Impact of oviductal versus ovarian epithelial cell of origin on ovarian endometrioid carcinoma phenotype in the mouse

Increased expression of the receptor tyrosine kinase c-Met has been shown to correlate with enhanced cell proliferation, motility, and invasion. The objectives of this study were to characterize total and activated c-Met expression in both normal and malignant human ovarian epithelial cells and to determine the effects of inhibiting the activation of c-Met on ovarian epithelial cell growth, motility, and invasion. Total c-Met was overexpressed in 82 (68%) of 119 ovarian carcinomas, as shown by immunohistochemistry. Quantitative reverse transcription–polymerase chain reaction and Western blot analyses revealed that ovarian carcinoma cell lines had higher levels of c-Met messenger RNA, total protein, and activated protein expression compared to normal ovarian epithelial cell cultures. Using a specific adenosine triphosphate-competitive small-molecule inhibitor, SU11274, activated c-Met was decreased in normal and ovarian carcinoma cell lines. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays showed that cell growth inhibition directly correlated to the level of activated c-Met detected in each cell line (r=−0.87, P= 0.012). Using modified Boyden chamber assays, ovarian carcinoma cells treated with SU11274 demonstrated significantly decreased cell motility and invasion compared to untreated cells (P= 0.003 and P< 0.001, respectively). These data indicate that c-Met is overexpressed in the majority of malignant ovarian epithelial cells both In vivo and in vitro and that decreasing activated c-Met in vitro can significantly decrease ovarian carcinoma cell growth, motility, and invasion. Developing therapies that specifically inhibit the activation of c-Met may represent a novel therapeutic modality for patients with ovarian carcinomas expressing high levels of c-Met.

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Loss of ARID1A Expression Is an Early Molecular Event in Tumor Progression From Ovarian Endometriotic Cyst to Clear Cell and Endometrioid Carcinoma

International Journal of Gynecological Cancer ◽

10.1097/igc.0b013e31826b5dcc ◽

2012 ◽

Vol 22 (8) ◽

pp. 1310-1315 ◽

Cited By ~ 98

Author(s):

Ayse Ayhan ◽

Tsui-Lien Mao ◽

Tamer Seckin ◽

Chen-Hsuan Wu ◽

Bin Guan ◽

...

Keyword(s):

Tumor Progression ◽

Chromatin Remodeling ◽

Clear Cell ◽

Immunohistochemical Study ◽

Molecular Event ◽

Endometrioid Carcinoma ◽

Cell Of Origin ◽

Endometriotic Cyst ◽

Well Differentiated ◽

Inactivating Mutations

ObjectivesARID1A is a recently identified tumor suppressor participating in chromatin remodeling. Somatic inactivating mutations of ARID1A and loss of its expression occur frequently in ovarian clear cell and endometrioid carcinomas and in uterine endometrioid carcinomas. Because endometriotic epithelium is thought to be the cell of origin of most ovarian clear cell and endometrioid carcinomas, we undertook an analysis of ARID1A expression of these tumors arising within an endometriotic cyst (endometrioma).Materials and MethodsOur immunohistochemical study set consisted of 47 endometriotic cysts containing clear cell carcinoma in 24 cases, well-differentiated ovarian endometrioid carcinoma in 20 cases, and mixed clear cell and endometrioid carcinoma in 3 cases.ResultsARID1A loss was observed in 31 (66%) of 47 carcinomas; and therefore, these cases were informative for determining the temporal sequence of loss of ARID1A expression in tumor progression. In 16 of the 47 cases, ARID1A immunoreactivity was retained in both the endometriotic cyst and the carcinoma; and thus, these cases were not informative. All of the 31 informative cases showed loss of ARID1A immunoreactivity in the carcinoma and in the endometriotic cyst epithelium in direct continuity with the carcinoma but not in the cyst epithelium that was not adjacent to the tumor.ConclusionsLoss of ARID1A function as shown by loss of expression, presumably due to mutations, is an early molecular event in the development of most ovarian clear cell and endometrioid carcinomas arising in endometriomas.

