxification enzymes, like GALT and GSTM, have been implicated in the pathogenesis of endometriosis as well as in development of ovarian cancer. Mutations in PTEN, a tumour-suppressive gene, have been documented in endometriosis as well as in certain histologic types of ovarian carcinomas. PTEN mutations as well as loss of heterozygosity (LOH) at locus 10q23.3 are quite common in ovarian endometriomas, in atypical endometriosis as well as in endometrioid and clear-cell ovarian cancers. K-ras is an oncogene that has been related to endometriosis and ovarian cancer. Mutations of K-ras are found in clear-cell ovarian carcinomas in women with endometriosis. K-ras mutations were found in cancerous cells, but not in the neighbouring cells with endometriosis or atypical endometriosis. According to the investigators, K-ras mutations are associated with malignant transformation of benign endometriosis to clear-cell carcinoma of the ovaries. In a rodent model, activation of the oncogenic K-ras or conditional PTEN deletion within the ovarian surface epithelium gave rise to pre-neoplastic ovarian lesions with an endometrioid glandular morphology. The authors were able to demonstrate that a combination of the two mutations in the ovary leads to the induction of invasive and widely metastatic endometrioid ovarian adenocarcinomas.
The p-53 and c-erbB-2 genes have also been found to associate with endometriosis-related ovarian cancer. The expression of these two oncogenes was significantly higher in the endometriosis-associated clear-cell tumours compared with those patients without endometriosis. These findings were in agreement with the report by Sainz de la Cuesta et al. In their study, 17 out of 410 (4.1%) women with epithelial ovarian cancer had endometriosis, whereas six out of 521 (1.2%) women with endometriosis had atypical lesions. Of the 17 patients, 14 (82.4%) with endometriosis-associated ovarian cancer and six out of six (100%) women with atypical endometriosis had an over-expression of the p-53 gene. Only two out of 17 (11.8%) women with endometriosis had a mutation of the p-53 gene, and this difference was statistically significant.
Endometriosis and ovarian cancer: response to oestrogen stimulation
Oestrogens have been linked to the pathogenesis and growth of three common women’s cancers (i.e., breast, endometrium and ovary). The key enzyme for oestrogen biosynthesis or, in fact, conversion of androgens to oestrogens is aromatase. Tissue-specific aromatase expression is regulated by tissue-specific promoters located upstream of a common coding region. Aromatase gene expression in malignant tumours of the breast, endometrium and ovary is primarily regulated by a promoter located in the 1.3/II region. These promoters are stimulated by PGE2 via a cAMP/PKA-dependent pathway. Thus, inflammatory substances such as PGE2 may play an important role in inducing local production of oestrogens that promote tumour growth.
Agents that block the function of this enzyme, ‘aromatase inhibitors’, have been used successfully in the treatment of breast cancer, whereas their roles in endometrial and ovarian cancers are less clear. Aromatase inhibitors have also been used in the treatment of endometriosis.
Oestrogen-induced triggering is similar in both endometriosis and oestrogen-dependent neoplasms. Normally, oestradiol is being metabolised to oestrone, a weak oestrogen, by the action of the enzyme 17-β-hydroxysteroid dehydrogenase (17-β-HSD) type-2, which is being induced by progesterone in the endometrium. In endometriosis, a local increase in oestradiol concentration has been described, attributed to an increased expression of cytochromal-P450 aromatase and a simultaneous insufficient expression of 17-β-HSD type-2, which has been attributed to a resistance of the endometriotic lesions to progesterone.
Ovarian cancer seems to be connected to oestrogen action as well. Seeger et al. concluded that oestradiol and its derivatives may have a variable impact on the survival and growth of ovarian cell lines and the quantification of these derivatives may be of prognostic value of the risk women have for the development of ovarian cancer. O’Donnell et al. have shown that the potential carcinogenic action of oestrogen are mediated through oestrogen receptor (ER-α). In ovarian cancer cell lines, genes controlled through ER-α-mediated transcription had a threefold increase in their expression, whereas there was no change in the expression of genes controlled by ER-β-mediated transcription.
Increased expression of ER-α has also been shown in active endometriosis. Samples from 33 peritoneal and 37 ovarian endometriotic lesions were examined and analysed, using polymerase chain reaction (PCR) and in situ hybridisation (ISH). In active endometriosis lesions, higher ER-α than ER-β levels have been observed, a finding that is in contrast to what happens in the non-active lesions. These findings support the role of the increased expression of oestrogen receptors (especially ER-α) in the pathogenesis of endometriosis.
Growth factors such as TGF-a and IGF-I have also been implicated in the development of endometriosis as well as of ovarian cancer. Women with severe endometriosis have significantly higher IGF-I levels in their plasma compared with controls. Moreover, menopausal and premenopausal women with high-IGF-I serum levels are at increased risk of developing ovarian, endometrial and cervical cancer.
Resistance to apoptotic mechanisms: Bcl-2 over-expression, Bax down-regulation
Over-expression of anti-apoptotic (Bcl-2) genes and under-expression of pre-apoptotic (Bax) factors, as well as deactivation of the p53 tumour-suppressive gene, through gene mutations are often involved in the pathogenesis of malignancy. Spontaneous apoptosis is significantly decreased in the eutopic endometrium of women with endometriosis compared with healthy controls. In addition, increased expression of the anti-apoptotic gene Bcl-2 and suppression of the pre-apoptotic gene Bax has also been noted during the proliferative-phase endometrium of those women.
Local tissue invasion and metastatic potential
Both endometriosis and ovarian cancer have the ability to invade and spread to neighbouring structures as well as in remote locations. The mechanism of tumour invasion involves the secretion of matrix metalloproteinases (MMPs) to penetrate the basal membrane and stroma. In endometriosis, a similarly increased action of MMPs is observed. The expression and localisation of several MMPs were evaluated by immunohistochemistry in women with endometriomas. MMP-1, -2 and -9 were strongly detected in both stromal and epithelial cells, whereas MMP-3 was mainly expressed in macrophages containing haemosiderin. Based on these results, the authors suggested that the destruction of the surrounding matrix by endometriosis might be caused by various MMPs, which are mainly produced in stromal cells.
In the study conducted by Ueda et al., the expression of E-cadherin, a- and b-katenin, MMP-2, MMP-9 and membrane-type-1-MMP (MT1-MMP) were evaluated in 35 women with endometriosis and in 12 normal controls. The expression of MMP-2, MMP-9 and MT1-MMP in coloured lesions was significantly higher in comparison to normal endometrium, whereas the expression of E-cadherin, a- and b-katenin was not suppressed in the endometriosis lesions. B-katenin, E-cadherin and P-cadherin in combination with increased expression of MMPs probably play a role in the pathogenesis of endometriosis and in the development of several malignant conditions, including ovarian cancer.
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