Natural history of ovarian high-grade serous carcinoma from time effects of ovulation inhibition and progesterone clearance of p53-defective lesions

Abstract

High-grade serous carcinoma is the most common and devastating type of ovarian cancer; its etiology, mechanism of malignant transformation, and origin remain controversial. Recent studies have identified secretory cells at the fimbria of the fallopian tube as the cell-of-origin of high-grade serous carcinoma, acquiring TP53 mutation, evolving to tubal precursor lesions, including "p53 signature" and serous tubal intraepithelial carcinoma, and metastasizing to the ovary as clinically evident ovarian cancer. The etiological mechanisms associated with known epidemiological risk factors, i.e., ovulation and retrograde menstruation, have also been suggested. Mutagens and transforming growth factors, such as reactive oxygen species and insulin-like growth factor axis proteins, as well as the apoptosis-rescuing protein hemoglobin are abundantly present in the ovulatory follicular fluid and peritoneum fluid, which bathes the fimbrial epithelium, and induces malignant transformation after repeated exposure. In accordance with the proposed cleansing effect of progesterone from studies on oral contraceptive use or term pregnancy, a recent study indicated that the p53-null tubal epithelial cells are selectively cleared by progesterone depending on its progesterone receptor. In this report, by analyzing different time effects of oral contraceptive use or pregnancy in the prevention of ovarian cancer and by aligning them with the carcinogenic and cleansing clearance concepts of ovulation and progesterone, as well as the fact of progressive loss of progesterone receptor during tubal transformation, we deduced the natural history of ovarian high-grade serous carcinoma. The natural history begins at the first ovulation and spans for more than 30 years, taking 10 years from the normal tubal epithelium to the "p53 signature" status, another 15 years to progesterone receptor negative serous tubal intraepithelial carcinoma, and a final 5+ years to highgrade serous carcinoma. The estimated natural history may help understand the pathogenesis of high-grade serous carcinoma and defines the window for early detection and chemoprevention.

The Origin of Ovarian Cancer Species and Precancerous Landscape

“…17 This proposed timeline is remarkably similar to the estimate from a study that assessed the time effects of oral contraceptive use or pregnancy in the prevention of ovarian cancer alongside other clinicopathologic parameters. 60 In that study, the natural history began at first ovulation in an adolescent, requiring 10 years from first ovulation for normal tubal epithelium to acquire the p53 signature, another 15 years to STIC, and over 5 years to progress to HGSC. 60…”

“…60 In that study, the natural history began at first ovulation in an adolescent, requiring 10 years from first ovulation for normal tubal epithelium to acquire the p53 signature, another 15 years to STIC, and over 5 years to progress to HGSC. 60…”

Cellular models of development of ovarian high‐grade serous carcinoma: A review of cell of origin and mechanisms of carcinogenesis

“…The fimbria part of the fallopian tube as TA B L E 2 Immortalized human fallopian tube fimbrial epithelial cell lines the tissue of origin of HGSC has multiple folds of significance; it is the site that is mostly affected by ovulatory carcinogens, and thus, the site that most heavily bears the inflammatory injury and requires regenerates after ovulation. 64 Thus, it is also the site where stem cells most abundantly present and pre-cancerous lesions are most frequently found. 102 Following the putative sequence of driver mutations in HGSC, that is TP53 mutation, CCNE1/RB aberration, 103,104 primary FTECs were immortalized and transformed stepwise by further genetic manipulation.…”

Lin28A Regulates Stem-like Properties of Ovarian Cancer Cells by Enriching RAN and HSBP1 mRNA and Up-regulating its Protein Expression

“…International Publisher 70%-90% [5,6]. At present, the main treatments for OC patients include surgery, platinum and paclitaxel combined chemotherapy, Cetuximab, a monoclonal antibody that inhibits epidermal growth factor receptor (EGFR) [7][8][9].…”