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Methylation status of oestrogen receptor-α gene promoter sequences in human ovarian epithelial cell lines

British Journal of Cancer ◽

10.1038/sj.bjc.6600028 ◽

2002 ◽

Vol 86 (2) ◽

pp. 282-284 ◽

Cited By ~ 14

Author(s):

A M O'Doherty ◽

S W Church ◽

S E H Russell ◽

J Nelson ◽

I Hickey

Keyword(s):

Epithelial Cell ◽

Cell Lines ◽

Oestrogen Receptor ◽

Methylation Status ◽

Gene Promoter ◽

Promoter Sequences ◽

Epithelial Cell Lines ◽

Oestrogen Receptor Α ◽

Ovarian Epithelial Cell

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Prostate epithelial cell of origin determines cancer differentiation state in an organoid transformation assay

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1603645113 ◽

2016 ◽

Vol 113 (16) ◽

pp. 4482-4487 ◽

Cited By ~ 48

Author(s):

Jung Wook Park ◽

John K. Lee ◽

John W. Phillips ◽

Patrick Huang ◽

Donghui Cheng ◽

...

Keyword(s):

Prostate Cancer ◽

Epithelial Cell ◽

Specific Antigen ◽

Human Prostate ◽

Functional Evaluation ◽

Cell Of Origin ◽

Immunodeficient Mice ◽

Organoid Culture ◽

Transformation Assay ◽

Luminal Cells

The cell of origin for prostate cancer remains a subject of debate. Genetically engineered mouse models have demonstrated that both basal and luminal cells can serve as cells of origin for prostate cancer. Using a human prostate regeneration and transformation assay, our group previously demonstrated that basal cells can serve as efficient targets for transformation. Recently, a subpopulation of multipotent human luminal cells defined by CD26 expression that retains progenitor activity in a defined organoid culture was identified. We transduced primary human prostate basal and luminal cells with lentiviruses expressing c-Myc and activated AKT1 (myristoylated AKT1 or myrAKT1) to mimic the MYC amplification and PTEN loss commonly detected in human prostate cancer. These cells were propagated in organoid culture before being transplanted into immunodeficient mice. We found that c-Myc/myrAKT1–transduced luminal xenografts exhibited histological features of well-differentiated acinar adenocarcinoma, with strong androgen receptor (AR) and prostate-specific antigen (PSA) expression. In contrast, c-Myc/myrAKT1–transduced basal xenografts were histologically more aggressive, with a loss of acinar structures and low/absent AR and PSA expression. Our findings imply that distinct subtypes of prostate cancer may arise from luminal and basal epithelial cell types subjected to the same oncogenic insults. This study provides a platform for the functional evaluation of oncogenes in basal and luminal epithelial populations of the human prostate. Tumors derived in this fashion with defined genetics can be used in the preclinical development of targeted therapeutics.

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A single cell atlas of the healthy breast tissues reveal clinically relevant clusters of breast epithelial cells

10.1101/2020.06.25.171793 ◽

2020 ◽

Author(s):

Poornima Bhat-Nakshatri ◽

Hongyu Gao ◽

Patrick C. McGuire ◽

Xiaoling Xuei ◽

Liu Sheng ◽

...

Keyword(s):

Epithelial Cell ◽

Single Cell ◽

Breast Tumors ◽

Normal Breast ◽

Breast Epithelial Cell ◽

Breast Cancers ◽

Cell Of Origin ◽

Intrinsic Subtypes ◽

Breast Epithelial ◽

Breast Tissues

SummarySingle cell RNA sequencing is an evolving field to elucidate cellular architecture of adult organs. Using normal breast tissues from healthy volunteers and a rapid procurement/processing/sequencing protocol, 13 breast epithelial cell clusters were identified. Approximately 90% of breast cancers were enriched for cell-of-origin signatures derived from differentiated luminal clusters and two minor luminal progenitor clusters. Expression of cell cycle and chromosome segregation-related genes were higher in one of the minor clusters and breast tumors with this cluster signature displayed the highest mutation rate and poor outcome. We identified TBX3 and PDK4 as genes co-expressed with estrogen receptor (ER) in the normal breasts and their expression analyses in >550 breast cancers enabled prognostically relevant cell-of-origin based subclassification of ER+ breast cancers.SignificanceThis study elucidates different epithelial cell types of the normal breasts and identifies a minor subpopulation of cells from which the majority of breast cancers may originate. This observation should help to develop methods to characterize breast tumors based on cell-of-origin. Although it was suggested that intrinsic subtypes of breast cancers have distinct cells of origins, this study suggests multiple cell-of-origin for an intrinsic subtype of breast cancer, including for hormone responsive breast cancers. Cell-of-origin signatures allowed survival-associated subclassification of intrinsic subtypes. Critically, this normal breast cell atlas would allow for the classification of genes differentially expressed in a breast tumor compared to normal breast due to the cell-of-origin of tumor and those that are acquired due to genomic aberrations.

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