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Obesity-Driven Increase in Endometrial Cancer Risk

Endometrial cancer (EC), sometimes called uterine cancer, begins in the layer of cells that form the lining (endometrium) of the uterus and is the most common cancer of the female reproductive organs. ECs are commonly divided into estrogen-dependent Type I and the more clinically aggressive estrogen-independent Type II, where Type I tumors comprise the large majority of endometrial cancers that develop. There are a number of risk factors that increase the likelihood of a woman developing EC, including obesity, age, hormone therapy, and more.

There has been an increase in the incidence of Type 1 EC over the past two decades, due in part to the increasing rate of obesity. Of all cancers showing a positive correlation between body mass index (BMI) and incidence, endometrial cancer exhibits the strongest association with obesity. This had led researchers to examine how increased adipose tissue can lead to EC development.

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Recent Endometrial Cancer Research Using Lifeline Products

A recent publication by Lin and Colleagues was aimed at uncovering the mechanisms driving the increased incidence of type 1 EC in obese individuals by studying the adipose tissue-derived stem cells (ASCs), including the parametrial fat near the uterus, and how they can alter gene expression in endometrial epithelial cells (EECs) to potentiate them towards an oncogenic phenotype. In previous work by these researchers, plasminogen activator inhibitor-1 (PAI-1), a primary ASC-secreted adipokine secreted was found to act as an oncogenic ligand that deregulates transcriptional programs of EECs in vitro; therefore, this adipokine was the focus of the new study.

Immunofluorescence staining of EC tumor tissue microarrays and non-cancerous controls in obese and normal BMI individuals showed that ASCs (WA7+) infiltrated the tumor microenvironment at a much higher frequency than in the non-cancerous and normal BMI groups. Multiplex assay of adipokines and cytokines secreted by ASCs confirmed that PAI-1 was the most abundant adipokine. To understand how ASC-secreted PAI-1 influences epithelial cell transcriptomes, an endometrial cancer cell line (EME6/7t), and normal primary endometrial (uterine) epithelial cells from Lifeline Cell Technology were exposed to ASC-conditioned media (CM) for 24 h to simulate ASC paracrine effects in vitro prior to transcriptome analysis. A pro-tumorigenic phenotype was induced in this exposure model, including enhanced cellular invasion, proliferation, and mobility in both groups exposed to ASC-CM.

Single-cell RNA-seq transcriptomic profiling and pathway enrichment analysis identified TGF-β/SMAD as a key pathway that is negatively regulated by PAI-1. Genes associated with junction and adhesion complex (JAC) positively linked to TGF-β/SMAD signaling, were found to be uncoupled by PAI-1 in cells exposed to ASC-CM. Proximity ligation assay (PLA) showed an increase in the interaction between PAI-1 and lipoprotein receptor-related protein 1 (LRP1) on the cell surface of ASC-CM-exposed EME6/7t cells. Further evaluation using chromatin immunoprecipitation (ChIP)-qPCR showed that LRP1 acts as a transcription repressor to downregulate SMAD4 gene expression in ASC-CM-exposed cells. Inhibitors of LRP1 and PAI-1 could reverse the suppressive effects. Taken together, these results demonstrate that PAI-1-LRP1 downregulates SMAD4, which attenuated tumor-suppressive activities of TGF-β/SMAD signaling leading to deregulation of JAC genes in EECs.

To determine the role of obesity on modulating this molecular pathway, mass spectrometry (CyTOF) protein expression analysis of EC tumors from both normal and obese individuals was performed. Low SMAD4-expressing cells, and associated JAC reduction were found at a higher frequency in EC tumors from obese patients compared to controls, further confirming the role of ASC paracrine effects on ECCs to promote a pro-tumorigenic phenotype.

Overall, this study provides mechanistic insights that show ASC-secreted PAI-1/LRP1 suppresses TGF-β/SMAD signaling and JAC gene expression in ECCs. The breakdown of cell-cell adhesion and ECM interactions regulated by SMAD4 promotes ASC motility and invasiveness into the endometrial microenvironment. These pro-tumorigenic paracrine effects were found to occur at a higher frequency in obese individuals, who have increased adipose tissue adjacent to the uterus. Increased PAI-1 secretion mobilizes ASCs into the endometrial microenvironment and suppresses TGF-β/SMAD signaling and JAC gene expression in ECCs, which have anti-tumor functions, to promote epithelial tumorigenesis and obesity-driven endometrial cancer.

This publication as well as others that have been reviewed on the Lifeline blog highlight the importance of high-quality control cells to facilitate comparative studies that can shed light on mechanisms driving disease onset and progression. In previous blog posts, we reviewed publications by Min and Chen and Lui and Colleagues, who utilized Lifeline’s Normal Human Endometrial (Uterine) Epithelial Cells cultured in cultured in ReproLife™ Reproductive Medium as normal controls for their EC research.

We look forward to sharing more research topics with you in our continued coverage of the latest publications here on the blog.

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