Expression of RON in colorectal cancer and its relationships with tumor cell behavior and prognosis

Park, Young‐Lan; Lee, Gi-Hoon; Kim, Kyu-Yeol; Myung, Eun; Kim, Jong-Sun; Myung, Dae‐Seong; Park, Kang-Jin; Cho, Sung-Bum; Lee, Wan‐Sik; Jung, Yoon Young; Kim, Hyunsoo; Joo, Young‐Eun

doi:10.1177/030089161209800517

Cited by 12 publications

(18 citation statements)

References 40 publications

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“…Therefore, we used the FAHZUSM cohort, a larger patient cohort complete with pathological tumor samples, to further study the expression of RON and PD-L1 in colorectal cancer tissues and to determine the pathological significance of elevated RON and PD-L1 expression in TC and in the cells of the tumor microenvironment.Dysregulation of RON and PD-L1 signal transduction is a key feature of many tumors. Our results and previous studies demonstrate that high expression of RON or PD-L1 in CRC tumor tissues correlates with the extent of primary tumor, lymph node metastasis, and distant metastasis(39,40). Furthermore, high expression of RON or PD-L1 in the tumor microenvironment was associated with poor survival in CRC patients(22,(39)(40)(41)(42).…”

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confidence: 75%

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The pathological significance of abnormal RON and PD-L1 expression in colorectal cancer

Liu¹,

Han²,

Shi³

et al. 2020

Preprint

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Background: PD-L1 immunotherapy remains poorly efficacious in colorectal cancer. The RON receptor tyrosine kinase plays an important role in regulating tumor immunity. Here, we identify patterns of RON and PD-L1 expression and explore the clinical significance of these patterns in colorectal cancer. Methods: Gene expression data were obtained from the Gene Expression Omnibus database (GEO; n = 290) and patients at the First Affiliated Hospital, Zhejiang University School of Medicine (FAHZUSM; n = 381) and were analyzed to determine the prognostic value of RON and PD-L1 expression within the tumor cells and the tumor microenvironment of colorectal cancer. Human colorectal cancer cell lines were treated with BMS-777607 to explore the relationship between RON activity and PD-L1 protein expression. Signaling pathways and protein expression perturbed by RON inhibition were evaluated by cellular immunofluorescence and western blot. Results: In the GEO cohort, cut-off values for RON and PD-L1 expression of 7.70 and 4.30, respectively, were determined. Stratification of patients based on these cutoffs demonstrated that high expression of RON and PD-L1 associated with poor prognosis. In the FAHZUSM cohort, rates of high expression of RON in tumor cells, high PD-L1 expression in tumor cells and in tumor infiltrating monocytes, and both high RON and high PD-L1 expression in the tumor microenvironment were 121 (32%), 43 (11%), 91 (24%), and 51 (13.4%), respectively. High expression of RON and high expression of PD-L1 in the tumor cell compartment was significantly correlated (p < 0.001). High expression of RON and PD-L1 were independent prognostic factors for poorer overall survival. Concurrent high expression of both RON and PD-L1 in the tumor microenvironment was significantly associated with poor prognosis. In vitro , BMS-777607 inhibited the phosphorylation of RON, inhibited PD-L1 expression, and attenuated activation of the ERK1/2 and AKT signaling pathways in colorectal cancer cells. Conclusions: RON, PD-L1 and the crosstalk between these proteins plays an important role in predicting the prognostic value of colorectal cancer. Moreover, phosphorylation of RON upregulates the expression of PD-L1, which provides a novel approach to immunotherapy in colorectal cancer.

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confidence: 75%

“…Our results and previous studies demonstrate that high expression of RON or PD-L1 in CRC tumor tissues correlates with the extent of primary tumor, lymph node metastasis, and distant metastasis(39,40). Furthermore, high expression of RON or PD-L1 in the tumor microenvironment was associated with poor survival in CRC patients(22,(39)(40)(41)(42).…”

supporting

confidence: 75%

The pathological significance of abnormal RON and PD-L1 expression in colorectal cancer

Liu¹,

Han²,

Shi³

et al. 2020

Preprint

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“…The consequence of these abnormalities is the activation of various intracellular signaling pathways that facilitate CRC cell growth, invasion, and chemoresistance (3). Overexpression of RON in CRC also has prognostic value in predicting patient survival and clinical outcomes (11). Thus, aberrant RON expression is a pathogenic feature in CRC cells, which contributes to tumorigenic phenotype and malignant progression (3)(4)(5)(11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

Efficacy of Anti-RON Antibody Zt/g4–Drug Maytansinoid Conjugation (Anti-RON ADC) as a Novel Therapeutics for Targeted Colorectal Cancer Therapy

