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HGSCs Carcinogenic Hypotheses and Origins: Comparison
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Please note this is a comparison between Version 2 by Bruce Ren and Version 1 by Isao Otsuka.

Ovarian high-grade serous carcinomas (HGSCs) are a heterogeneous group of diseases. They include fallopian-tube-epithelium (FTE)-derived and ovarian-surface-epithelium (OSE)-derived tumors. The risk/protective factors suggest that the etiology of HGSCs is multifactorial.

  • ovarian cancer
  • high-grade serous carcinoma
  • carcinogenesis
  • molecular alterations

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1. Introduction

Ovarian cancer is the most lethal gynecological malignancy. Epithelial ovarian cancers (EOCs) are a heterogeneous group of diseases and can be divided into five main types, based on histopathology and molecular genetics [1]: high-grade serous, low-grade serous, endometrioid, clear cell, and mucinous tumors. These tumors may be classified into type I and II tumors. Type I tumors include endometriosis-related tumors (endometrioid and clear cell carcinomas), low-grade serous carcinoma, and mucinous carcinoma. Type II tumors are composed of high-grade serous carcinomas, for the most part [2]. Although this classification conflicts with recent molecular insights into the etiology of EOCs [3], type II tumors that also include carcinosarcomas could be classed together.

High-grade serous carcinoma (HGSC) is the most common and lethal subtype of EOC, as most women with HGSC are diagnosed at a late stage, when achieving a cure is rare [4]. The vast majority of serous carcinomas are high-grade tumors [5]. To develop an effective method for prevention and early detection, elucidation of carcinogenesis is essential. Recently, our understanding of the origins and pathogenesis of HGSC has substantially progressed through whole genome and bioinformatic analyses.

2. Carcinogenic Hypotheses and Risk/Protective Factors

2.1. Incessant Ovulation

EOCs were traditionally thought to arise from the ovarian surface epithelium (OSE). The OSE is the pelvic mesothelium that overlies the ovary and lines ovarian epithelial inclusion cysts, and is derived from the coelomic epithelium [6,7]. The risk/protective factors for EOCs include parity, breast-feeding, and oral contraceptive use; all of these factors reduce ovarian cancer risk [8] (

EOCs were traditionally thought to arise from the ovarian surface epithelium (OSE). The OSE is the pelvic mesothelium that overlies the ovary and lines ovarian epithelial inclusion cysts, and is derived from the coelomic epithelium [6][7]. The risk/protective factors for EOCs include parity, breast-feeding, and oral contraceptive use; all of these factors reduce ovarian cancer risk [8] (

Figure 1

). These reproductive and hormonal factors are associated with ovulation suppression. Thus, the risk of EOC is thought to be associated with the number of ovulatory cycles.

Ijms 22 04409 g001 550
Figure 1.

Carcinogenic hypotheses and risk/protective factors. * including menstruation and postmenopausal bleeding.

The incessant ovulation hypothesis was proposed by Fathalla in 1971 based on these observations [9]. This hypothesis proposes that recurrent damage and repair of the OSE from repeated ovulation increase the risk of cell damage and subsequent neoplastic transformation. A study showed that a higher number of ovulatory cycles may be associated with increased amounts of DNA damage [10].

2.2. Gonadotropin Stimulation

The majority of women with ovarian cancer present in the postmenopausal period, when pituitary gonadotropin levels are elevated. The gonadotropin stimulation hypothesis proposes that high gonadotropin levels can have an effect on OSE cells and promote carcinogenesis [11,12]. Gonadotropins that persist in high levels for many years after menopause may stimulate the OSE, in which gonadotropin receptors are expressed, and OSE cells may subsequently undergo malignant transformation [12]. Surges of gonadotropins that initiate each ovulation may also play a role in carcinogenesis; thus, the incessant ovulation and gonadotropin hypotheses are interrelated.

