Distinct Patterns of Stromal and Tumor Expression of ROR1 and ROR2 in Histological Subtypes of Epithelial Ovarian Cancer

Abstract

OBJECTIVE: The ROR1 and ROR2 receptor tyrosine kinases have both been implicated in ovarian cancer progression and have been shown to drive migration and invasion. There is an increasing importance of the role of stroma in ovarian cancer metastasis; however, neither ROR1 nor ROR2 expression in tumor or stromal cells has been analyzed in the same clinical cohort. AIM: To determine ROR1 and ROR2 expression in ovarian cancer and surrounding microenvironment and examine associations with clinicopathological characteristics. METHODS: Immunohistochemistry for ROR1 and ROR2 was used to assess receptor expression in a cohort of epithelial ovarian cancer patients (n = 178). Results were analyzed in relation to clinical and histopathological characteristics and survival. Matched patient sample case studies of normal, primary, and metastatic lesions were used to examine ROR expression in relation to ovarian cancer progression. RESULTS: ROR1 and ROR2 are abnormally expressed in malignant ovarian epithelium and stroma. Higher ROR2 tumor expression was found in early-stage, low-grade endometrioid carcinomas. ROR2 stromal expression was highest in the serous subtype. In matched patient case studies, metastatic samples had higher expression of ROR2 in the stroma, and a recurrent sample had the highest expression of ROR2 in both tumor and stroma. CONCLUSION: ROR1 and ROR2 are expressed in tumor-associated stroma in all histological subtypes of ovarian cancer and hold potential as therapeutic targets which may disrupt tumor and stroma interactions.

Mesenchymal stem cell‐derived CXCL16 promotes progression of gastric cancer cells by STAT3‐mediated expression of Ror1

“…Thus, Ror2 exhibits either tumor‐promotive or tumor‐suppressive function depending on the type of tumors. Furthermore, Ror2 is expressed in not only tumor cells but also tumor stroma, and high Ror2 expression in tumor stroma is associated with poor prognosis in ovarian cancer and pancreatic ductal adenocarcinoma, suggesting that tumor progression can be promoted by Ror2‐mediated signaling in either tumor cells themselves or tumor stromal cells through tumor stroma interaction.…”

“…Ror2 and Wnt5a are highly expressed in various types of cancer cells, resulting in constitutive activation of Wnt5a‐Ror2 signaling in a cell‐autonomous manner, eventually contributing to tumor progression . However, expression of Ror2 is also observed in cellular components of tumor stroma, and higher levels of Ror2 expression in tumor stroma seem to be associated with poor prognosis in ovarian cancer and pancreatic ductal adenocarcinoma, suggesting an important role of stromal Ror2 in tumor progression. We have previously shown that MSC express both Wnt5a and Ror2, even though Wnt5a‐Ror2 signaling in MSC seems not to affect proliferation and viability of themselves .…”

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

“…In vitro, we have demonstrated (Henry et al 2016) that overexpression of both RORs results in increased invasion, while their knockdown inhibits migration and invasion and sensitises chemotherapy resistant cell lines to cisplatin in ovarian cancer. In a cohort of 178 patient samples with matched benign, primary and metastatic lesions, both receptors were abnormally expressed in both epithelium and stroma -ROR2 most prominently in early stage, low-grade endometrioid ovarian tumours and in the stroma of the serous subtype (Henry et al 2017). Therefore there is evidence for the potential of ROR1 and ROR2 as therapeutic targets in the related endometrial tumours.…”

Silencing ROR1 and ROR2 inhibits invasion and adhesion in an organotypic model of ovarian cancer metastasis

“…We previously found ROR2, but not ROR1 upregulation in ovarian cancer associated stroma, in particular in metastatic samples of matched patient study cases [ 12 ]. ROR2 expression in stroma has otherwise only been reported in pancreatic cancer [ 33 ].…”

“…These results were then supported in a chemoresistant cell line model [ 9 ], and by other studies using in vivo xenografts, where a ROR1 monoclonal inhibitor significantly decreased tumour burden [ 10 , 11 ]. We recently identified an upregulation of ROR2 in stromal compartments of tissue samples from patients with metastatic disease [ 12 ]. Here we aimed to further investigate the role of these receptors in tumour and stroma, in the setting of omental metastasis using a patient derived organotypic model.…”