In situ validation of an intestinal stem cell signature in colorectal cancer

Ziskin, Jennifer; Dunlap, Debra; Yaylaoglu, Murat; Fodor, Imola K; Forrest, William F.; Patel, Rajesh; Ge, Nianfeng; Hutchins, Gordon; Pine, James; Quirke, Philip; Koeppen, Hartmut; Jubb, Adrian M.

doi:10.1136/gutjnl-2011-301195

Cited by 94 publications

(99 citation statements)

References 32 publications

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“…While tissue microarray analysis of 143 colon cancers revealed a LGR5 positivity rate of 40% (57 of 143), a LGR5 positivity rate of 84% (16 of 19) was observed when using whole tissue sections. This is in line with previously published data showing a LGR5 positivity rate of 74% (42 of 57) colorectal adenocarcinomas using mRNA in situ hybridization (20).…”

supporting

confidence: 82%

Targeting colorectal cancer (stem-like) cells using LGR5 directed antibody drug conjugates

Hirsch

Ried

2016

Ann. Transl. Med.

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supporting

confidence: 82%

Targeting colorectal cancer (stem-like) cells using LGR5 directed antibody drug conjugates

Hirsch

Ried

2016

Ann. Transl. Med.

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“…On the other hand, there are controversial reports regarding the intestinal stem cell marker LGR5. Ziskin and colleagues reported that LGR5 did not have prognostic significance in CRC patients (44). On the other hand, Saigusa and colleagues reported that LGR5 expression and CD44 expression in cancer stroma may be coordinately associated with tumor relapse in locally advanced rectal cancer after preoperative chemoradiotherapy and that they are related to poorer overall survival (45).…”

Section: Discussionmentioning

confidence: 99%

Olfactory Receptor Family 7 Subfamily C Member 1 Is a Novel Marker of Colon Cancer–Initiating Cells and Is a Potent Target of Immunotherapy

Morita

Hirohashi

Torigoe

et al. 2016

Clinical Cancer Research

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Purpose: Cancer-initiating cells (CICs) are thought to be essential for tumor maintenance, recurrence, and distant metastasis, and they are therefore reasonable targets for cancer therapy. Cancer immunotherapy is a novel approach to target cancer. In this study, we aimed to establish novel CIC-targeting immunotherapy.Experimental Design: Colorectal cancer (CRC) CICs were isolated as side population (SP) cells. The gene expression profile of CRC CICs was analyzed by cDNA microarray and RT-PCR. Protein expression of olfactory receptor family 7 subfamily C member 1 (OR7C1) were analyzed by Western blot and immunohistochemical staining. The functions of OR7C1 were analyzed by gene overexpression and gene knockdown using siRNAs. OR7C1-positive cells were isolated by a flow cytometer and analyzed. CTLs specific for OR7C1 peptide were generated, and the antitumor effect was addressed by mice adoptive transfer model.Results: OR7C1 has essential roles in the maintenance of colon CICs, and the OR7C1-positive population showed higher tumorigenicity than that of the OR7C1-negative population, indicating that OR7C1 is a novel functional marker for colon CIC. Immunohistochemical staining revealed that OR7C1 high expression was correlated with poorer prognosis in CRC patients. OR7C1-derived antigenic peptide-specific CTLs showed specific cytotoxicity for CICs, and an OR7C1-specific CTL clone showed a greater antitumor effect than did a CTL clone targeting all cancer cells in a CTL adoptive transfer mouse model.Conclusions: OR7C1 is a novel marker for colon CICs and can be a target of potent CIC-targeting immunotherapy. Clin Cancer Res; 22(13); 3298-309. Ó2016 AACR.

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“…Although LGR5 expression in colon cancers is usually believed to be associated with poor survival, some studies have reported conflicting results regarding the prognostic influence of LGR5. Ziskin et al [14] and Takahashi et al [37] have shown no link between LGR5 expression and overall survival of colon cancer patients. These two studies examined LGR5 mRNA by RNA ISH or real time-PCR, whereas all the other studies reporting worse correlation of LGR5 with survival were based on the detection of LGR5 protein by immunohistochemistry.…”

Section: Snu484mentioning

confidence: 98%

“…Subsequent studies investigated the clinical and functional implications of LGR5 in a variety of human malignant tumors-for example, colorectal cancers [14][15][16], GCs [17,18], and hepatocellular carcinomas [19]. Even in lung adenocarcinomas [20] and gliomas [21], LGR5 expression and its clinicopathological significance were examined although LGR5-expressing stem cells normally do not exist in the lung and brain.…”

Section: Introductionmentioning

confidence: 99%

Prognostic significance of leucine-rich-repeat-containing G-protein-coupled receptor 5, an intestinal stem cell marker, in gastric carcinomas

2015

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Background Cells expressing LGR5, an intestinal stem cell marker, have been suggested as cancer stem cells in human colon cancers. Previously, we discovered that LGR5-expressing cells exist in the gastric antrum and remarkably increase in number in intestinal metaplasia. In addition, most gastric adenomas contain abundant LGR5-expressing cells coexpressing intestinal stem cell signatures. However, LGR5 expression in gastric cancers (GCs) and its prognostic significance remain unknown. Methods We examined the LGR5 expression in GC tissues by real time-PCR and RNA in situ hybridization, and analyzed its clinicopathological relevance and prognostic value. The effects of LGR5 on cancer cell proliferation and migration were assessed with an in vitro transfection technique. Results LGR5 expression was significantly lower in GCs than in matched nontumorous gastric mucosa. RNA in situ hybridization on tissue microarrays showed that 7 % of GCs were positive for LGR5. LGR5 positivity was associated with old age, well to moderate differentiation, and nuclear b-catenin positivity. Although LGR5 did not show any prognostic significance for all GC cases, it was associated with poor survival in GCs with nuclear b-catenin expression. LGR5 expression was induced by transfection in GC cell lines with abnormal Wnt activation, which, however, showed no influence on the growth and migration of GC cells. Conclusion A small portion of GCs expressed LGR5. Although LGR5 was associated with poor survival in GCs with nuclear b-catenin, LGR5 expression in GC cells had no effects on the growth and migration, requiring a further study exploring a biological role of LGR5 in GCs.

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In situ validation of an intestinal stem cell signature in colorectal cancer

Cited by 94 publications

References 32 publications

Targeting colorectal cancer (stem-like) cells using LGR5 directed antibody drug conjugates

Targeting colorectal cancer (stem-like) cells using LGR5 directed antibody drug conjugates

Olfactory Receptor Family 7 Subfamily C Member 1 Is a Novel Marker of Colon Cancer–Initiating Cells and Is a Potent Target of Immunotherapy

Prognostic significance of leucine-rich-repeat-containing G-protein-coupled receptor 5, an intestinal stem cell marker, in gastric carcinomas

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