In vitro and in vivo correlates of physiological and neoplastic human Fallopian tube stem cells

Abstract

High-grade serous cancer (HGSC) progresses to advanced stages without symptoms and the 5-year survival rate is a dismal 30%. Recent studies of ovaries and Fallopian tubes in patients with BRCA1 or BRCA2 mutations have documented a pre-metastatic intramucosal neoplasm that is found almost exclusively in the Fallopian tube, termed ‘serous tubal intraepithelial carcinoma’ or STIC. Moreover, other proliferations, termed p53 signatures, secretory cell outgrowths (SCOUTs), and lower-grade serous tubal intraepithelial neoplasms (STINs) fall short of STIC but share similar alterations in expression, in keeping with an underpinning of genomic disturbances involved in, or occurring in parallel with, serous carcinogenesis. To gain insight into the cellular origins of this unique tubal pathway to high-grade serous cancer, we cloned and both immortalized and transformed Fallopian tube stem cells (FTSCs). We demonstrated that pedigrees of FTSCs were capable of multipotent differentiation and that the tumours derived from transformed FTSCs shared the histological and molecular features of HGSC. We also demonstrated that altered expression of some biomarkers seen in transformed FTSCs and HGSCs (stathmin, EZH2, CXCR4, CXCL12, and FOXM1) could be seen as well in immortalized cells and their in vivo counterparts SCOUTs and STINs. Thus, a whole-genome transcriptome analysis comparing FTSCs, immortalized FTSCs, and transformed FTSCs showed a clear molecular progression sequence that is recapitulated by the spectrum of accumulated perturbations characterizing the range of proliferations seen in vivo. Biomarkers unique to STIC relative to normal tubal epithelium provide a basis for novel detection approaches to early HGSC, but must be viewed critically given their potential expression in lesser proliferations. Perturbations shared by both immortalized and transformed FTSCs may provide unique early targets for prevention strategies. Central to these efforts has been the ability to clone and perpetuate multipotent FTSCs.

PAX2 function, regulation and targeting in fallopian tube-derived high-grade serous ovarian cancer

“…Studies published so far have shown divergent roles of PAX2 depending on the tumor histotype(23–25, 36, 37). Consistent with pathological observations, published microarray data indicates that PAX2 was significantly downregulated in STIC and HGSC tissues compared to normal FTE(27). A small subset of TCGA patients with amplification in the PAX2 gene, had a longer disease-free interval before relapse.…”

“…In order to validate the clinical significance of PAX2 mRNA loss, microarray data from a Gene Expression Omnibus-GSE69429 was retrospectively analyzed by comparing PAX2 expression between normal FTE, STICs and invasive HGSC samples (n=6 per group)(26, 27). PAX2 expression progressively declined from STICs to HGSC when compared to normal FTE (Supplementary Fig.…”

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

“…The third lesion is p53 signature, which is defined as a linear expansion of >12 of morphologically normal epithelium with p53 overexpression (12). This lesion shares identical p53 mutations and other genomic changes with HGSC, but lacks excessive cell proliferation (16). p53 signature is seen predominantly in continuity with STIC, localizes to the same (fimbria) region as STIC and shares preneoplastic properties with HGSC including p53 mutations (5,17).…”

“…Investigators have characterized the stepwise changes of molecular profiles identified by genomic, proteomic and immunohistochemical approaches, including BCL2 (BCL2 apoptosis regulator), p73 (tumor protein p73), PAX2 (paired box 2), p53, PAX8 (paired box 8), H2AX (H2A histone family member X), STMN1 (stathmin 1), EZH2 (enhancer of zeste 2 polycomb repressive complex 2 subunit), Ki67, ALDH1A1 (aldehyde dehydrogenase 1 family member A1), CTNNB1 (β-catenin), CCNE1 (cyclin E1), LAMC1 (Laminin γ1), and HMGA2 (high mobility group AT-hook 2) genes and telomere shortening (Table I) (3,5,12,13,16,(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37).…”

“…A member of the PAX family, PAX8, also plays a role in organogenesis of the Müllerian system and is a marker of fallopian tubal secretory cells and ovarian surface epithelium (OSE) (16,27). Other molecular characteristics identified in fallopian tube epithelium are as follows: Fallopian tubal epithelium comprises different phenotypic and molecular subtypes; secretory cells (BCL2+, PAX2+, PAX8+, HMFG2+, p73-, FOXJ1-, and acety lated tubulin-) and cilia ted cells (BCL2-, PAX2-, PAX8-, HMFG2-, p73+, FOXJ1+, LhS28+, acetylated tubulin+, and Sall2+) (16,(25)(26)(27). p73 is a homologue of the p53 and induces cell cycle arrest, conferring its tumor suppressive activity.…”