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Molecular Imaging and Biology
Published in: Molecular Imaging and Biology 4/2020

01-08-2020 | Radioimmunotherapy | Research Article

Radiotheranostic Targeting Cancer Stem Cells in Human Colorectal Cancer Xenografts

Authors: Xianliang She, Saimei Qin, Boping Jing, Xueyan Jin, Xun Sun, Xiaoli Lan, Rui An

Published in: Molecular Imaging and Biology | Issue 4/2020

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Abstract

Purpose

The aim of this study was to perform radiotheranostics with radioiodinated monoclonal antibodies (mAbs) for targeting cancer stem cells (CSCs) in human colorectal cancer xenografts and evaluate the relative advantage of a cocktail containing both [131I]CD133 mAb and [131I]CD44 mAb.

Procedures

Tumor-bearing mice were randomly divided into eight groups: [131I]CD133mAb, [131I]CD44 mAb, [131I]IgG isotype control, radioiodinated mAb cocktail, CD133 mAb, CD44 mAb, unradioiodinated mAb cocktail, and saline groups. In vivo single photon emission computed tomography (SPECT) imaging was used to monitor dynamically changes in the CSC population after treatment. The radioactivity uptake of tumors was quantified ex vivo. The expression of CD133 and CD44 after treatment was also assessed by immunohistochemistry and western blot. Tumor growth curves and survival curves were generated to assess treatment efficacy. Cell apoptosis and proliferation in xenografts 30 days after treatment were measured by TdT-mediated dUTP-biotin nick end labeling (aka, TUNEL) and Ki67 staining. The expression levels of biomarkers in xenografts 30 days after treatment were measured by flow cytometry.

Results

The radioimmunoimaging (RII) with in vivo SPECT showed that the CSC-targeting radioimmunotherapy (RIT) groups ([131I]CD133 mAb, [131I]CD44 mAb, and radioiodinated mAb cocktail groups) had intense accumulations of radiolabeled agents in the tumor areas. The ex vivo biodistribution confirmed these findings. In the CSC-targeting RIT groups, immunohistochemistry and western blot indicated significant reduction of specific target expression in the xenografts. The tumor growth curves and survival curves showed that the CSC-targeting RIT significantly inhibited tumor growth and prolonged mean survival, respectively. Significantly increased apoptosis and decreased proliferation in xenografts further confirmed the therapeutic efficacy of CSC-targeting RIT. Flow cytometry showed that the decreases in CSCs correlated with the presence of the corresponding antibodies.

