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Journal of Cancer Research and Clinical Oncology

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Open Access 01-10-2020 | Metastasis | Original Article – Cancer Research

The prognostic value of leucine-rich repeat-containing G-protein (Lgr5) and its impact on clinicopathological features of colorectal cancer

Authors: Arkadiusz Gzil, Izabela Zarębska, Damian Jaworski, Paulina Antosik, Justyna Durślewicz, Joanna Maciejewska, Ewa Domanowska, Natalia Skoczylas-Makowska, Navid Ahmadi, Dariusz Grzanka, Łukasz Szylberg

Published in: Journal of Cancer Research and Clinical Oncology | Issue 10/2020

Abstract

Introduction

Colorectal cancer (CRC) constitutes one of the most prevalent malignancies in the world. Recent research suggests that cancer stem cells (CSCs) are responsible for tumor cell’s malignant behavior in CRC. This study has been designed to determinate clinical implications of CSC markers: CD44, DCLK1, Lgr5, and ANXA2 in CRC.

Materials and methods

The study was performed on tissue samples which were collected from 89 patients undergoing colectomy. Formalin-fixed paraffin-embedded tissue blocks with representative tumor areas were identified and corded. Immunohistochemical staining was performed using anti-CD44, anti-LGR5, anti-ANXA2, and anti-DCLK1 antibodies. The H-score system was utilized to determine the immunointensity of CRC cells.

Results

The lower expression of Lgr5 was significantly correlated with the presence of lymph-node metastases (p = 0.011), while high expression of Lgr5 was statistically significant in vascular invasion in examined cancer tissue samples (p = 0.027). Moreover, a high H-score value of Lgr5 expression was significantly related to a reduced overall survival rate (p = 0.043).

Conclusion

Our results suggest a strong relationship between CSC marker Lgr5 and vascular invasion, presence of lymph-node metastasis, and overall poor survival. The presence of Lgr5 might be an unfavorable prognostic factor, and its high level in cancer tissue is related to an aggressive course. This marker could also be used to access the effectiveness of the treatment.

Amin MB, Greene FL, Edge SB et al (2017) The Eighth Edition AJCC Cancer Staging Manual: continuing to build a bridge from a population-based to a more “personalized” approach to cancer staging. CA Cancer J Clin. https://doi.org/10.3322/caac.21388CrossRefPubMedPubMedCentral

Boddupally K, Wang G, Chen Y, Kobielak A (2016) Lgr5 marks neural crest derived multipotent oral stromal stem cells. Stem Cells 34:720–731. https://doi.org/10.1002/stem.2314CrossRefPubMed

Cairns AP, Crockard AD, McConnell JR et al (2001) Reduced expression of CD44 on monocytes and neutrophils in systemic lupus erythematosus: relations with apoptotic neutrophils and disease activity. Ann Rheum Dis 60:950–955. https://doi.org/10.1136/ard.60.10.950CrossRefPubMedPubMedCentral

Carmon KS, Gong X, Yi J et al (2017) LGR5 receptor promotes cell-cell adhesion in stem cells and colon cancer cells via the IQGAP1-Rac1 pathway. J Biol Chem 292:14989–15001. https://doi.org/10.1074/jbc.M117.786798CrossRefPubMedPubMedCentral

Cheng CC, Chang J, Huang SCC et al (2017) YM155 as an inhibitor of cancer stemness simultaneously inhibits autophosphorylation of epidermal growth factor receptor and G9a-mediated stemness in lung cancer cells. PLoS ONE. https://doi.org/10.1371/journal.pone.0182149CrossRefPubMedPubMedCentral

Cheng C-C, Liao P-N, Ho A-S et al (2018) STAT3 exacerbates survival of cancer stem-like tumorspheres in EGFR-positive colorectal cancers: RNAseq analysis and therapeutic screening. J Biomed Sci 25:60. https://doi.org/10.1186/s12929-018-0456-yCrossRefPubMedPubMedCentral

Christensen MV, Høgdall C, Jensen SG et al (2019) Annexin A2 and S100A10 as candidate prognostic markers in epithelial ovarian cancer. Anticancer Res 39:2475–2482. https://doi.org/10.21873/anticanres.13367CrossRefPubMed

Dai T, Hu Y, Lv F et al (2018) Analysis of the clinical significance of DCLK1+ colorectal cancer using novel monoclonal antibodies against DCLK1. Onco Targets Ther 11:5047–5057. https://doi.org/10.2147/OTT.S169928CrossRefPubMedPubMedCentral

Dame MK, Attili D, McClintock SD et al (2018) Identification, isolation and characterization of human LGR5-positive colon adenoma cells. Development. https://doi.org/10.1242/dev.153049CrossRefPubMedPubMedCentral