The majority of women with ovarian cancer present in the postmenopausal period, when pituitary gonadotropin levels are elevated. The gonadotropin stimulation hypothesis proposes that high gonadotropin levels can have an effect on OSE cells and promote carcinogenesis [11][12]. Gonadotropins that persist in high levels for many years after menopause may stimulate the OSE, in which gonadotropin receptors are expressed, and OSE cells may subsequently undergo malignant transformation [12]. Surges of gonadotropins that initiate each ovulation may also play a role in carcinogenesis; thus, the incessant ovulation and gonadotropin hypotheses are interrelated.

2.3. Tubal Inflammation

These two hypotheses, however, have limitations. If the number of lifetime ovulatory cycles and exposure to high levels of gonadotropins are associated with EOC development, fertility treatment might increase the risk of EOC via the multiple ovulations stimulated by gonadotropins, specifically luteinizing hormone (LH) and follicle stimulating hormone (FSH). In fact, studies suggest that there is no significant relationship between in vitro fertilization treatment using gonadotropin stimulation and subsequent risk of EOC [13,14]. In addition, as the ovulatory rupture sites appear to be random, the repeated rupture and repair that occurs with each ovulation should not affect the same population of surface epithelial cells [15]. Furthermore, neither the incessant ovulation nor gonadotropin stimulation hypotheses explains the protective effect of tubal ligation and hysterectomy on the development of EOC [16].

These two hypotheses, however, have limitations. If the number of lifetime ovulatory cycles and exposure to high levels of gonadotropins are associated with EOC development, fertility treatment might increase the risk of EOC via the multiple ovulations stimulated by gonadotropins, specifically luteinizing hormone (LH) and follicle stimulating hormone (FSH). In fact, studies suggest that there is no significant relationship between in vitro fertilization treatment using gonadotropin stimulation and subsequent risk of EOC [13][14]. In addition, as the ovulatory rupture sites appear to be random, the repeated rupture and repair that occurs with each ovulation should not affect the same population of surface epithelial cells [15]. Furthermore, neither the incessant ovulation nor gonadotropin stimulation hypotheses explains the protective effect of tubal ligation and hysterectomy on the development of EOC [16].

The fallopian tube, in particular the fimbriae, emerged as another site of origin based on findings related to prophylactic surgery for ovarian cancer risk reduction in women with genetic predisposition to the disease [17]. Based on these observations, the tubal inflammation hypothesis was proposed by Salvador [7]. Chronic inflammation is known to be a risk for cancer. The fallopian tube is regularly exposed to a variety of inflammatory agents, and can show signs of acute and chronic inflammation, through the process of retrograde bleeding from the endometrial cavity during menstruation. Infection also induces inflammation in the fallopian tube [7]. Chlamydia trachomatis infection may be associated with serous carcinogenesis [18].

2.4. Incessant Menstruation

The incessant menstruation hypothesis, proposed by Vercellini [16], also explains why ovarian cancer risk is decreased by tubal ligation and ovulation suppression. In this theory, pathogenesis of endometriosis-associated carcinomas, specifically endometrioid and clear cell carcinomas, as well as serous carcinomas, can be explained. In serous carcinomas, retrograde menstruation from the endometrial cavity into the Douglas pouch is the causative mechanism that generates fallopian tube inflammation [7,16]. The incessant menstruation hypothesis explains ovarian cancer risk well in the premenopausal period. However, in postmenopausal women, another risk factor is related to ovarian carcinogenesis, that is, menopausal hormone therapy (MHT).

The incessant menstruation hypothesis, proposed by Vercellini [16], also explains why ovarian cancer risk is decreased by tubal ligation and ovulation suppression. In this theory, pathogenesis of endometriosis-associated carcinomas, specifically endometrioid and clear cell carcinomas, as well as serous carcinomas, can be explained. In serous carcinomas, retrograde menstruation from the endometrial cavity into the Douglas pouch is the causative mechanism that generates fallopian tube inflammation [7][16]. The incessant menstruation hypothesis explains ovarian cancer risk well in the premenopausal period. However, in postmenopausal women, another risk factor is related to ovarian carcinogenesis, that is, menopausal hormone therapy (MHT).

