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Current Gene Therapy

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ISSN (Print): 1566-5232
ISSN (Online): 1875-5631

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Research Article

AEG-1 as a Novel Therapeutic Target in Colon Cancer: A Study from Silencing AEG-1 in BALB/c Mice to Large Data Analysis

Author(s): Sushmitha Sriramulu, Sarubala Malayaperumal, Antara Banerjee, Muralidharan Anbalagan, Makalakshmi Murali Kumar, Rajesh Kanna Nandagopal Radha, Xingyi Liu, Hong Zhang, Guang Hu, Xiao-Feng Sun* and Surajit Pathak*

Volume 24, Issue 4, 2024

Published on: 06 February, 2024

Page: [307 - 320] Pages: 14

DOI: 10.2174/0115665232273077240104045022

Price: $65

Abstract

Background: Astrocyte elevated gene-1 (AEG-1) is overexpressed in various malignancies. Exostosin-1 (EXT-1), a tumor suppressor, is an intermediate for malignant tumors. Understanding the mechanism behind the interaction between AEG-1 and EXT-1 may provide insights into colon cancer metastasis.

Methods: AOM/DSS was used to induce tumor in BALB/c mice. Using an in vivo-jetPEI transfection reagent, transient transfection of AEG-1 and EXT-1 siRNAs were achieved. Histological scoring, immunohistochemical staining, and gene expression studies were performed from excised tissues. Data from the Cancer Genomic Atlas and GEO databases were obtained to identify the expression status of AEG-1 and itsassociation with the survival.

Results: In BALB/c mice, the AOM+DSS treated mice developed necrotic, inflammatory and dysplastic changes in the colon with definite clinical symptoms such as loss of goblet cells, colon shortening, and collagen deposition. Administration of AEG-1 siRNA resulted in a substantial decrease in the disease activity index. Mice treated with EXT-1 siRNA showed diffusely reduced goblet cells. In vivo investigations revealed that PTCH-1 activity was influenced by upstream gene AEG-1, which in turn may affect EXT-1 activity. Data from The Cancer Genomic Atlas and GEO databases confirmed the upregulation of AEG-1 and downregulation of EXT-1 in cancer patients.

Conclusions: This study revealed that AEG-1 silencing might alter EXT-1 expression indirectly through PTCH-1, influencing cell-ECM interactions, and decreasing dysplastic changes, proliferation and invasion.