Duncan R, Carpenter B, Main LC et al (2008) Characterisation and protein expression profiling of annexins in colorectal cancer. Br J Cancer 98:426–433. https://doi.org/10.1038/sj.bjc.6604128CrossRefPubMed

Fan X-S, Wu H-Y, Yu H-P et al (2010) Expression of Lgr5 in human colorectal carcinogenesis and its potential correlation with beta-catenin. Int J Colorectal Dis 25:583–590. https://doi.org/10.1007/s00384-010-0903-zCrossRefPubMed

Furuta K, Zahurak M, Yang XL et al (1996) Relationship between CD44 expression and cell proliferation in epithelium and stroma of colorectal neoplasms. Am J Pathol 149(4):1147–1155PubMedPubMedCentral

Furuta K, Zahurak M, Goodman SN et al (1998) CD44 expression in the stromal matrix of colorectal cancer: association with prognosis. Clin Cancer Res 4:21–29PubMed

Genetics M (2005) Lynch syndrome genes. Fam Cancer 63:227–232. https://doi.org/10.1007/s10689-004-7993-0CrossRef

Gzil A, Szylberg Ł, Jaworski D et al (2019a) The essential role of DCLK1 in pathogenesis, diagnostic procedures and prognostic stratification of colorectal cancer. Anticancer Res 39:2689–2697CrossRef

Gzil A, Szylberg Ł, Jaworski D et al (2019b) The essential role of DCLK1 in pathogenesis, diagnostic procedures and prognostic stratification of colorectal cancer. Anticancer Res 39:2689–2697. https://doi.org/10.21873/anticanres.13394CrossRefPubMed

He S, Zhou H, Zhu X et al (2014) Expression of Lgr5, a marker of intestinal stem cells, in colorectal cancer and its clinicopathological significance. Biomed Pharmacother 68:507–513. https://doi.org/10.1016/j.biopha.2014.03.016CrossRefPubMed

Hou MF, Chen PM, Chu PY (2018) LGR5 overexpression confers poor relapse-free survival in breast cancer patients. BMC Cancer. https://doi.org/10.1186/s12885-018-4018-1CrossRefPubMedPubMedCentral

Hsu H-C, Liu Y-S, Tseng K-C et al (2013) Overexpression of Lgr5 correlates with resistance to 5-FU-based chemotherapy in colorectal cancer. Int J Colorectal Dis 28:1535–1546. https://doi.org/10.1007/s00384-013-1721-xCrossRefPubMed

Jang BG, Kim HS, Chang WY et al (2018) Expression profile of LGR5 and its prognostic significance in colorectal cancer progression. Am J Pathol 188:2236–2250. https://doi.org/10.1016/j.ajpath.2018.06.012CrossRefPubMed

Jia H, Xiang L, Wang Z, Zhou Q (2015) A study on the mechanism of low-expressed cancer stem cell marker Lgr5 in inhibition of the proliferation and invasion of colorectal carcinoma. Cell Biochem Biophys 73:393–397. https://doi.org/10.1007/s12013-015-0640-6CrossRefPubMed

Jiang Y, Li W, He X et al (2015) Lgr5 expression is a valuable prognostic factor for colorectal cancer: evidence from a meta-analysis. BMC Cancer. https://doi.org/10.1186/s12885-015-1985-3CrossRefPubMedPubMedCentral

Kobayashi S, Yamada-Okabe H, Suzuki M et al (2012) LGR5-positive colon cancer stem cells interconvert with drug-resistant LGR5-negative cells and are capable of tumor reconstitution. Stem Cells 30:2631–2644. https://doi.org/10.1002/stem.1257CrossRefPubMed

Lee JH, Tammela T, Hofree M et al (2017) Anatomically and functionally distinct lung mesenchymal populations marked by Lgr5 and Lgr6. Cell 170:1149–1163.e12. https://doi.org/10.1016/j.cell.2017.07.028CrossRefPubMedPubMedCentral

Leng Z, Xia Q, Chen J et al (2018) Lgr5+CD44+EpCAM+ strictly defines cancer stem cells in human colorectal cancer. Cell Physiol Biochem 46:860–872. https://doi.org/10.1159/000488743CrossRefPubMed

Marley AR, Nan H (2016) Epidemiology of colorectal cancer. Int J Mol Epidemiol Genet

Mukohyama J, Shimono Y, Minami H et al (2017) Roles of microRNAs and RNA-binding proteins in the regulation of colorectal cancer stem cells. Cancers (Basel). https://doi.org/10.3390/cancers9100143CrossRef

