ROR1 and ROR2 play distinct and opposing roles in endometrial cancer

Henry, Claire; Llamosas, Estelle; Daniels, Benjamin; Coopes, Amy; Tang, Katrina; Ford, Caroline

doi:10.1016/j.ygyno.2018.01.025

Cited by 31 publications

(36 citation statements)

References 31 publications

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“…This study confirms ROR1 as a potential therapeutic target in EC. Despite the different ROR1 primary antibody used in the IHC compared to our previous smaller cohort 31 , we have shown the same effect of ROR1 on OS and PFS in our clinical cohort. Patients with high ROR1 expression have a significant lower OS and PFS compared to those with low or moderate level of ROR1 expression.…”

Section: Discussionsupporting

confidence: 59%

“…In ovarian cancer, we have demonstrated that both ROR1 and ROR2 are overexpressed in large cohorts of tumour tissue 26 , and that silencing ROR1 and ROR2 inhibits metastatic potential 26 , which supported the oncogenic role of the two receptors. In contrast, when we conducted a similar study in EC of limited sample size (n = 87), we identified potential distinct roles for ROR1 and ROR2 31 . The aim of this study was to investigate the role of ROR1 and ROR2 in EC in a larger Australian population-based EC cohort, encompassing all major subtypes of the disease, and to perform a series of in-vitro experiments to clarify the role of each receptor.…”

mentioning

confidence: 82%

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ROR1 is upregulated in endometrial cancer and represents a novel therapeutic target

Liu

Gunther

Enriquez

et al. 2020

Sci Rep

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ROR1 and ROR2 are receptor tyrosine kinases with altered expression in a range of cancers. Silencing ROR1 or ROR2 in different tumour types has been shown to inhibit proliferation and decrease metastatic potential. The aim of this study was to investigate the role of ROR1 and ROR2 in endometrial cancer via immunohistochemistry (IHC) in a large endometrial cancer patient cohort (n = 499) and through in vitro analysis in endometrial cancer cell lines. Correlation was assessed between ROR1/2 expression and clinicopathological parameters. Kaplan Meier curves were produced for 5-year progression free survival (PFS) and overall survival (OS) with low/moderate versus high ROR1/2 intensity. Cox multivariate regression was applied to analyse the effect of selected covariates on the PFS and OS. The effect of ROR1 and/or ROR2 modulation on cell proliferation, adhesion, migration and invasion was analysed in two endometrial cancer cell lines (KLE and MFE-296). We observed a significant decrease in OS and PFS in patients with high ROR1 expression. ROR1 silencing and ROR2 overexpression significantly inhibited proliferation of KLE endometrial cancer cells and decreased migration. This study supports the oncogenic role of ROR1 in endometrial cancer, and warrants investigation of future application of ROR1-targeting therapies in endometrial cancer patients. Endometrial cancer (EC) is the most prevalent gynaecological cancer and the sixth most common malignancy worldwide 1. Incidence has increased significantly over the last decade, particularly in developed countries 2. This escalating worldwide burden and poor survival outcomes from advanced stage and aggressive subtypes warrants further research into novel targets and new therapies. The pathogenesis for EC is multifactorial, with risk factors including genetic variants 3 , high BMI 4,5 , high number of cumulative menstrual cycles 6,7 , and infertility 8. In 1983, Bokhman 9 proposed the classic dualistic model which divided EC into estrogen driven endometrioid subtype (Type I) and the more aggressive nonendometrioid subtype (Type II). Based on the histopathological features, EC is also commonly classified into endometrioid adenocarcinoma, serous carcinoma, mucinous carcinoma, clear cell carcinoma mixed carcinoma etc. 10. There are certain overlaps between the two classification systems: Type I is generally endometrioid subtype and Type II is mostly serous. These traditional classification systems based on endocrine or histopathological features failed to take into account the heterogeneity of EC and were limited due to technical difficulties and controversies in histopathological assessment 11,12. In 2013, the Cancer Genome Atlas (TCGA) defined four genomic subgroups: Polymerase epsilon (POLE)-mutant tumours (ultrahypermutated), MSI (hypermutated), copy-number low (endometrioid) and copy-number high tumours (serous-like) through integration of multiomics data 13. Although this system is not yet in widespread clinical use, the identification of molecular targets correlate to dis...