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[1]
Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin 2023; 73(1): 17-48.
[http://dx.doi.org/10.3322/caac.21763] [PMID: 36633525]
[2]
Bishehsari F, Mahdavinia M, Vacca M, Malekzadeh R, Mariani-Costantini R. Epidemiological transition of colorectal cancer in developing countries: Environmental factors, molecular pathways, and opportunities for prevention. World J Gastroenterol 2014; 20(20): 6055-72.
[http://dx.doi.org/10.3748/wjg.v20.i20.6055] [PMID: 24876728]
[3]
Malayaperumal S, Sriramulu S, Banerjee A, Makalakshmi MK, Pathak S. Is biotechnological next-generation therapeutics promising enough in clinical development to treat advanced colon cancer? Curr Pharm Biotechnol 2021; 22(10): 1287-301.
[http://dx.doi.org/10.2174/1389201021666201126142716] [PMID: 33243115]
[4]
Hossain MS, Karuniawati H, Jairoun AA, et al. Colorectal cancer: A review of carcinogenesis, global epidemiology, current challenges, risk factors, preventive and treatment strategies. Cancers 2022; 14(7): 1732.
[http://dx.doi.org/10.3390/cancers14071732] [PMID: 35406504]
[5]
Bagaria SP, Heckman MG, Diehl NN, Parker A, Wasif N. Delay to colectomy and survival for patients diagnosed with colon cancer. J Invest Surg 2019; 32(4): 350-7.
[http://dx.doi.org/10.1080/08941939.2017.1421732] [PMID: 29351008]
[6]
Xie YH, Chen YX, Fang JY. Comprehensive review of targeted therapy for colorectal cancer. Signal Transduct Target Ther 2020; 5(1): 22.
[http://dx.doi.org/10.1038/s41392-020-0116-z] [PMID: 32296018]
[7]
Dominguez O, Yilmaz S, Steele SR. Stage IV colorectal cancer management and treatment. J Clin Med 2023; 12(5): 2072.
[http://dx.doi.org/10.3390/jcm12052072] [PMID: 36902858]
[8]
Su Z, Kang D, Chen Y, et al. Identification and cloning of human astrocyte genes displaying elevated expression after infection with HIV-1 or exposure to HIV-1 envelope glycoprotein by rapid subtraction hybridization, RaSH. Oncogene 2002; 21(22): 3592-602.
[http://dx.doi.org/10.1038/sj.onc.1205445] [PMID: 12032861]
[9]
Vartak-Sharma N, Nooka S, Ghorpade A. Astrocyte elevated gene-1 (AEG-1) and the A(E)Ging HIV/AIDS-HAND. Prog Neurobiol 2017; 157: 133-57.
[http://dx.doi.org/10.1016/j.pneurobio.2016.03.006] [PMID: 27090750]
[10]
Vartak-Sharma N, Gelman BB, Joshi C, Borgamann K, Ghorpade A. Astrocyte elevated gene-1 is a novel modulator of HIV-1-associated neuroinflammation via regulation of nuclear factor-κB signaling and excitatory amino acid transporter-2 repression. J Biol Chem 2014; 289(28): 19599-612.
[http://dx.doi.org/10.1074/jbc.M114.567644] [PMID: 24855648]
[11]
Brown DM, Ruoslahti E. Metadherin, a cell surface protein in breast tumors that mediates lung metastasis. Cancer Cell 2004; 5(4): 365-74.
[http://dx.doi.org/10.1016/S1535-6108(04)00079-0] [PMID: 15093543]
[12]
Yoo BK, Emdad L, Lee SG, et al. Astrocyte elevated gene-1 (AEG-1): A multifunctional regulator of normal and abnormal physiology. Pharmacol Ther 2011; 130(1): 1-8.
[http://dx.doi.org/10.1016/j.pharmthera.2011.01.008] [PMID: 21256156]
[13]
Khan M, Sarkar D. The scope of astrocyte elevated gene-1/metadherin (AEG-1/MTDH) in cancer clinicopathology: A review. Genes 2021; 12(2): 308.
[http://dx.doi.org/10.3390/genes12020308] [PMID: 33671513]
[14]
Lee SG, Su ZZ, Emdad L, Sarkar D, Fisher PB. Astrocyte elevated gene-1 (AEG-1) is a target gene of oncogenic Ha-ras requiring phosphatidylinositol 3-kinase and c-Myc. Proc Natl Acad Sci 2006; 103(46): 17390-5.
[http://dx.doi.org/10.1073/pnas.0608386103] [PMID: 17088530]
[15]