Nishioka M, Suehiro Y, Sakai K et al (2018) TROY is a promising prognostic biomarker in patients with colorectal cancer. Oncol Lett 15:5989–5994. https://doi.org/10.3892/ol.2018.8079CrossRefPubMedPubMedCentral

Paliwal VK, Rahi SK, Singh P, Gupta RK (2012) “Wine-glass appearance” of pyramidal tracts in a patient with primary lateral sclerosis. Neurol India 60:110–111. https://doi.org/10.4103/0028-3886.93606CrossRefPubMed

Pang R, Law WL, Chu ACY et al (2010) A subpopulation of CD26+cancer stem cells with metastatic capacity in human colorectal cancer. Cell Stem Cell. https://doi.org/10.1016/j.stem.2010.04.001CrossRefPubMedPubMedCentral

Ricci-Vitiani L, Fabrizi E, Palio E, De Maria R (2009) Colon cancer stem cells. J Mol Med 87:1097–1104. https://doi.org/10.1007/s00109-009-0518-4CrossRefPubMed

Rohani P, Noroozinia F, Modarresi P, Abbasi A (2017) CD44 standard isoform; not a good marker for colon cancer. Int J Cancer Manag. https://doi.org/10.5812/ijcm.9166CrossRef

Salehizadeh S, Hasanzad M, Kadijani AA, Akbari A (2019) The expression analysis of intestinal cancer stem cell marker Lgr5 in colorectal cancer patients and the correlation with histopathological markers. J Gastrointest Cancer. https://doi.org/10.1007/s12029-019-00295-wCrossRef

Sato K, Uehara T, Iwaya M et al (2019) Correlation of clinicopathological features and LGR5 expression in colon adenocarcinoma. Ann Diagn Pathol 40:161–165. https://doi.org/10.1016/j.anndiagpath.2019.05.002CrossRefPubMed

Shimokawa M, Ohta Y, Nishikori S et al (2017) Visualization and targeting of LGR5+ human colon cancer stem cells. Nature 545:187–192. https://doi.org/10.1038/nature22081CrossRefPubMed

Siegel RL, Miller KD, Jemal A (2019) Cancer statistics, 2019. CA Cancer J Clin 69:7–34. https://doi.org/10.3322/caac.21551CrossRef

Simon K (2016) Colorectal cancer development and advances in screening. Clin Interv Aging 11:967–976. https://doi.org/10.2147/CIA.S109285CrossRefPubMedPubMedCentral

Solomon H, Dinowitz N, Pateras IS et al (2018) Mutant p53 gain of function underlies high expression levels of colorectal cancer stem cells markers. Oncogene 37:1669–1684. https://doi.org/10.1038/s41388-017-0060-8CrossRefPubMedPubMedCentral

Sureban SM, May R, Mondalek FG et al (2011) Nanoparticle-based delivery of siDCAMKL-1 increases microRNA-144 and inhibits colorectal cancer tumor growth via a Notch-1 dependent mechanism. J Nanobiotechnol 9:40. https://doi.org/10.1186/1477-3155-9-40CrossRef

Takahashi H, Ishii H, Nishida N et al (2011) Significance of Lgr5(+ve) cancer stem cells in the colon and rectum. Ann Surg Oncol 18:1166–1174. https://doi.org/10.1245/s10434-010-1373-9CrossRefPubMed

Tao H, Tanaka T, Okabe K (2017) Doublecortin and CaM kinase-like-1 expression in pathological stage I non-small cell lung cancer. J Cancer Res Clin Oncol 143:1449–1459. https://doi.org/10.1007/s00432-017-2405-7CrossRefPubMed

Uhlen M, Oksvold P, Fagerberg L et al (2010) Towards a knowledge-based Human Protein Atlas. Nat Biotechnol 28(12):1248–1250. https://doi.org/10.1038/nbt1210-1248CrossRefPubMed

Walker F, Zhang H-H, Odorizzi A, Burgess AW (2011) LGR5 is a negative regulator of tumourigenicity, antagonizes Wnt signalling and regulates cell adhesion in colorectal cancer cell lines. PLoS ONE 6:e22733. https://doi.org/10.1371/journal.pone.0022733CrossRefPubMedPubMedCentral

Wang JL, Su WY, Lin YW et al (2017) CD44v6 overexpression related to metastasis and poor prognosis of colorectal cancer: a meta-analysis. Oncotarget. https://doi.org/10.18632/oncotarget.14163CrossRefPubMedPubMedCentral

Wang Q, Shi Y-L, Zhou K et al (2018a) PIK3CA mutations confer resistance to first-line chemotherapy in colorectal cancer. Cell Death Dis 9:739. https://doi.org/10.1038/s41419-018-0776-6CrossRefPubMedPubMedCentral

