Fallopian tube initiation of high grade serous ovarian cancer and ovarian metastasis: Mechanisms and therapeutic implications

Abstract

Ovarian cancer is the most lethal gynecologic malignancy and the fifth leading cause of cancer-related death in women. Although outcomes have improved in recent years, there remains an unmet clinical need to understand the early pathogenesis of ovarian cancer in order to identify new diagnostic approaches and agents of chemoprevention and chemotherapy. While high grade serous ovarian cancer (HGSOC), the most abundant histotype, was initially thought to arise from the ovarian surface epithelium, there is an increasing body of evidence suggesting that HGSOC originates in the fallopian tube. With this new understanding of cell of origin, understanding of disease development requires analysis with a novel perspective. Currently, factors that drive the initiation and migration of dysplastic tubal epithelial cells from the fallopian tube to the ovary are not yet fully defined. These factors include common mutations to fallopian tube epithelial cells, as well as factors originating from both the fallopian tube and ovary which are capable of inducing transformation and dissemination in said cells. Here, we review these changes, their causative agents, and various potential means of intervention.

Keywords: Carcinogenesis; Chemoprevention; Chemotherapy; Oviduct; STIC; TP53.

Figure 1.. Signals of Interest in Ovarian Cancer Development

Serous tubal intraepithelial carcinomas (STICs) and other precursor lesions of ovarian cancer exist throughout the fallopian tubes and are regularly exposed to several potentially oncogenic factors. These factors stem from secretions, from fallopian tube and ovarian epithelium, and follicular fluid that is released upon follicle rupture during the reproductive cycle. They can be protective or transformative, and stimulate proliferation or metastasis of fallopian tube epithelial cells.

Figure 2.. Changes in Ovarian-Fallopian Tube Communication from Normal Fallopian Tube Epithelium to Intraepithelial Carcinoma

Before the occurrence of any transformational events, normal fallopian tube epithelium secretes several factors that likely play a role in disease development. If the epithelium forms a SCOUT lesion, a serous outgrowth typically PAX2 null, it then expresses increased estrogen receptor leading to increased estrogen signaling. If cells undergo loss of PTEN, they express higher levels of WNT4 and are susceptible to the proliferative and metastatic effects of norepinephrine. Mutation of p53 leads to the development of a signature lesion. In p53 null signature lesion cells, progesterone (P4) can protectively induce necroptosis. Combinations of these mutation and factor-induced transformations promote development of serous tubal intraepithelial carcinomas (STICs). STICs are considered malignant and are capable of dissemination to and invasion of the ovary.