Sriramulu S, Sun XF, Malayaperumal S, et al. Emerging role and clinicopathological significance of AEG-1 in different cancer types: A concise review. Cells 2021; 10(6): 1497.
[http://dx.doi.org/10.3390/cells10061497] [PMID: 34203598]
[16]
Yoo BK, Emdad L, Su Z, et al. Astrocyte elevated gene-1 regulates hepatocellular carcinoma development and progression. J Clin Invest 2009; 119(3): 465-77.
[http://dx.doi.org/10.1172/JCI36460] [PMID: 19221438]
[17]
Emdad L, Das SK, Dasgupta S, Hu B, Sarkar D, Fisher PB. AEG-1/MTDH/LYRIC: Signaling pathways, downstream genes, interacting proteins, and regulation of tumor angiogenesis. Adv Cancer Res 2013; 120: 75-111.
[http://dx.doi.org/10.1016/B978-0-12-401676-7.00003-6] [PMID: 23889988]
[18]
Dhiman G, Srivastava N, Goyal M, et al. Metadherin: A therapeutic target in multiple cancers. Front Oncol 2019; 9: 349.
[http://dx.doi.org/10.3389/fonc.2019.00349] [PMID: 31131259]
[19]
Shi X, Wang X. The role of MTDH/AEG-1 in the progression of cancer. Int J Clin Exp Med 2015; 8(4): 4795-807.
[PMID: 26131054]
[20]
Wang N, Du X, Zang L, et al. Prognostic impact of Metadherin–SND1 interaction in colon cancer. Mol Biol Rep 2012; 39(12): 10497-504.
[http://dx.doi.org/10.1007/s11033-012-1933-0] [PMID: 23065261]
[21]
Ghafar MT, Soliman NA. Metadherin (AEG-1/MTDH/LYRIC) expression: Significance in malignancy and crucial role in colorectal cancer. Adv Clin Chem 2022; 106: 235-80.
[http://dx.doi.org/10.1016/bs.acc.2021.09.007] [PMID: 35152973]
[22]
Kumar AR, Devan AR, Nair B, Vinod BS, Nath LR. Harnessing the immune system against cancer: Current immunotherapy approaches and therapeutic targets. Mol Biol Rep 2021; 48(12): 8075-95.
[http://dx.doi.org/10.1007/s11033-021-06752-9] [PMID: 34671902]
[23]
Leisico F, Omeiri J, Le Narvor C, et al. Structure of the human heparan sulfate polymerase complex EXT1-EXT2. Nat Commun 2022; 13(1): 7110.
[http://dx.doi.org/10.1038/s41467-022-34882-6] [PMID: 36402845]
[24]
Annaval T, Wild R, Crétinon Y, Sadir R, Vivès RR, Lortat-Jacob H. Heparan sulfate proteoglycans biosynthesis and post synthesis mechanisms combine few enzymes and few core proteins to generate extensive structural and functional diversity. Molecules 2020; 25(18): 4215.
[http://dx.doi.org/10.3390/molecules25184215] [PMID: 32937952]
[25]
Lind T, Tufaro F, McCormick C, Lindahl U, Lidholt K. The putative tumor suppressors EXT1 and EXT2 are glycosyltransferases required for the biosynthesis of heparan sulfate. J Biol Chem 1998; 273(41): 26265-8.
[http://dx.doi.org/10.1074/jbc.273.41.26265] [PMID: 9756849]
[26]
Hecht JT, Hogue D, Wang Y, et al. Hereditary multiple exostoses (EXT): Mutational studies of familial EXT1 cases and EXT-associated malignancies. Am J Hum Genet 1997; 60(1): 80-6.
[PMID: 8981950]
[27]
Alexandrou A, Salameh N, Papaevripidou I, et al. Hereditary multiple exostoses caused by a chromosomal inversion removing part of EXT1 gene. Mol Cytogenet 2023; 16(1): 8.
[http://dx.doi.org/10.1186/s13039-023-00638-0] [PMID: 37217936]
[28]
Wilson LFL, Dendooven T, Hardwick SW, et al. The structure of EXTL3 helps to explain the different roles of bi-domain exostosins in heparan sulfate synthesis. Nat Commun 2022; 13(1): 3314.
[http://dx.doi.org/10.1038/s41467-022-31048-2] [PMID: 35676258]
[29]
Beltrami G, Ristori G, Scoccianti G, Tamburini A, Capanna R. Hereditary Multiple Exostoses: a review of clinical appearance and metabolic pattern. Clin Cases Miner Bone Metab 2016; 13(2): 110-8.
[http://dx.doi.org/10.11138/ccmbm/2016.13.2.110] [PMID: 27920806]
[30]