2.5. Incessant Retrograde Bleeding

Incessant retrograde bleeding is an expansion of the concept of incessant menstruation and may explain more accurately the etiology of HGSCs in both premenopausal and postmenopausal women [19]. Some types of MHT, also called hormone replacement therapy, increase ovarian cancer risk. The risk of serous ovarian cancer differs by regimen of MHT. Its risk in women with intact uteri is increased with the use of estrogen alone, and estrogen with sequentially added progestin [20,21]. Both regimens cause endometrial bleeding. In contrast, serous ovarian cancer risk is not altered by the use of continuous estrogen and progestin, which results in endometrial atrophy with bleeding cessation [19,21]. Thus, MHT regimens that cause endometrial bleeding are associated with an increased risk of serous ovarian carcinoma.

Incessant retrograde bleeding is an expansion of the concept of incessant menstruation and may explain more accurately the etiology of HGSCs in both premenopausal and postmenopausal women [19]. Some types of MHT, also called hormone replacement therapy, increase ovarian cancer risk. The risk of serous ovarian cancer differs by regimen of MHT. Its risk in women with intact uteri is increased with the use of estrogen alone, and estrogen with sequentially added progestin [20][21]. Both regimens cause endometrial bleeding. In contrast, serous ovarian cancer risk is not altered by the use of continuous estrogen and progestin, which results in endometrial atrophy with bleeding cessation [19][21]. Thus, MHT regimens that cause endometrial bleeding are associated with an increased risk of serous ovarian carcinoma.

3. Sites of Origin of HGSCs

Although the dominant site of origin for HGSCs is the distal fallopian tube (fimbriae) [17,22], HGSCs can also arise from the ovary [23,24,25,26,27]. In experimental models, HGSCs developed from both the fallopian tube and ovary with inactivation of a few genes [26,28,29,30]. Cancer may originate from the transition of stem cells, as the acquisition of multiple mutagenic events can occur in long-lived stem cells that are capable of self-renewal [31], and stem cells can be found both in the fallopian tube and ovary, in particular in the distal fallopian tube and in the transition area between the OSE, mesothelium, and tubal epithelium [23,32,33].

Although the dominant site of origin for HGSCs is the distal fallopian tube (fimbriae) [17][22], HGSCs can also arise from the ovary [23][24][25][26][27]. In experimental models, HGSCs developed from both the fallopian tube and ovary with inactivation of a few genes [26][28][29][30]. Cancer may originate from the transition of stem cells, as the acquisition of multiple mutagenic events can occur in long-lived stem cells that are capable of self-renewal [31], and stem cells can be found both in the fallopian tube and ovary, in particular in the distal fallopian tube and in the transition area between the OSE, mesothelium, and tubal epithelium [23][32][33].

3.1. Fallopian Tube Epithelium

A substantial percentage (60–88%) of HGSCs originate in the fallopian tube [17,22,25,34,35], both in women with

A substantial percentage (60–88%) of HGSCs originate in the fallopian tube [17][22][25][34][35], both in women with

BRCA mutations and in sporadic cases [2,17,36]. The molecular profile and immunophenotype of HGSCs are more closely related to the FTE than OSE [22,37,38]. Although fallopian tube epithelial secretory cells are believed to give rise to HGSCs [28], ciliated cells may be another cell-of-origin in the fallopian tube epithelium (FTE) [26].

mutations and in sporadic cases [2][17][36]. The molecular profile and immunophenotype of HGSCs are more closely related to the FTE than OSE [22][37][38]. Although fallopian tube epithelial secretory cells are believed to give rise to HGSCs [28], ciliated cells may be another cell-of-origin in the fallopian tube epithelium (FTE) [26].