Feng

Yao

Wang

et al. 2014

Clinical Cancer Research

137

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Purpose: The receptor tyrosine kinase RON is critical in epithelial tumorigenesis and a drug target for cancer therapy. Here, we report the development and therapeutic efficacy of a novel anti-RON antibody Zt/g4-maytansinoid (DM1) conjugates for targeted colorectal cancer (CRC) therapy.Experimental Design: Zt/g4 (IgG1a/k) was conjugated to DM1 via thioether linkage to form Zt/g4-DM1 with a drug-antibody ratio of 4:1. CRC cell lines expressing different levels of RON were tested in vitro to determine Zt/g4-DM1-induced RON endocytosis, cell-cycle arrest, and cytotoxicity. Efficacy of Zt/g4-DM1 in vivo was evaluated in mouse xenograft CRC tumor model.Results: Zt/g4-DM1 rapidly induced RON endocytosis, arrested cell cycle at G 2 -M phase, reduced cell viability, and caused massive cell death within 72 hours. In mouse xenograft CRC models, Zt/g4-DM1 at a single dose of 20 mg/kg body weight effectively delayed CRC cell-mediated tumor growth up to 20 days. In a multiple dose-ranging study with a five injection regimen, Zt/g4-DM1 inhibited more than 90% tumor growth at doses of 7, 10, and 15 mg/kg body weight. The minimal dose achieving 50% of tumor inhibition was approximately 5.0 mg/kg. The prepared Zt/g4-DM1 is stable at 37 C for up to 30 days. At 60 mg/kg, Zt/g4-DM1 had a moderate toxicity in vivo with an average of 12% reduction in mouse body weight. Conclusion: Zt/g4-DM1 is highly effective in targeted inhibition of CRC cell-derived tumor growth in mouse xenograft models. This work provides the basis for development of humanized Zt/g4-DM1 for RON-targeted CRC therapy in the future. Clin Cancer Res; 20(23); 6045-58. Ó2014 AACR.

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“…The expression of RON is highly altered in many primary cancer samples including colon, breast and bladder cancer, and has prognostic value in predicting patient survival and clinical outcome (9–11). Aberrant RON activation, featured by overexpression of RON protein (12–14), isoform generation (15–17), and persistent activation of downstream signaling pathways (18), has been found in various types of cancers.…”

Section: Introductionmentioning

confidence: 99%

“…Aberrant RON activation, featured by overexpression of RON protein (12–14), isoform generation (15–17), and persistent activation of downstream signaling pathways (18), has been found in various types of cancers. Those aberrations contribute to tumorigenic phenotype, malignant progression and chemoresistance (9,11,19). Due to the importance of RON in cancer pathogenesis, targeting RON signal pathway has therapeutic potential.…”

Section: Introductionmentioning

confidence: 99%

Monoclonal antibody Zt/g4 targeting RON receptor tyrosine kinase enhances chemosensitivity of bladder cancer cells to Epirubicin by promoting G1/S arrest and apoptosis

Chen

et al. 2017

Oncology Reports

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Epirubicin (EPI) is one of the most used intravesical chemotherapy agents after transurethral resection to non-muscle invasive bladder tumors (NMIBC) to prevent cancer recurrence and progression. However, even after resection of bladder tumors and intravesical chemotherapy, half of them will recur and progress. RON is a membrane tyrosine kinase receptor usually overexpressed in bladder cancer cells and associated with poor pathological features. This study aims to investigate the effects of anti-RON monoclonal antibody Zt/g4 on the chemosensitivity of bladder cells to EPI. After Zt/g4 treatment, cell cytotoxicity was significantly increased and cell invasion was markedly suppressed in EPI-treated bladder cancer cells. Further investigation indicated that combing Zt/g4 with EPI promoted cell G1/S-phase arrest and apoptosis, which are the potential mechanisms that RON signaling inhibition enhances chemosensitivity of EPI. Thus, combing antibody-based RON targeted therapy enhances the therapeutic effects of intravesical chemotherapy, which provides new strategy for further improvement of NMIBC patient outcomes.

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Expression of RON in colorectal cancer and its relationships with tumor cell behavior and prognosis

Abstract: These results suggest that RON overexpression may help in predicting poor clinical outcomes in colorectal cancer.

Cited by 12 publications

References 40 publications

The pathological significance of abnormal RON and PD-L1 expression in colorectal cancer

The pathological significance of abnormal RON and PD-L1 expression in colorectal cancer

Efficacy of Anti-RON Antibody Zt/g4–Drug Maytansinoid Conjugation (Anti-RON ADC) as a Novel Therapeutics for Targeted Colorectal Cancer Therapy

Monoclonal antibody Zt/g4 targeting RON receptor tyrosine kinase enhances chemosensitivity of bladder cancer cells to Epirubicin by promoting G1/S arrest and apoptosis

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