Katta K, Imran T, Busse-Wicher M, Grønning M, Czajkowski S, Kusche-Gullberg M. Reduced expression of EXTL2, a member of the exostosin (EXT) family of glycosyltransferases, in human embryonic kidney 293 cells results in longer heparan sulfate chains. J Biol Chem 2015; 290(21): 13168-77.
[http://dx.doi.org/10.1074/jbc.M114.631754] [PMID: 25829497]
[31]
Manna D, Sarkar D. Multifunctional role of astrocyte elevated gene-1 (AEG-1) in cancer: Focus on drug resistance. Cancers (Basel) 2021; 13(8): 1792.
[http://dx.doi.org/10.3390/cancers13081792] [PMID: 33918653]
[32]
Ying Z, Li J, Li M. Astrocyte elevated gene 1: Biological functions and molecular mechanism in cancer and beyond. Cell Biosci 2011; 1(1): 36.
[http://dx.doi.org/10.1186/2045-3701-1-36] [PMID: 22060137]
[33]
Fu L, Niu X, Jin R, et al. Triptonide inhibits metastasis potential of thyroid cancer cells via astrocyte elevated gene-1. Transl Cancer Res 2020; 9(2): 1195-204.
[http://dx.doi.org/10.21037/tcr.2019.12.94] [PMID: 35117464]
[34]
Wu S, Yang L, Wu D, et al. AEG ‐1 induces gastric cancer metastasis by upregulation of eIF 4E expression. J Cell Mol Med 2017; 21(12): 3481-93.
[http://dx.doi.org/10.1111/jcmm.13258] [PMID: 28661037]
[35]
Gnosa S, Capodanno A, Murthy RV, Jensen LD, Sun XF. AEG-1 knockdown in colon cancer cell lines inhibits radiation-enhanced migration and invasion in vitro and in a novel in vivo zebrafish model. Oncotarget 2016; 7(49): 81634-44.
[http://dx.doi.org/10.18632/oncotarget.13155] [PMID: 27835571]
[36]
Sriramulu S, Nandy SK, Ganesan H, Banerjee A, Pathak S. In silico analysis and prediction of transcription factors of the proteins interacting with astrocyte elevated gene-1. Comput Biol Chem 2021; 92: 107478.
[http://dx.doi.org/10.1016/j.compbiolchem.2021.107478] [PMID: 33866140]
[37]
Sriramulu S, Malayaperumal S, Nandy SK, et al. Silencing of astrocyte elevated gene-1 (AEG-1) inhibits the proliferative and invasive potential through interaction with Exostosin-1 (EXT-1) in primary and metastatic colon cancer cells. Biocell 2021; 45(3): 563.
[http://dx.doi.org/10.32604/biocell.2021.014756]
[38]
Cooper HS, Murthy SN, Shah RS, Sedergran DJ. Clinicopathologic study of dextran sulfate sodium experimental murine colitis. Lab Invest 1993; 69(2): 238-49.
[PMID: 8350599]
[39]
Matsuyama T, Ishikawa T, Mogushi K, et al. MUC12 mRNA expression is an independent marker of prognosis in stage II and stage III colorectal cancer. Int J Cancer 2010; 127(10): 2292-9.
[http://dx.doi.org/10.1002/ijc.25256] [PMID: 20162577]
[40]
Tsukamoto S, Ishikawa T, Iida S, et al. Clinical significance of osteoprotegerin expression in human colorectal cancer. Clin Cancer Res 2011; 17(8): 2444-50.
[http://dx.doi.org/10.1158/1078-0432.CCR-10-2884] [PMID: 21270110]
[41]
Solé X, Crous-Bou M, Cordero D, et al. Discovery and validation of new potential biomarkers for early detection of colon cancer. PLoS One 2014; 9(9): e106748.
[http://dx.doi.org/10.1371/journal.pone.0106748] [PMID: 25215506]
[42]
Kwon Y, Park M, Jang M, et al. Prognosis of stage III colorectal carcinomas with FOLFOX adjuvant chemotherapy can be predicted by molecular subtype. Oncotarget 2017; 8(24): 39367-81.
[http://dx.doi.org/10.18632/oncotarget.17023] [PMID: 28455965]
[43]
Hu Y, Gaedcke J, Emons G, et al. Colorectal cancer susceptibility loci as predictive markers of rectal cancer prognosis after surgery. Genes Chromosomes Cancer 2018; 57(3): 140-9.
[http://dx.doi.org/10.1002/gcc.22512] [PMID: 29119627]
[44]
Guo H, Zeng W, Feng L, et al. Integrated transcriptomic analysis of distance-related field cancerization in rectal cancer patients. Oncotarget 2017; 8(37): 61107-17.