Conclusions

Our results suggest that the CSC-targeting RIT can effectively reduce CSCs which consequently inhibits tumor development. The radioiodinated mAb cocktail may generate enhanced CSC-targeting specificity.
Appendix
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Literature
1.
Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A (2015) Global cancer statistics, 2012. CA Cancer J Clin 65:87–108PubMed
2.
Siegel RL, Miller KD, Jemal A (2017) Cancer statistics, 2017. CA Cancer J Clin 67:7–30PubMed
3.
Siegel RL, Miller KD, Fedewa SA, Ahnen DJ, Meester RGS, Barzi A, Jemal A (2017) Colorectal cancer statistics, 2017. CA Cancer J Clin 67:177–193PubMed
4.
Ricci-Vitiani L, Lombardi DG, Pilozzi E et al (2007) Identification and expansion of human colon-cancer-initiating cells. Nature 445:111–115PubMed
5.
O'Brien CA, Pollett A, Gallinger S, Dick JE (2007) A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445:106–110PubMed
6.
Al-Hajj M, Becker MW, Wicha M et al (2004) Therapeutic implications of cancer stem cells. Curr Opin Genet Dev 14:43–47PubMed
7.
Kim JJ, Tannock IF (2005) Repopulation of cancer cells during therapy: an important cause of treatment failure. Nat Rev Cancer 5:516–525PubMed
8.
Cojoc M, Mäbert K, Muders MH, Dubrovska A (2015) A role for cancer stem cells in therapy resistance: cellular and molecular mechanisms. Semin Cancer Biol 31:16–27PubMed
9.
Clarke MF, Dick JE, Dirks PB, Eaves CJ, Jamieson CH, Jones DL, Visvader J, Weissman IL, Wahl GM (2006) Cancer stem cells--perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Res 66:9339–9344PubMed
10.
Croker AK, Allan AL (2008) Cancer stem cells: implications for the progression and treatment of metastatic disease. J Cell Mol Med 12:374–390PubMed
11.
Dalerba P, Dylla SJ, Park IK et al (2007) Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci U S A 104:10158–10163PubMedPubMedCentral
12.
Haraguchi N, Ohkuma M, Sakashita H, Matsuzaki S, Tanaka F, Mimori K, Kamohara Y, Inoue H, Mori M (2008) CD133+CD44+ population efficiently enriches colon cancer initiating cells. Ann Surg Oncol 15:2927–2933PubMed
13.
Gerweck LE, Wakimoto H (2016) At the crossroads of cancer stem cells, radiation biology, and radiation oncology. Cancer Res 76:994–998PubMedPubMedCentral
14.
Sahlberg SH, Spiegelberg D, Glimelius B et al (2014) Evaluation of cancer stem cell markers CD133, CD44, CD24: association with AKT isoforms and radiation resistance in colon cancer cells. PLoS One 9:e94621PubMedPubMedCentral
15.
16.
Jadvar H, Chen X, Cai W, Mahmood U (2018) Radiotheranostics in cancer diagnosis and management. Radiology 286:388–400PubMed
17.
Blumenthal RD, Kashi R, Stephens R, Sharkey RM, Goldenberg DM (1991) Improved radioimmunotherapy of colorectal cancer xenografts using antibody mixtures against carcinoembryonic antigen and colon-specific antigen-p. Cancer Immunol Immunother 32:303–310PubMed
18.
Meredith RF, Khazaeli MB, Plott WE et al (1996) Phase II study of dual 131I-labeled monoclonal antibody therapy with interferon in patients with metastatic colorectal cancer. Clin Cancer Res 2:1811–1818PubMed
19.
DeNardo GL, Tobin E, Chan K et al (2005) Direct antilymphoma effects on human lymphoma cells of monotherapy and combination therapy with CD20 and HLA-DR antibodies and 90Y-labeled HLA-DR antibodies. Clin Cancer Res 11:7075s–7079sPubMed
20.
Milenic DE, Brady ED, Garmestani K, Albert PS, Abdulla A, Brechbiel MW (2010) Improved efficacy of alpha-particle-targeted radiation therapy: dual targeting of human epidermal growth factor receptor-2 and tumor-associated glycoprotein 72. Cancer 116:1059–1066PubMed
21.
Sharkey RM, Goldenberg DM (2011) Cancer radioimmunotherapy. Immunotherapy 3:349–370PubMed
22.
Pasternack JB, Domogauer JD, Khullar A et al (2014) The advantage of antibody cocktails for targeted alpha therapy depends on specific activity. J Nucl Med 55:2012–2019PubMed
23.
Pagel JM, Pantelias A, Hedin N, Wilbur S, Saganic L, Lin Y, Axworthy D, Hamlin DK, Wilbur DS, Gopal AK, Press OW (2007) Evaluation of CD20, CD22, and HLA-DR targeting for radioimmunotherapy of B-cell lymphomas. Cancer Res 67:5921–5928PubMed
24.
Lang J, Lan X, Liu Y et al (2015) Targeting cancer stem cells with an 131I-labeled anti-AC133 monoclonal antibody in human colorectal cancer xenografts. Nucl Med Biol 42:505–512PubMed
25.
Weng D, Jin X, Qin S, Lan X, Chen C, Sun X, She X, Dong C, An R (2017) Radioimmunotherapy for CD133(+) colonic cancer stem cells inhibits tumor development in nude mice. Oncotarget 8:44004–44014PubMedPubMedCentral
26.