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Section: Discussionsupporting

confidence: 59%

mentioning

confidence: 82%

ROR1 is upregulated in endometrial cancer and represents a novel therapeutic target

Liu

Gunther

Enriquez

et al. 2020

Sci Rep

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“…Our recent study investigated both ROR1 and ROR2 in a small clinical cohort of 77 endometrioid endometrial tumours and 10 serous endometrial tumours and identified distinct roles for these sister receptors (Henry et al 2018). ROR2 overexpression correlated with better survival, and when silenced in the endometrial RL95-2 line, cells increased their ability to migrate and invade.…”

Section: Rors and Endometrial Cancermentioning

confidence: 99%

“…In light of the established role for Wnt signalling in endometrial development, and median age of endometrial cancer diagnosis being 61 years (Hüsing et al 2016), the effect of menopause on ROR1 and ROR2 expression warrants investigation. In our recent study of ROR1 and ROR2 (Henry et al 2018), we did not have access to the menopause status of our patient cohort, but future studies should seek this information for both benign controls and cancer patients.…”

Section: Rors and Endometrial Cancermentioning

confidence: 99%

“…Recruitment is ongoing for the other, a basket design, dose-escalating study including ROR1-positive tumours such as breast cancer, lymphoma, leukaemia and lung cancer (NCT02706392). As we have demonstrated opposing roles for ROR1 and ROR2 in endometrial cancer (Henry et al 2018), it will be critical to monitor the effect on ROR2, when targeting ROR1 in endometrial cancer. Current Wnt-targeting therapies and which components of the pathway they target are shown in Fig.…”

Section: :12mentioning

confidence: 99%

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An update of Wnt signalling in endometrial cancer and its potential as a therapeutic target

Coopes

Henry

Llamosas

et al. 2018

Endocrine-Related Cancer

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Endometrial cancer is the most common gynaecological malignancy in developed nations, and its prevalence is rising as women defer or decide not to have children and as obesity rises, both key risk factors. Despite this, treatment options remain limited, particularly for advanced or refractory disease. New genomic analyses have revealed distinct mutational profiles with therapeutic and prognostic potential. Wnt signalling, which is pivotal in embryogenesis, healing and homeostasis, is of importance in the endometrium and has been linked to carcinogenesis. This review aims to update and discuss the current evidence for the role of β-catenin dependent and independent Wnt signalling, including the ROR receptors in the endometrium and its potential as a therapeutic target, in light of recent trials of Wnt-targeted therapy in multiple tumour types.

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ROR2 promotes cell cycle progression and cell proliferation through the PI3K/AKT signaling pathway in gastric cancer

Liu,

Zhao,

Shao

et al. 2024

Molecular Carcinogenesis

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Proliferation is a critical characteristic of the progression of gastric cancer (GC). Receptor tyrosine kinase‐like orphan receptor 2 (ROR2), the orphan receptor tyrosine kinase‐like receptor, exhibits effects on tumor growth due to its abnormal expression in cancer. The goal of our study was to assess the potential regulatory role exerted by the ROR2 on GC cells. Through previous bioinformatics analysis, we discovered an association between ROR2 and the G2/M phase of the GC cell cycle. However, little is known about the link between ROR2 and the G2/M phase cell cycle in GC. Here, the findings of our study indicate that ROR2, after transcribed expression by Twist1, activates the PI3K/AKT/mTOR/S6K signal transduction pathway, thus leading to the acceleration of the G2/M phase and subsequent promotion of cell proliferation in GC. Furthermore, the functional link among ROR2, Twist1, and G2/M phase of cell cycle was also confirmed in mouse xenograft tissues and human tissues. ROR2 expression was correlated with Twist expression and lower survival in vivo. Notably, our suggestion is that focusing on ROR2 as a potential therapeutic approach could show potential for the management of GC.

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ROR1 and ROR2 play distinct and opposing roles in endometrial cancer

Cited by 31 publications

References 31 publications

ROR1 is upregulated in endometrial cancer and represents a novel therapeutic target

ROR1 is upregulated in endometrial cancer and represents a novel therapeutic target

An update of Wnt signalling in endometrial cancer and its potential as a therapeutic target

ROR2 promotes cell cycle progression and cell proliferation through the PI3K/AKT signaling pathway in gastric cancer

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