Overexpression of Lgr5 correlates with resistance to 5-FU-based chemotherapy in colorectal cancer

Hsu, Hung‐Chih; Liu, Yi-Shiuan; Tseng, Kai-Chi; Hsu, Cheng–Lung; Li, Ying; Yang, Tsung‐Ming; Chen, Jinn‐Shiun; Tang, Reiping; Chen, Shu‐Jen; Chen, Hua‐Chien

doi:10.1007/s00384-013-1721-x

Cited by 75 publications

(76 citation statements)

References 38 publications

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“…Regarding CRC, many study groups reported that LGR5 is overexpressed in CRC tissues and is associated with unfavorable outcome in CRC patients (24)(25)(26)(27). In the present study, although univariate analysis showed overexpression of LGR5 to be a possible biomarker of unfavorable outcome of CRC, its clinical usefulness in predicting relapse of CRC was not as expected.…”

Section: Discussioncontrasting

confidence: 50%

TROY is a promising prognostic biomarker in patients with colorectal cancer

et al. 2018

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Abstract. Tumor necrosis factor receptor superfamily member 19 (TROY) is involved in the Wnt/β-catenin signaling pathway and interacts with leucine-rich repeat containing G-proteincoupled receptor 5 (LGR5), which is a well-known biomarker of cancer stem cells and a prognostic marker of colorectal cancer (CRC). Because there have been no studies to evaluate the prognostic significance of TROY, we performed the present study to determine whether TROY can be a prognostic biomarker in CRC patients. We evaluated TROY expression levels in 100 CRC tissues by quantitative real-time PCR and investigated the association of TROY expression levels with clinicopathologic features. Cancer stage and TROY expression level were found to be independent prognostic factors of disease-free survival. Moreover, TROY overexpression was the sole independent prognostic factor of disease-free survival in patients with stage II and III CRC. These results suggest that analysis of TROY might help predict clinical outcome in patients with CRC. To support our findings, confirmatory studies using independent data sets are needed.

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Section: Discussioncontrasting

confidence: 50%

TROY is a promising prognostic biomarker in patients with colorectal cancer

et al. 2018

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“…LSD1 inactivation was also found to selectively impair the growth of lung, breast and ovarian carcinoma cells that express Sox2, a pluripotent stem cell marker ). LGR5, a functional stem cell marker of CRC, can regulate the proliferation and colony formation of CRC cells (Kemper et al 2012;Hsu et al 2013). We therefore used CBB1003 as a probe to study the associations between LSD1 and LGR5 in CRC carcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

CBB1003, a lysine-specific demethylase 1 inhibitor, suppresses colorectal cancer cells growth through down-regulation of leucine-rich repeat-containing G-protein-coupled receptor 5 expression

Hsu

Liu

Tseng

et al. 2014

J Cancer Res Clin Oncol

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“…LGR5 was shown to increase drug resistance, and in colon primary tumors, LGR5-high expression correlated with chemoresistance and lower disease-free and overall survival (16,17,20,23,42,43). Thus, an LGR5-targeting ADC may not only effectively treat gastrointestinal tumors, but also function to eliminate CSCs.…”

Section: Discussionmentioning

confidence: 99%

“…A series of studies using mouse models with loss of the tumor suppressor APC (adenomatous polyposis coli) gene have established that LGR5-positive stem cells are the cells-of-origin that drive intestinal and gastric tumor development (6,15). LGR5-high cancer cells have been shown to exhibit the properties of tumor-initiating cells or cancer stem cells (CSC), which retain the capacity for self-renewal (2,(15)(16)(17)(18)(19)(20). CSCs can fuel tumor growth, confer resistance to standard chemotherapy and radiation, and are likely to contribute to recurrent disease (21).…”

Section: Introductionmentioning

confidence: 99%

LGR5-Targeted Antibody–Drug Conjugate Eradicates Gastrointestinal Tumors and Prevents Recurrence

Gong

Azhdarinia

Ghosh

et al. 2016

Molecular Cancer Therapeutics

119

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Gastrointestinal cancer is one of the leading causes of cancerrelated mortality in men and women worldwide. The adult stem cell marker LGR5 (leucine-rich repeat-containing, G proteincoupled receptor 5) is highly expressed in a significant fraction of gastrointestinal tumors of the colon, liver, pancreas, and stomach, relative to normal tissues. LGR5 is located on the cell surface and undergoes rapid, constitutive internalization independent of ligand. Furthermore, LGR5-high cancer cells have been shown to exhibit the properties of tumor-initiating cells or cancer stem cells (CSC). On the basis of these attributes, we generated two LGR5-targeting antibody-drug conjugates (ADC) by tethering the tubulin-inhibiting cytotoxic drug monomethyl auristatin E to a highly specific anti-LGR5 mAb via a protease cleavable or noncleavable chemical linker and compared them in receptor binding, cell internalization, and cytotoxic efficacy in cancer cells. Here, we show that both ADCs bind LGR5 with high specificity and equivalent nanomolar affinity and rapidly internalize to the lysosomes of LGR5-expressing gastrointestinal cancer cells. The anti-LGR5 ADCs effectively induced cytotoxicity in LGR5-high gastrointestinal cancer cells, but not in LGR5-negative or -knockdown cancer cell lines. Overall, we demonstrate that the cleavable ADC exhibited higher potency in vitro and was able to eradicate tumors and prevent recurrence in a xenograft model of colon cancer. These findings provide preclinical evidence for the potential of LGR5-targeting ADCs as effective new therapeutics for the treatment and eradication of gastrointestinal tumors and CSCs with high LGR5 expression. Mol Cancer Ther; 15(7); 1580-90. Ó2016 AACR.

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Overexpression of Lgr5 correlates with resistance to 5-FU-based chemotherapy in colorectal cancer

Abstract: These results suggest that elevated Lgr5 level is associated with CRC progression and treatment response and has the potential to serve as a therapeutic target in CRC patients.

Cited by 75 publications

References 38 publications

TROY is a promising prognostic biomarker in patients with colorectal cancer

TROY is a promising prognostic biomarker in patients with colorectal cancer

CBB1003, a lysine-specific demethylase 1 inhibitor, suppresses colorectal cancer cells growth through down-regulation of leucine-rich repeat-containing G-protein-coupled receptor 5 expression

LGR5-Targeted Antibody–Drug Conjugate Eradicates Gastrointestinal Tumors and Prevents Recurrence

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