Expression of ROR1, pAkt, and pCREB in gastric adenocarcinoma

Chang, Hyeyoon; Jung, Woon Yong; Kang, Youngran; Lee, Hyun-Joo; Kim, Aeree; Kim, Baek Hui

doi:10.1016/j.anndiagpath.2015.06.010

Cited by 25 publications

(21 citation statements)

References 23 publications

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“…It has been shown that Ror1 and CXCR6 are expressed highly in gastric cancer tissues, and their higher expression levels seem to be associated with progression of gastric cancer, while STAT3 is expressed ubiquitously . We examined expression patterns of Ror1, STAT3 and CXCR6 in poorly differentiated gastric adenocarcinoma tissues by immunohistochemistry.…”

Section: Resultsmentioning

confidence: 99%

“…Because MSC can be a source of CAF, our co–culture experiments, in which we used media containing 10% FBS, might induce differentiation of the MSC into CAF‐like cells. Unlike Ror2, Ror1 exhibits mainly, if not exclusively, tumor‐promoting functions in a variety of tumors, and increased expression of Ror1 has been shown in a broader range of cancers, including lung, breast, colon, pancreas, renal, ovarian and gastric cancers . Thus, further understanding of how Ror1 expression is regulated in various cancer cells is important for developing effective therapeutic strategies that target Ror1.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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Bone marrow‐derived mesenchymal stem or stromal cells (MSC) have been shown to be recruited to various types of tumor tissues, where they interact with tumor cells to promote their proliferation, survival, invasion and metastasis, depending on the type of the tumor. We have previously shown that Ror2 receptor tyrosine kinase and its ligand, Wnt5a, are expressed in MSC, and Wnt5a‐Ror2 signaling in MSC induces expression of CXCL16, which, in turn, promotes proliferation of co–cultured MKN45 gastric cancer cells via the CXCL16‐CXCR6 axis. However, it remains unclear how CXCL16 regulates proliferation of MKN45 cells. Here, we show that knockdown of CXCL16 in MSC by siRNA suppresses not only proliferation but also migration of co–cultured MKN45 cells. We also show that MSC‐derived CXCL16 or recombinant CXCL16 upregulates expression of Ror1 through activation of STAT3 in MKN45 cells, leading to promotion of proliferation and migration of MKN45 cells in vitro. Furthermore, co–injection of MSC with MKN45 cells in nude mice promoted tumor formation in a manner dependent on expression of Ror1 in MKN45 cells, and anti–CXCL16 neutralizing antibody suppressed tumor formation of MKN45 cells co–injected with MSC. These results suggest that CXCL16 produced through Ror2‐mediated signaling in MSC within the tumor microenvironment acts on MKN45 cells in a paracrine manner to activate the CXCR6‐STAT3 pathway, which, in turn, induces expression of Ror1 in MKN45 cells, thereby promoting tumor progression.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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“…Multiple groups have demonstrated protein and cell-surface expression of ROR1 in B-CLL, mantle cell lymphoma (MCL), and a subset of B-cell ALL using flow cytometry (2, 5, 12, 18). Immunohistochemistry (IHC) of both frozen and formalin fixed paraffin embedded (FFPE) tumor samples using antibodies targeting the N-terminal region of ROR1, detected ROR1 in many solid tumors, however many studies described mainly cytoplasmic staining, not the expected cell-surface expression of Ror1-v1 (3, 4, 6, 7, 10, 11). ROR1 expression has also been characterized in normal human tissues by transcriptomics, immunoblot and IHC.…”

