The conceptual advances of carcinogenic sequence model in high-grade serous ovarian cancer

Abstract

Abstract. The present review focuses on the current status of molecular pathology in high-grade serous cancer (HGSC) and preneoplastic conditions. This article reviews the English-language literature on HGSC, precursor, fallopian tubal epithelium, secretory cells, ciliated cells, secretory cell expansion, secretory cell outgrowth (SCOUT), p53 signature, serous tubal intraepithelial carcinoma (STIC), DNA damage and immunohistochemistry in an effort to identify the precursor-carcinoma sequence in HGSC. The majority of HGSC originates from the fimbriated end of the fallopian tube secretory epithelial cells, while the small part of this disease may develop from ovarian cortical inclusion cyst (CIC). A series of morphological changes from normal fallopian epithelium to preneoplastic to neoplastic lesions were concomitant with the multistep accumulation of molecular and genetic alterations. Recent studies provide a stepwise progression of fallopian tubal epithelium to precursor lesions to carcinoma, with the aid of a 'secretory cell-SCE-SCOUT-p53 signature-STIC-HGSC sequence' model. Immunohistochemical markers, including p53, STMN1, EZH2, CCNE1, Ki67 and γ-H2AX, were gradua lly increased during the SCOUT-p53 signature-STIC-HGSC sequence. Conversely, PAX2 expression was decreased during the early phase of SCOUT development. Potential genes and proteins are involved in the evolutionary trajectory of the precursor-cancer lineage model. In the present review we examined detailed aspects of the molecular changes involved in malignant transformation from fallopian tube epithelium to HGSC. A precursor condition originating in 'field cancerization' may gain a growth advantage, leading to HGSC.

Loss of tubal ciliated cells as a risk for “ovarian” or pelvic serous carcinoma

“…Approximately 10-17% of decreased ciliated cells in the fallopian tube are attributed to age, while 83-90% attributed to O/PSC and high-risk status, respectively. Patients with BRCA mutations show the strongest association with decreased number of ciliated cells in the fallopian tube, consistent with its known risk for O/PSC development (28,(30)(31)(32). While there is still an association found of reduction of ciliated cells as well in the O/PSC group, this group is not restricted to cases with serous neoplasia.…”

Fallopian tube epithelial changes in ovarian serous tumors compared with control group: A single-center study

“…They suggested the cell of origin could influence therapeutic response 15. Clarifying the exact origin of HGSC will improve the early detection and prevention of ovarian cancer, and reduce ovarian cancer mortality 16…”

“…PAX8 was considerably expressed in serous tumors and FTE samples, while it did not happen in ovarian serous epithelium samples. p53 was gradually increased during the secretory outgrowth-p53 signature-STIC-HGSC sequence 3141617…”

Revisiting ovarian cancer microenvironment: a friend or a foe?

“…Ovarian cancer cells that have metastasized to adjacent adipose tissues have upregulated expression of genes encoding fatty acid transport proteins such as CD36 and FABP4, together with other molecules including CD31, CD34, VEGFR1, and VEGFR2 (Gusky et al, 2016 ). Unlike many solid malignancies, HGSC rarely metastasizes outside the adipocyte-rich abdominal cavity (Kobayashi et al, 2017 ). A recent study discovered that salt-inducible kinase 2 (SIK2) overexpressed in adipocyte-rich metastatic deposits promotes abdominal metastasis, while adipocyte-induced calcium-dependent activation and autophosphorylation of SIK2 not only augments adenosine monophosphate-activated protein kinase (AMPK)-induced acetyl-CoA carboxylase phosphorylation but also activate the PI3K/AKT pathway via p85a-S154 phosphorylation (Miranda et al, 2016 ).…”