[http://dx.doi.org/10.18632/oncotarget.17864] [PMID: 28977850]
[45]
Marisa L, de Reyniès A, Duval A, et al. Gene expression classification of colon cancer into molecular subtypes: characterization, validation, and prognostic value. PLoS Med 2013; 10(5): e1001453.
[http://dx.doi.org/10.1371/journal.pmed.1001453] [PMID: 23700391]
[46]
Loboda A, Nebozhyn MV, Watters JW, et al. EMT is the dominant program in human colon cancer. BMC Med Genomics 2011; 4(1): 9.
[http://dx.doi.org/10.1186/1755-8794-4-9] [PMID: 21251323]
[47]
Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 2014; 15(12): 550.
[http://dx.doi.org/10.1186/s13059-014-0550-8] [PMID: 25516281]
[48]
Zhao M, Kim P, Mitra R, Zhao J, Zhao Z. TSGene 2.0: An updated literature-based knowledgebase for tumor suppressor genes. Nucleic Acids Res 2016; 44(D1): D1023-31.
[http://dx.doi.org/10.1093/nar/gkv1268] [PMID: 26590405]
[49]
Chakravarty D, Gao J, Phillips S, et al. OncoKB: A precision oncology knowledge base. JCO Precis Oncol 2017; 2017(1): 1-16.
[http://dx.doi.org/10.1200/PO.17.00011] [PMID: 28890946]
[50]
Szklarczyk D, Gable AL, Nastou KC, et al. The STRING database in 2021: Customizable protein–protein networks, and functional characterization of user-uploaded gene/measurement sets. Nucleic Acids Res 2021; 49(D1): D605-12.
[http://dx.doi.org/10.1093/nar/gkaa1074] [PMID: 33237311]
[51]
Shannon P, Markiel A, Ozier O, et al. Cytoscape: A software environment for integrated models of biomolecular interaction networks. Genome Res 2003; 13(11): 2498-504.
[http://dx.doi.org/10.1101/gr.1239303] [PMID: 14597658]
[52]
Wu T, Hu E, Xu S, et al. clusterProfiler 4.0: A universal enrichment tool for interpreting omics data. Innovation 2021; 2(3): 100141.
[http://dx.doi.org/10.1016/j.xinn.2021.100141] [PMID: 34557778]
[53]
Xi Y, Xu P. Global colorectal cancer burden in 2020 and projections to 2040. Transl Oncol 2021; 14(10): 101174.
[http://dx.doi.org/10.1016/j.tranon.2021.101174] [PMID: 34243011]
[54]
Rawla P, Sunkara T, Barsouk A. Epidemiology of colorectal cancer: Incidence, mortality, survival, and risk factors. Prz Gastroenterol 2019; 14(2): 89-103.
[http://dx.doi.org/10.5114/pg.2018.81072] [PMID: 31616522]
[55]
Brouwer NPM, Bos ACRK, Lemmens VEPP, et al. An overview of 25 years of incidence, treatment and outcome of colorectal cancer patients. Int J Cancer 2018; 143(11): 2758-66.
[http://dx.doi.org/10.1002/ijc.31785] [PMID: 30095162]
[56]
Venook AP, Weiser MR, Tepper JE. Colorectal cancer: All hands on deck. Am Soc Clin Oncol Educ Book 2014; (34): 83-9.
[http://dx.doi.org/10.14694/EdBook_AM.2014.34.83] [PMID: 24857064]
[57]
Lawler M, Alsina D, Adams RA, et al. Critical research gaps and recommendations to inform research prioritisation for more effective prevention and improved outcomes in colorectal cancer. Gut 2018; 67(1): 179-93.
[http://dx.doi.org/10.1136/gutjnl-2017-315333] [PMID: 29233930]
[58]
Racca L, Rosso G, Carofiglio M, et al. Effective combination of biocompatible zinc oxide nanocrystals and high-energy shock waves for the treatment of colorectal cancer. Cancer Nanotechnol 2023; 14(1): 37.
[http://dx.doi.org/10.1186/s12645-023-00195-6]
[59]
Haddock MG. Intraoperative radiation therapy for colon and rectal cancers: a clinical review. Radiat Oncol 2017; 12(1): 11.
[http://dx.doi.org/10.1186/s13014-016-0752-1] [PMID: 28077144]
[60]
Chen YC, Hsu HS, Chen YW, et al. Oct-4 expression maintained cancer stem-like properties in lung cancer-derived CD133-positive cells. PLoS One 2008; 3(7): e2637.
