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Characterization of Primary Cilia in Normal Fallopian Tube Epithelium and Serous Tubal Intraepithelial Carcinoma.

ABSTRACT: OBJECTIVES:The aim of this study was to investigate the distribution of primary cilia on secretory cells in normal fallopian tube (FT) and serous tubal intraepithelial carcinoma (STIC). METHODS:Fallopian tube tissue samples were obtained from 4 females undergoing prophylactic hysterectomies and 6 patients diagnosed with STIC. A mogp-TAg transgenic mouse STIC sample was also compared with a wild-type mouse FT sample. Serous tubal intraepithelial carcinoma was identified by hematoxylin and eosin staining and confirmed by positive Ki-67 and p53 immunohistochemical staining of tissue sections. We assessed the relative distribution of primary cilia on secretory cells and motile cilia on multiple ciliated cells by immunofluorescence and immunohistochemical staining. Ciliary function was assessed by immunofluorescence staining of specific ciliary marker proteins and responsiveness to Sonic Hedgehog signaling. RESULTS:Primary cilia are widespread on secretory cells in the ampulla, isthmus, and in particular, the fimbriae of human FT where they may appear to mediate ciliary-mediated Sonic Hedgehog signaling. A statistically significant reduction in the number of primary cilia on secretory cells was observed in human STIC samples compared with normal controls (P < 0.0002, Student t test), supported by similar findings in a mouse STIC sample. Immunohistochemical staining for dynein axonemal heavy chain 5 discriminated multiple motile cilia from primary cilia in human FT. CONCLUSIONS:Primary cilia are widespread on secretory cells in the ampulla, isthmus, and in particular, the fimbriae of the human FT but are significantly reduced in both human and mouse STIC samples. Immunohistochemical staining for ciliary proteins may have clinical utility for early detection of STIC.

SUBMITTER: Abdelhamed ZA

PROVIDER: S-EPMC6166701 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Characterization of Primary Cilia in Normal Fallopian Tube Epithelium and Serous Tubal Intraepithelial Carcinoma.

Abdelhamed Zakia A ZA Ryan Thomas A TA Fuller Martin M Coulson-Gilmer Camilla C Abdelmottaleb Dina I DI Wang Tian-Li TL Kaun Jen-Chun JC Wang Peiyi P Hutson Richard R Wilkinson Nafisa N Bell Sandra M SM Johnson Colin A CA

International journal of gynecological cancer : official journal of the International Gynecological Cancer Society 20181001 8

<h4>Objectives</h4>The aim of this study was to investigate the distribution of primary cilia on secretory cells in normal fallopian tube (FT) and serous tubal intraepithelial carcinoma (STIC).<h4>Methods</h4>Fallopian tube tissue samples were obtained from 4 females undergoing prophylactic hysterectomies and 6 patients diagnosed with STIC. A mogp-TAg transgenic mouse STIC sample was also compared with a wild-type mouse FT sample. Serous tubal intraepithelial carcinoma was identified by hematoxy ...[more]

PMID: 30095490

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Project description:ObjectiveSerous tubal intra-epithelial carcinoma (STIC) lesions are thought to be precursors to high-grade serous ovarian cancer (HGSOC), but HGSOC is not always accompanied by STIC. Our study was designed to determine if there are global visual and subvisual microenvironmental differences between fallopian tubes with and without STIC lesions.MethodsComputational image analyses were used to identify potential morphometric and topologic differences in stromal and epithelial cells in samples from three age-matched groups of fallopian tubes. The Benign group comprised normal fallopian tubes from women with benign conditions while the STIC and NoSTIC groups consisted of fallopian tubes from women with HGSOC, with and without STIC lesions, respectively. For the morphometric feature extraction and analysis of the stromal architecture, the image tiles in the STIC group were further divided into the stroma away from the STIC (AwaySTIC) and the stroma near the STIC (NearSTIC). QuPath software was used to identify and quantitate secretory and ciliated epithelial cells. A secretory cell expansion (SCE) or a ciliated cell expansion (CCE) was defined as a monolayered contiguous run of >10 secretory or ciliated cells uninterrupted by the other cell type.ResultsImage analyses of the tubal stroma revealed gradual architectural differences from the Benign to NoSTIC to AwaySTIC to NearSTIC groups. In the epithelial topology analysis, the relative number of SCE and the average number of cells within SCE were higher in the STIC group than in the Benign and NoSTIC groups. In addition, aging was associated with an increased relative number of SCE and a decreased relative number of CCE. ROC analysis determined that an average of 15 cells within SCE was the optimal cutoff value indicating the presence of a STIC lesion in the tubal epithelium.ConclusionsOur findings suggest that global stromal alterations and age-associated reorganization of tubal secretory and ciliated cells are associated with STIC lesions. Further studies will need to determine if these alterations precede STIC lesions and provide permissible conditions for the formation of STIC.

Project description:High grade serous ovarian carcinoma (HGSC) without identifiable serous tubal intraepithelial carcinoma (STIC) within the fallopian tube (FT) occurs in approximately 50% of patients. The objective of this study was to use a multisite tumor sampling approach to study HGSC with and without STIC. RNAseq analysis of HGSC samples collected from multiple sites e.g. ovary, FT and peritoneum, revealed moderate levels of intrapatient heterogeneity in gene expression that could influence molecular profiles. Mixed-model ANOVA analysis of gene expression in tumor samples from patients with multiple tumor sites (n = 13) and patients with a single site tumor sample (n = 11) to compare HGSC-STIC to HGSC-NOSTIC identified neurotensin (NTS) as significantly higher (> two-fold change, False Discovery Rate (FDR) < 0.10) in HGSC-STIC. This data was validated using publicly available RNA-Seq datasets. Concordance between higher NTS gene expression and NTS peptide levels in HGSC-STIC samples was demonstrated by immunohistochemistry. To determine the role of NTS in HGSC, five ovarian cancer (OvCa) cell lines were screened for expression of NTS and its receptors, NTSR1 and NTSR3. Increased expression of NTS and NSTR1 was observed in several of the OvCa cells, whereas the NTSR3 receptor was lower in all OvCa cells, compared to immortalized FT epithelial cells. Treatment with NTSR1 inhibitor (SR48692) decreased cell proliferation, but increased cell migration in OvCa cells. The effects of SR48692 were receptor mediated, since transient RNAi knockdown of NTSR1 mimicked the migratory effects and knockdown of NTSR3 mimicked the anti-proliferative effects. Further, knockdown of NTSR1 or NTSR3 was associated with acquisition of distinct morphological phenotypes, epithelial or mesenchymal, respectively. Taken together, our results reveal a difference in a biologically active pathway between HGSC with and without STIC. Furthermore, we identify neurotensin signaling as an important pathway involved in cell proliferation and epithelial-mesenchymal transition in HGSC-STIC which warrants further study as a potential therapeutic target. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Dataset Information

Characterization of Primary Cilia in Normal Fallopian Tube Epithelium and Serous Tubal Intraepithelial Carcinoma.

Publications

Characterization of Primary Cilia in Normal Fallopian Tube Epithelium and Serous Tubal Intraepithelial Carcinoma.

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