Integrative Transcriptome Analyses of the Human Fallopian Tube: Fimbria and Ampulla—Site of Origin of Serous Carcinoma of the Ovary

Abstract

Epithelial ovarian cancer represents a group of heterogeneous diseases with high grade serous cancer (HGSC) representing the most common histotype. Molecular profiles of precancerous lesions found in the fallopian tube have implicated this tissue as the presumptive site of origin of HGSC. Precancerous lesions are primarily found in the distal fallopian tube (fimbria), near the ovary relative to the proximal tissue (ampulla), nearer to the uterus. The proximity of the fimbria to the ovary and the link between ovulation, through follicular fluid release, and ovarian cancer risk led us to examine transcriptional responses of fallopian tube epithelia (FTE) at the different anatomical sites of the human fallopian tube. Gene expression profiles of matched FTE from the fimbria and from premenopausal women resulted in differentially expressed genes (DEGs): CYYR1, SALL1, FOXP2, TAAR1, AKR1C2/C3/C4, NMBR, ME1 and GSTA2. These genes are part of the antioxidant, stem and inflammation pathways. Comparisons between the luteal phase (post-ovulation) to the follicular phase (pre-ovulation) demonstrated greater differences in DEGs than a comparison between fimbria and fallopian tube anatomical differences alone. This data suggests that cyclical transcriptional changes experienced in pre-menopause are inherent physiological triggers that expose the FTE in the fimbria to cytotoxic stressors. These cyclical exposures induce transcriptional changes reflective of genotoxic and cytotoxic damage to the FTE in the fimbria which are closely related to transcriptional and genomic alterations observed in ovarian cancer.

Cellular heterogeneity of human fallopian tubes in normal and hydrosalpinx disease states identified by scRNA-seq

“…In NCSEs, some ovarian cancerassociated markers and genes regulating cellular redox homeostasis (e.g., BIRC3, FGA, IER3) are elevated in fimbriae (Supplemental Figure 5B; Supplemental Table 6), supporting the hypothesis that the cell of origin of ovarian cancer resides in the fimbriae, and highlighting the increased oxidative stress in the distal tube in response to ovulation (Sowamber et al 2020). Further, the non-ciliated cells express higher levels of inflammatory cytokines CXCL1 (IL-1), CXCL8 (IL-8), and the sperm chemoattractant CCL20 in the fimbriae (Supplemental Figure 5A), consistent with previous reports (Sowamber et al 2020). Taken together, although transcriptomic differences are subtle, the genes identified point to functional differences across segment compartments, servings as a baseline for future studies exploring the genes dynamically regulated in response to disease or during pregnancy.…”

Inexpensive Systemic Inflammatory Biomarkers in Ovarian Cancer: An Umbrella Systematic Review of 17 Prognostic Meta-Analyses

“…This inflammatory pathway can contribute to cancer capabilities by providing growth factors and cytokines to the tumor stroma to sustain proliferation, angiogenesis, activation of epithelial-to-mesenchymal transition, invasion, and metastasis, as well as inhibition of cell death programs ( 1 ). In EOC, inflammation is considered as an important factor that impacts the tumorigenesis of the fallopian tubes, which were recently suggested as the principal origins of ovarian carcinogenesis ( 51 , 52 ). In addition to its involvement in the early steps of EOC, inflammation has a notable role in the late process of ovarian tumorigenesis.…”

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

“…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. Moreover, the human telomerase reverse transcriptase gene (hTERT) is routinely introduced to overcome the senescence crisis.…”