Mini-reviewOvarian clear cell carcinoma as a stress-responsive cancer: Influence of the microenvironment on the carcinogenesis and cancer phenotype
Highlights
► Ovarian endometriosis is known to transform into ovarian cancer, but its etiology is not clarified. ► A stressful microenvironment within the endometriotic cyst may lead to cancer development. ► Ovarian clear cell carcinoma has unique gene expressions, which may serve as a molecular marker. ► Carcinogenic microenvironment affects the phenotype, character and gene expression of a cancer. ► We might be able to develop new treatment based on the analysis of the influence of microenvironment.
Introduction
Endometriosis is a benign gynecological disease that affects 5–10% of women [1]. It is clinically well known that ovarian cancer arises from ovarian endometriosis with a relatively high frequency. A prospective randomized trial in Japan, in which over 8000 asymptomatic postmenopausal women were followed for up to 17 years, demonstrated that 0.72% of women with endometriosis develop ovarian cancer [2]. This rate is higher than the incidence of cancer in other benign ovarian tumors such as serous or mucinous cystoadenomas [2], suggesting the presence of discrete risk factors for oncogenesis in ovarian endometriosis. In addition, unlike typical ovarian cancers, the cancers arising from endometriosis more commonly comprise clear cell and endometrioid subtypes [3], [4]. These findings strongly suggest that the carcinogenic process in ovarian endometriosis is unique and different from that of ordinary ovarian cancers. With this in mind, we sought to clarify the mechanism by which endometriosis gives rise to a discrete phenotype of cancer with a high frequency, and we hypothesized that the unique microenvironment in the endometriotic cyst plays a pivotal role in cancer development.
Pathological evidences as well as recent molecular analyses have been clarifying the precancerous property of endometriosis. Pathologically, co-existence of endometriosis and ovarian cancer is frequently observed, and they sometimes accompany “atypical endometriosis”, a putative precursor lesion [5]. Common genetic events such as LOH and genetic mutation have been demonstrated in carcinoma and adjacent endometriosis [5]. Overexpression of HNF-1β, a putative hallmark of clear cell carcinoma, is also frequently expressed in benign and atypical endometriosis [6]. Moreover, mutation of the ARID1A gene, which is recently identified in approximately a half of clear cell carcinoma and one thirds of endometrioid carcinoma, is also found in a part of atypical endometriosis adjacent to the carcinoma [7]. These data collectively suggest that endometriosis really transform into carcinoma, occasionally passing through an intermediate lesion, namely, atypical endometriosis. However, little is known about the mechanisms that drive benign epithelium into malignant transformation within the endometriotic cyst.
Section snippets
High iron concentration and its potential influence in the development of ovarian cancer in endometriosis
Endometriosis is characterized by repeated bleeding into the cyst cavity during the menstrual cycle. As a result, the content of an endometriotic cyst consists of highly concentrated old blood, and the endometriotic epithelial cells within the cyst are consistently exposed to an unusual microenvironment that is rarely encountered in the body. Recently it has been recognized that carcinogenesis and tumor progression are significantly influenced by the microenvironment in which the tumor arises
Influence of microenvironment on the gene expression and phenotype of cancer arising in endometriosis
There is likely to be an association between endometrioid adenocarcinoma and endometriosis because of the similarity to the relationship between endometrioid adenocarcinoma and the uterine endometrium. Several studies suggest the etiological role of estrogen in both cases [20]. In contrast, no clear explanation has been found for the observation that clear cell carcinoma frequently occurs in endometriosis.
We then hypothesized that the microenvironment within the endometriosis, which appears to
Possible application of the OCCC signature in the treatment of disease
Is it possible to apply the OCCC signature to the treatment of ovarian clear cell carcinoma? To answer this question, we evaluated the malignant tumors in the whole body to ascertain whether there are cancers with elevated expression of the OCCC signature [23]. Among various cancers, only renal cell carcinomas (RCC) express significantly higher levels of the OCCC signature. In hierarchical clustering using the OCCC signature, ovarian clear cell carcinoma was indistinguishable from RCC,
Further directions, especially future treatment approaches for clear cell carcinoma (Fig. 4)
Most of the clear cell carcinomas are resistant to current chemotherapy, and the treatment of this tumor remains an important clinical challenge in the treatment of ovarian cancer. As mentioned above, our comprehensive gene expression analyses revealed that the molecular targeting drugs effective for RCC are potentially useful in the treatment of OCCC, one of which is sorafenib. There are several other reagents that are expected to be effective in RCC, and such drugs are thought to be
Conflict of interest
All the authors in this study do not have any financial and personal relationships with other people or organizations that could inappropriately influence (bias) our work.
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