[http://dx.doi.org/10.1371/journal.pone.0002637] [PMID: 18612434]
[61]
Kalyan A, Kircher S, Shah H, Mulcahy M, Benson A. Updates on immunotherapy for colorectal cancer. J Gastrointest Oncol 2018; 9(1): 160-9.
[http://dx.doi.org/10.21037/jgo.2018.01.17] [PMID: 29564182]
[62]
Menyhart O, Kakisaka T, Pongor LS, Uetake H, Goel A, Győrffy B. Uncovering potential therapeutic targets in colorectal cancer by deciphering mutational status and expression of druggable oncogenes. Cancers 2019; 11(7): 983.
[http://dx.doi.org/10.3390/cancers11070983] [PMID: 31337155]
[63]
Grassilli E, Cerrito MG. Emerging actionable targets to treat therapy-resistant colorectal cancers. Cancer Drug Resist 2022; 5(1): 36-63.
[http://dx.doi.org/10.20517/cdr.2021.96] [PMID: 35582524]
[64]
Crutcher MM, Snook AE, Waldman SA. Overview of predictive and prognostic biomarkers and their importance in developing a clinical pharmacology treatment plan in colorectal cancer patients. Expert Rev Clin Pharmacol 2022; 15(11): 1317-26.
[http://dx.doi.org/10.1080/17512433.2022.2138339] [PMID: 36259230]
[65]
Cerrito MG, Grassilli E. Identifying novel actionable targets in colon cancer. Biomedicines 2021; 9(5): 579.
[http://dx.doi.org/10.3390/biomedicines9050579] [PMID: 34065438]
[66]
Banerjee A, Bizzaro D, Burra P, et al. Umbilical cord mesenchymal stem cells modulate dextran sulfate sodium induced acute colitis in immunodeficient mice. Stem Cell Res Ther 2015; 6(1): 79.
[http://dx.doi.org/10.1186/s13287-015-0073-6] [PMID: 25890182]
[67]
Hua R, Yu J, Yan X, et al. Syndecan-2 in colorectal cancer plays oncogenic role via epithelial-mesenchymal transition and MAPK pathway. Biomed Pharmacother 2020; 121: 109630.
[http://dx.doi.org/10.1016/j.biopha.2019.109630] [PMID: 31707342]
[68]
Wang Q, Zhu G, Lin C, et al. Vimentin affects colorectal cancer proliferation, invasion, and migration via regulated by activator protein 1. J Cell Physiol 2021; 236(11): 7591-604.
[http://dx.doi.org/10.1002/jcp.30402] [PMID: 34041752]
[69]
Al-Maghrabi J. Vimentin immunoexpression is associated with higher tumor grade, metastasis, and shorter survival in colorectal cancer. Int J Clin Exp Pathol 2020; 13(3): 493-500.
[PMID: 32269687]
[70]
Xu H, Lan Q, Huang Y, et al. The mechanisms of colorectal cancer cell mesenchymal-epithelial transition induced by hepatocyte exosome-derived miR-203a-3p. BMC Cancer 2021; 21(1): 718.
[http://dx.doi.org/10.1186/s12885-021-08419-x] [PMID: 34147083]
[71]
Li N, Li C, Zhang X, et al. Diagnostic value of human fecal SDC2 gene in colorectal cancer. Am J Transl Res 2023; 15(4): 2843-9.
[PMID: 37193183]
[72]
Mytilinaiou M, Nikitovic D, Berdiaki A, Kostouras A, Papoutsidakis A, Tsatsakis AM. Emerging roles of syndecan 2 in epithelial and mesenchymal cancer progression. IUBMB Life 2017; 69: 824-33.
[73]
Han YD, Oh TJ, Chung TH, et al. Early detection of colorectal cancer based on presence of methylated syndecan-2 (SDC2) in stool DNA. Clin Epigenetics 2019; 11(1): 51.
[http://dx.doi.org/10.1186/s13148-019-0642-0] [PMID: 30876480]
[74]
Le Du JL, Lei L, He H, Chen E, Dong J, Yang J. High vimentin expression predicts a poor prognosis and progression in colorectal cancer: A study with meta-analysis and tcga database. Biomed Research International 2018; 2018: 6387810.
[75]
Ngan CY, Yamamoto H, Seshimo I, et al. Quantitative evaluation of vimentin expression in tumour stroma of colorectal cancer. Br J Cancer 2007; 96(6): 986-92.
[http://dx.doi.org/10.1038/sj.bjc.6603651] [PMID: 17325702]

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