Workman P, Aboagye EO, Balkwill F, Balmain A, Bruder G, Chaplin DJ, Double JA, Everitt J, Farningham DA, Glennie MJ, Kelland LR, Robinson V, Stratford IJ, Tozer GM, Watson S, Wedge SR, Eccles SA, Committee of the National Cancer Research Institute (2010) Guidelines for the welfare and use of animals in cancer research. Br J Cancer 102:1555–1577PubMedPubMedCentral
27.
Larson SM, Carrasquillo JA, Cheung NK, Press OW (2015) Radioimmunotherapy of human tumours. Nat Rev Cancer 15:347–360PubMedPubMedCentral
28.
Wahl RL, Jacene H, Kasamon Y, Lodge MA (2009) From RECIST to PERCIST: evolving considerations for PET response criteria in solid tumors. J Nucl Med 50(Suppl 1):122S–150SPubMed
29.
Spiegelberg D, Mortensen AC, Selvaraju RK, Eriksson O, Stenerlöw B, Nestor M (2016) Molecular imaging of EGFR and CD44v6 for prediction and response monitoring of HSP90 inhibition in an in vivo squamous cell carcinoma model. Eur J Nucl Med Mol Imaging 43:974–982PubMed
30.
Lin S, Xu Y, Gan Z, Han K, Hu H, Yao Y, Huang M, Min D (2016) Monitoring cancer stem cells: insights into clinical oncology. Onco Targets Ther 9:731–740PubMedPubMedCentral
31.
Dallas NA, Xia L, Fan F, Gray MJ, Gaur P, van Buren G 2nd, Samuel S, Kim MP, Lim SJ, Ellis LM (2009) Chemoresistant colorectal cancer cells, the cancer stem cell phenotype, and increased sensitivity to insulin-like growth factor-I receptor inhibition. Cancer Res 69:1951–1957PubMedPubMedCentral
32.
Wang C, Xie J, Guo J, Manning HC, Gore JC, Guo N (2012) Evaluation of CD44 and CD133 as cancer stem cell markers for colorectal cancer. Oncol Rep 28:1301–1308PubMedPubMedCentral
33.
Wang T, Shigdar S, Gantier MP, Hou Y, Wang L, Li Y, Shamaileh HA, Yin W, Zhou SF, Zhao X, Duan W (2015) Cancer stem cell targeted therapy: progress amid controversies. Oncotarget 6:44191–44206PubMedPubMedCentral
34.
Rahman M, Deleyrolle L, Vedam-Mai V et al (2011) The cancer stem cell hypothesis: failures and pitfalls. Neurosurgery 68:531–545PubMed
35.
Grotenhuis BA, Wijnhoven BP, van Lanschot JJ (2012) Cancer stem cells and their potential implications for the treatment of solid tumors. J Surg Oncol 106:209–215PubMed
36.
Yang T, Rycaj K, Liu ZM, Tang DG (2014) Cancer stem cells: constantly evolving and functionally heterogeneous therapeutic targets. Cancer Res 74:2922–2927PubMedPubMedCentral
37.
Klonisch T, Wiechec E, Hombach-Klonisch S et al (2008) Cancer stem cell markers in common cancers - therapeutic implications. Trends Mol Med 14:450–460PubMed
38.
Sottoriva A, Verhoeff JJ, Borovski T et al (2010) Cancer stem cell tumor model reveals invasive morphology and increased phenotypical heterogeneity. Cancer Res 70:46–56PubMed
39.
Shimokawa M, Ohta Y, Nishikori S et al (2017) Visualization and targeting of LGR5(+) human colon cancer stem cells. Nature 545:187–192PubMed
40.
Herrmann K, Larson SM, Weber WA (2017) Theranostic concepts: more than just a fashion trend-introduction and overview. J Nucl Med 58:1S–2SPubMed
41.
Qin C, Liu H, Chen K et al (2014) Theranostics of malignant melanoma with 64CuCl2. J Nucl Med 55:812–817PubMed
42.
Muller C, Bunka M, Haller S et al (2014) Promising prospects for 44Sc-/47Sc-based theragnostics: application of 47Sc for radionuclide tumor therapy in mice. J Nucl Med 55:1658–1664PubMed
43.
Moek KL, Giesen D, Kok IC, de Groot DJA, Jalving M, Fehrmann RSN, Lub-de Hooge MN, Brouwers AH, de Vries EGE (2017) Theranostics using antibodies and antibody-related therapeutics. J Nucl Med 58:83S–90SPubMed
44.
Gaedicke S, Braun F, Prasad S, Machein M, Firat E, Hettich M, Gudihal R, Zhu X, Klingner K, Schüler J, Herold-Mende CC, Grosu AL, Behe M, Weber W, Mäcke H, Niedermann G (2014) Noninvasive positron emission tomography and fluorescence imaging of CD133+ tumor stem cells. Proc Natl Acad Sci U S A 111:E692–E701PubMedPubMedCentral
45.
Yoshii Y, Furukawa T, Kiyono Y, Watanabe R, Mori T, Yoshii H, Asai T, Okazawa H, Welch MJ, Fujibayashi Y (2011) Internal radiotherapy with copper-64-diacetyl-bis (N4-methylthiosemicarbazone) reduces CD133+ highly tumorigenic cells and metastatic ability of mouse colon carcinoma. Nucl Med Biol 38:151–157PubMed
46.
Aghevlian S, Boyle AJ, Reilly RM (2017) Radioimmunotherapy of cancer with high linear energy transfer (LET) radiation delivered by radionuclides emitting alpha-particles or Auger electrons. Adv Drug Deliv Rev 109:102–118PubMed
Metadata
Title
Radiotheranostic Targeting Cancer Stem Cells in Human Colorectal Cancer Xenografts
Authors
Xianliang She
Saimei Qin
Boping Jing
Xueyan Jin
Xun Sun
Xiaoli Lan
Rui An
Publication date
01-08-2020
Publisher
Springer International Publishing
Published in
Molecular Imaging and Biology / Issue 4/2020
Print ISSN: 1536-1632
Electronic ISSN: 1860-2002
DOI
https://doi.org/10.1007/s11307-019-01467-7

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