Wang X, Zhang X, Xu L et al (2018b) Expression of stem cell markers CD44 and Lgr5 in colorectal cancer and its relationship with lymph node and liver metastasis. Natl Med J China 98:2899–2904. https://doi.org/10.3760/cma.j.issn.0376-2491.2018.36.005CrossRef

Wang Z, Tang Y, Xie L, et al (2019) The prognostic and clinical value of CD44 in colorectal cancer: a meta-analysis. Front Oncol

Whorton J, Sureban SM, May R et al (2015) DCLK1 is detectable in plasma of patients with Barrett’s esophagus and esophageal adenocarcinoma. Dig Dis Sci 60:509–513. https://doi.org/10.1007/s10620-014-3347-4CrossRefPubMed

Wu W, Cao J, Ji Z et al (2016) Co-expression of Lgr5 and CXCR4 characterizes cancer stem-like cells of colorectal cancer. Oncotarget 7:81144–81155. https://doi.org/10.18632/oncotarget.13214CrossRefPubMedPubMedCentral

Wu X-S, Xi H-Q, Chen L (2012) Lgr5 is a potential marker of colorectal carcinoma stem cells that correlates with patient survival. World J Surg Oncol 10:244. https://doi.org/10.1186/1477-7819-10-244CrossRefPubMedPubMedCentral

Yang T, Peng H, Wang J et al (2013) Prognostic and diagnostic significance of annexin A2 in colorectal cancer. Colorectal Dis 15:e373–e381. https://doi.org/10.1111/codi.12207CrossRefPubMed

Yeo W, Chan SL, Mo FKF et al (2015) Phase I/II study of temsirolimus for patients with unresectable Hepatocellular Carcinoma (HCC)—a correlative study to explore potential biomarkers for response. BMC Cancer 15:395. https://doi.org/10.1186/s12885-015-1334-6CrossRefPubMedPubMedCentral

Zarour LR, Anand S, Billingsley KG et al (2017) Colorectal cancer liver metastasis: evolving paradigms and future directions. Cmgh 3:163–173. https://doi.org/10.1016/j.jcmgh.2017.01.006CrossRefPubMed

Zhang J, Cai H, Sun L et al (2018) LGR5, a novel functional glioma stem cell marker, promotes EMT by activating the Wnt/β-catenin pathway and predicts poor survival of glioma patients. J Exp Clin Cancer Res 37:225. https://doi.org/10.1186/s13046-018-0864-6CrossRefPubMedPubMedCentral

Zhang S, Chatterjee T, Godoy C et al (2019) GPR56 drives colorectal tumor growth and promotes drug resistance through upregulation of MDR1 expression via a RhoA-mediated mechanism. Mol Cancer Res. https://doi.org/10.1158/1541-7786.MCR-19-0436CrossRefPubMedPubMedCentral

Zheng Z, Yu H, Huang Q et al (2018) Heterogeneous expression of Lgr5 as a risk factor for focal invasion and distant metastasis of colorectal carcinoma. Oncotarget 9:30025–30033. https://doi.org/10.18632/oncotarget.23144CrossRefPubMedPubMedCentral

Zhou X, Geng L, Wang D et al (2017) R-Spondin1/LGR5 activates TGFβ signaling and suppresses colon cancer metastasis. Cancer Res 77:6589–6602. https://doi.org/10.1158/0008-5472.CAN-17-0219CrossRefPubMedPubMedCentral

Ziskin JL, Dunlap D, Yaylaoglu M et al (2013) In situ validation of an intestinal stem cell signature in colorectal cancer. Gut 62:1012–1023. https://doi.org/10.1136/gutjnl-2011-301195CrossRefPubMed

Title: The prognostic value of leucine-rich repeat-containing G-protein (Lgr5) and its impact on clinicopathological features of colorectal cancer
Authors: Arkadiusz Gzil
Izabela Zarębska
Damian Jaworski
Paulina Antosik
Justyna Durślewicz
Joanna Maciejewska
Ewa Domanowska
Natalia Skoczylas-Makowska
Navid Ahmadi
Dariusz Grzanka
Łukasz Szylberg
Publication date: 01-10-2020
Publisher: Springer Berlin Heidelberg
Keywords: Metastasis
Colorectal Cancer
Colorectal Cancer
Published in: Journal of Cancer Research and Clinical Oncology / Issue 10/2020
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-020-03314-7

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The prognostic value of leucine-rich repeat-containing G-protein (Lgr5) and its impact on clinicopathological features of colorectal cancer

Abstract

Introduction

Materials and methods

Results

Conclusion

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Abstract

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Conclusion

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