Ovarian Cancer Stem Cells with High ROR1 Expression Serve as a New Prophylactic Vaccine for Ovarian Cancer

Abstract

Tumor vaccines offer a number of advantages for cancer treatment. In the study, the vaccination with cancer stem cells (CSCs) with high expression of the type I receptor tyrosine kinase-like orphan receptor (ROR1) was evaluated in a murine model for the vaccine’s immunogenicity and protective efficacy against epithelial ovarian carcinoma (EOC). CD117+CD44+ CSCs were isolated from human EOC HO8910 cell line using a magnetic-activated cell sorting system; murine ID8 EOC suspension sphere cells, which are collectively known as cancer stem-like cells, were acquired from serum-free suspension sphere-forming culture. Mice were subcutaneously immunized with the repeat cycles of freezing and thawing whole HO8910 CD117+CD44+ CSCs and ID8 cancer stem-like cells, respectively, followed by a challenge with HO8910 or ID8 cells at one week after final vaccination. The results showed that the CSC vaccination significantly induced immunity against EOC growth and markedly prolonged the survival of EOC-bearing mice in the prophylactic setting compared with non-CSC vaccination. Flow cytometry showed significantly increased immunocyte cytotoxicities and remarkably reduced CSC counts in the CSC-vaccinated mice. Moreover, the protective efficacy against EOC was decreased when the ROR1 expression was downregulated by shRNA in CSC vaccines. The findings from the study suggest that CSC vaccines with high ROR1 expression were highly effective in triggering immunity against EOC in vaccinated mice and may serve as an effective vaccine for EOC immunoprophylaxis.

ROR1 regulates chemoresistance in Breast Cancer via modulation of drug efflux pump ABCB1

“…More interestingly, ROR1 was previously shown to be enriched in chemoresistant breast 8 and ovarian 11 cancers. High ROR1 expression has also been found to be associated with stemness and tumor recurrence in ovarian cancer, breast cancer, glioblastoma and chronic lymphocytic leukemia 8,[11][12][13][14] . In concordance with these findings, our analyses suggest ROR1 is highly expressed in patients with poor response to chemo agents, and enriched following chemotherapy.…”

“…ROR1 is an oncofetal receptor highly expressed in several human malignancies but not expressed in normal adult tissue [8][9][10] . Previous work has shown ROR1 to be enriched in chemoresistant stem cells and be a prognostic marker for relapse and poor therapeutic outcomes 8,[11][12][13][14][15] . Analysis of breast cancer patient gene expression data from NCBI's Gene Expression Omnibus (GEO) suggests ROR1 is enriched in patients with poor response to chemotherapy.…”

The WNT/ROR Pathway in Cancer: From Signaling to Therapeutic Intervention

“…An alternative approach in cancer immunotherapy is therapeutic cancer vaccination. In a preclinical study by Wu et al a vaccine based on ROR1-expressing ovarian cancer stem cells induced high immunogenicity and prophylactic effectiveness against ovarian cancer [ 177 ]. Although ROR1 could indeed serve as a promising tumor antigen with high immunogenicity, therapeutic cancer vaccines still face the challenges of overcoming cancer immunosuppression and eliciting an adequate immune response; major obstacles that have thus far resulted in disappointing results of the vaccination approach in patients.…”

Molecular Mechanisms Associated with ROR1-Mediated Drug Resistance: Crosstalk with Hippo-YAP/TAZ and BMI-1 Pathways

“…The identification of several CSC markers has facilitated the screening and study of many cancers, including those of the blood, breast, ovaries, brain, lung, colon and skin [44]. Currently, CD133, CD24, CD44 and aldehyde dehydrogenase 1 (ALDH1) are widely used to identify CSCs in various tumors, while other markers such as BMI-1 [45] and ROR1 [20,46,47] are starting to gain more attention for their involvement in the stemness of several malignancies. ROR1 has been associated with the CSC phenotype in several malignancies such as leukemia, ovarian and breast tumors.…”