In the FTE, p53 signatures and serous tubal intraepithelial carcinoma (STIC), both of which are intraepithelial lesions associated with HGSC, can be identified. The p53 signature is a focus of strong p53 immunostaining in benign tubal mucosa [39] and harbors

TP53

mutations and evidence of DNA damage [40]. Telomere shortening occurs in p53 signatures, suggesting that the p53 signature is the earliest precancer lesion [41]. However, the p53 signature may not always be a preneoplastic lesion of HGSC, as p53 overexpression has been found to be common both in

BRCA

carriers and in noncarriers who underwent surgery for benign disease or RRSO [42]. STIC, which is composed of secretory cells showing significant atypia, architectural alterations, a high proliferative index, and strong p53 immunostaining [43], is a putative precursor lesion of HGSC. Identical somatic

TP53

mutations have been detected in the majority of pairs of STIC and concurrent HGSCs [44]. However, not all HGSCs may arise from STIC lesions, even in high-risk women [45]. STIC was observed only in 11–61% (mean 31%) of HGSCs [46], and some STICs are actually metastases from HGSCs, rather than HGSC precursors [47]. Additionally, a subset of serous tubal intraepithelial neoplasias, including STIC, are an intraepithelial metastasis from a contralateral serous tubal intraepithelial neoplasia [48]. STICs and serous tubal intraepithelial lesions (STILs), which are intermediate lesions between the p53 signature and STIC, may not share the protective factors that are associated with HGSC [49]. The development of STICs may be related to random mutations occurring in target cancer drivers, including

TP53

[49]. Thus, many potential precursor or premalignant lesions do not advance to malignant tumors or lethal malignancies [45].

3.2. Ovarian Surface Epithelium

The OSE is another site of origin for HGSCs. Ovarian carcinoma in situ has been identified in ovaries removed in risk-reducing oophorectomies in women with a germline

BRCA

mutation [50]. A literature review of microscopic ovarian, fallopian tube, and peritoneal tumors in

BRCA1/2

mutation carriers showed that 60.5% were confined to the fallopian tube only, whereas 21.1% and 2.6% involved only the ovary and only the peritoneum, respectively [35]. Ovarian epithelial inclusion cysts are considered to be a possible site of origin of HGSCs. HGSCs may frequently arise within epithelial inclusion cysts, but not the surface epithelium itself [51]. A dysplastic precursor lesion within epithelial inclusion cysts, showing accumulation of p53, precedes carcinoma development. Recently, the concept of precursor escape has been postulated. Cells from early precursors, such as early serous proliferations, are shed from the fallopian tube and undergo subsequent malignant transformation on the surface of the ovary and peritoneum [52]. There are two known types of ovarian inclusion cysts; one is positive for PAX8 (mullerian marker), and the other is positive for calretinin (mesothelial marker) [53]. However, they may not represent FTE-derived and OSE-derived cysts, as many PAX8-positive cells arise from metaplasia of OSE-derived inclusion cysts [54]. In a mouse model, ectopic tubal-type epithelium (endosalpingiosis) in the ovary did not likely arise as a consequence of detachment and implantation of the tubal epithelium [55].

FTE-derived and OSE-derived HGSCs are different in their pattern of metastasis, transcriptome, and response to chemotherapy [26]. FTE-derived tumors have a greater propensity to disseminate, whereas OSE-derived tumors form large, solitary lesions, with less frequent metastasis [26]. OSE-derived HGSC may have a long latent period and a poor prognosis compared to FTE-derived HGSC [24,25]. The poorer prognosis associated with OSE-derived HGSC may partly be explained by its mesenchymal characteristics. OSE cells have a dual epithelia–mesenchymal phenotype [56], and in the mouse ovaries leiomyosarcoma developed with inactivation of

FTE-derived and OSE-derived HGSCs are different in their pattern of metastasis, transcriptome, and response to chemotherapy [26]. FTE-derived tumors have a greater propensity to disseminate, whereas OSE-derived tumors form large, solitary lesions, with less frequent metastasis [26]. OSE-derived HGSC may have a long latent period and a poor prognosis compared to FTE-derived HGSC [24][25]. The poorer prognosis associated with OSE-derived HGSC may partly be explained by its mesenchymal characteristics. OSE cells have a dual epithelia–mesenchymal phenotype [56], and in the mouse ovaries leiomyosarcoma developed with inactivation of

Brca1

and

Trp53

[57]. A histological subtype showing mesenchymal characteristics had the lowest overall survival among four histological subtypes of HGSC [58].

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