Section: Introductionmentioning

confidence: 99%

Analysis of ROR1 Protein Expression in Human Cancer and Normal Tissues

Balakrishnan

Goodpaster

Randolph‐Habecker

et al. 2017

Clinical Cancer Research

140

136

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Purpose This study examines cell-surface ROR1 expression in human tumors and normal tissues. ROR1 is considered a promising target for cancer therapy due to putative tumor-specific expression and multiple groups are developing antibodies and/or chimeric antigen receptor-modified T cells to target ROR1. On-target, off-tumor toxicity is a challenge for most non-mutated tumor antigens, however prior studies suggest that ROR1 is absent on most normal tissues. Experimental Design Our studies show that published antibodies lack sensitivity to detect endogenous levels of cell-surface ROR1 by immunohistochemistry (IHC) in FFPE tissues. We developed a ROR1-specific monoclonal antibody (mAb) targeting the carboxy-terminus of ROR1, and evaluated its specificity and sensitivity in IHC. Results The 6D4 mAb is a sensitive and specific reagent to detect cell-surface ROR1 by IHC. The data shows that ROR1 is homogenously expressed on a subset of ovarian cancer, triple negative breast cancer and lung adenocarcinomas. Contrary to previous findings, we found ROR1 is expressed on several normal tissues including parathyroid, pancreatic islets and regions of the esophagus, stomach and duodenum. The 6D4 mAb recognizes rhesus ROR1, and ROR1 expression was similar in human and macaque tissues suggesting that the macaque is a suitable model to evaluate safety of ROR1 targeted therapies. Conclusions ROR1 is a promising immunotherapeutic target in many epithelial tumors, however high cell-surface ROR1 expression in multiple normal tissues raises concerns for on-target off-tumor toxicities. Clinical translation of ROR1 targeted therapies warrants careful monitoring of toxicities to normal organs, and may require strategies to ensure patient safety.

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“…Receptor tyrosine kinase like orphan receptor 1 (ROR1) is a Wnt5a surface receptor expressed during embryonic development, but generally absent from adult tissue with the exception of adipocytes, gut, pancreas, and parathyroid glands [ 228 – 230 ]. In the case of cancer, ROR1 has shown high levels in several solid malignancies: pancreatic [ 231 , 232 ], ovarian [ 231 , 233 – 235 ], breast [ 231 , 236 – 238 ], lung [ 231 , 239 , 240 ], gastric cancer [ 241 ], and colorectal cancer [ 242 ]. High levels of ROR1 have shown strong correlation to poor patient outcome and also to developing metastasis [ 235 , 243 ].…”

Section: Current Clinical Targets For Solid Tumorsmentioning

confidence: 99%

The expansion of targetable biomarkers for CAR T cell therapy

Townsend

Shrestha

Robison

et al. 2018

J Exp Clin Cancer Res

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Biomarkers are an integral part of cancer management due to their use in risk assessment, screening, differential diagnosis, prognosis, prediction of response to treatment, and monitoring progress of disease. Recently, with the advent of Chimeric Antigen Receptor (CAR) T cell therapy, a new category of targetable biomarkers has emerged. These biomarkers are associated with the surface of malignant cells and serve as targets for directing cytotoxic T cells. The first biomarker target used for CAR T cell therapy was CD19, a B cell marker expressed highly on malignant B cells. With the success of CD19, the last decade has shown an explosion of new targetable biomarkers on a range of human malignancies. These surface targets have made it possible to provide directed, specific therapy that reduces healthy tissue destruction and preserves the patient’s immune system during treatment. As of May 2018, there are over 100 clinical trials underway that target over 25 different surface biomarkers in almost every human tissue. This expansion has led to not only promising results in terms of patient outcome, but has also led to an exponential growth in the investigation of new biomarkers that could potentially be utilized in CAR T cell therapy for treating patients. In this review, we discuss the biomarkers currently under investigation and point out several promising biomarkers in the preclinical stage of development that may be useful as targets.

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Expression of ROR1, pAkt, and pCREB in gastric adenocarcinoma

Cited by 25 publications

References 23 publications

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

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

Analysis of ROR1 Protein Expression in Human Cancer and Normal Tissues

The expansion of targetable biomarkers for CAR T cell therapy

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