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Journal of Hematology & Oncology
Published in: Journal of Hematology & Oncology 1/2019

Open Access 01-12-2019 | NSCLC | Research

High-affinity peptide ligand LXY30 for targeting α3β1 integrin in non-small cell lung cancer

Authors: Wenwu Xiao, Weijie Ma, Sixi Wei, Qianping Li, Ruiwu Liu, Randy P. Carney, Kevin Yang, Joyce Lee, Alan Nyugen, Ken Y. Yoneda, Kit S. Lam, Tianhong Li

Published in: Journal of Hematology & Oncology | Issue 1/2019

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Abstract

Background

α3β1 integrin is a promising cancer biomarker and drug target. We previously identified a 9-amino-acid cyclic peptide LXY30 for detecting α3β1 integrin on the surface of live tumor cells. This study was undertaken to characterize LXY30 in the detection, cellular function, imaging, and targeted delivery of in vitro and in vivo non-small cell lung cancer (NSCLC) models.

Methods

The whole-cell binding assay was performed by incubating NSCLC cells, extracellular vesicles (EVs), and peripheral blood mononuclear cells (PBMCs) with TentaGel resin beads coated with LXY30. In this study, we defined the nanosize EVs as exosomes, which were characterized by flow cytometry, transmission electron microscopy, dynamic light scattering, and Western blots. The function of LXY30 was determined by modulating the epidermal growth factor receptor (EGFR) signaling pathway by growth inhibition and Western blots. For in vivo biodistribution, mice bearing subcutaneous and intracranial NSCLC xenograft tumors were administrated intraveneously with LXY30-biotin/streptavidin-Cy5.5 complex and then analyzed for in vivo and ex vivo optical imaging and histopathology.

Results

We showed that LXY30 specifically and sensitively detected α3β1 integrin-expressing NSCLC cells and tumor-derived exosomes. Tumor DNA isolated from LXY30-enriched plasma exosomes might be used to detect driver oncogenic mutations in patients with metastatic NSCLC. LXY30 only enriches tumor cells but not neutrophils, macrophages, or monocytes in the malignant pleural effusion of NSCLC patients for detecting genomic alterations by next-generation sequencing. LXY30 detected increased α3β1 integrin expression on the EGFR-mutant NSCLC cells with acquired resistance to erlotinib compared to parental erlotinib-sensitive EGFR-mutant NSCLC cells. We further showed that LXY30 modulated the EGFR signaling pathway independently from another peptide ligand LXW64 targeting αvβ3 integrin in erlotinib-resistant, EGFR-mutant H1975 cells. Analysis of The Cancer Genome Atlas (TCGA) revealed high α3 integrin expression was associated with poor prognosis in lung squamous cell carcinoma. LXY30-biotin/streptavidin-Cy5.5 complex had higher uptakes in the subcutaneous and intracranial xenografts of various α3β1 integrin-expressing lung adenocarcinoma and patient-derived lung squamous cell carcinoma xenografts while sparing the surrounding normal tissues.

Conclusion

LXY30 is a promising peptide for the cancer diagnosis and in vivo targeted delivery of imaging agents and cancer drugs in NSCLC, independent of histology and tumor genotype.
Appendix
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Literature
1.
2.
Miller KD, Siegel RL, Lin CC, Mariotto AB, Kramer JL, Rowland JH, Stein KD, Alteri R, Jemal A. Cancer treatment and survivorship statistics, 2016. CA Cancer J Clin. 2016;66(4):271–89.PubMedCrossRef
3.
Li T, Kung HJ, Mack PC, Gandara DR. Genotyping and genomic profiling of non-small-cell lung cancer: implications for current and future therapies. J Clin Oncol. 2013;31(8):1039–49.PubMedPubMedCentralCrossRef
4.
Coate LE, Shepherd FA. Maintenance therapy in advanced non-small cell lung cancer: evolution, tolerability and outcomes. Ther Adv Med Oncol. 2011;3(3):139–57.PubMedPubMedCentralCrossRef
5.
Alghisi GC, Ruegg C. Vascular integrins in tumor angiogenesis: mediators and therapeutic targets. Endothelium. 2006;13(2):113–35.PubMedCrossRef
6.
7.
Seguin L, Desgrosellier JS, Weis SM, Cheresh DA. Integrins and cancer: regulators of cancer stemness, metastasis, and drug resistance. Trends Cell Biol. 2015;25(4):234–40.PubMedPubMedCentralCrossRef
8.
Legate KR, Wickstrom SA, Fassler R. Genetic and cell biological analysis of integrin outside-in signaling. Genes Dev. 2009;23(4):397–418.PubMedCrossRef
9.
Morse EM, Brahme NN, Calderwood DA. Integrin cytoplasmic tail interactions. Biochemistry. 2014;53(5):810–20.PubMedCrossRef
10.
Reticker-Flynn NE, Malta DF, Winslow MM, Lamar JM, Xu MJ, Underhill GH, Hynes RO, Jacks TE, Bhatia SN. A combinatorial extracellular matrix platform identifies cell-extracellular matrix interactions that correlate with metastasis. Nat Commun. 2012;3:1122.PubMedCrossRef
11.
12.
Morini M, Mottolese M, Ferrari N, Ghiorzo F, Buglioni S, Mortarini R, Noonan DM, Natali PG, Albini A. The alpha 3 beta 1 integrin is associated with mammary carcinoma cell metastasis, invasion, and gelatinase B (MMP-9) activity. Int J Cancer. 2000;87(3):336–42.PubMedCrossRef
13.
Varzavand A, Drake JM, Svensson RU, Herndon ME, Zhou B, Henry MD, Stipp CS. Integrin alpha3beta1 regulates tumor cell responses to stromal cells and can function to suppress prostate cancer metastatic colonization. Clin Exp Metastasis. 2013;30(4):541–52.PubMedCrossRef
14.
Zhou B, Gibson-Corley KN, Herndon ME, Sun Y, Gustafson-Wagner E, Teoh-Fitzgerald M, Domann FE, Henry MD, Stipp CS. Integrin alpha3beta1 can function to promote spontaneous metastasis and lung colonization of invasive breast carcinoma. Mol Cancer Res. 2014;12(1):143–54.PubMedCrossRef
15.
Pochec E, Litynska A, Amoresano A, Casbarra A. Glycosylation profile of integrin alpha 3 beta 1 changes with melanoma progression. Biochim Biophys Acta. 2003;1643(1-3):113–23.PubMedCrossRef
16.
Aina OH, Marik J, Liu R, Lau DH, Lam KS. Identification of novel targeting peptides for human ovarian cancer cells using “one-bead one-compound” combinatorial libraries. Mol Cancer Ther. 2005;4(5):806–13.PubMedCrossRef
17.
Xiao W, Yao N, Peng L, Liu R, Lam KS. Near-infrared optical imaging in glioblastoma xenograft with ligand-targeting alpha 3 integrin. Eur J Nucl Med Mol Imaging. 2009;36(1):94–103.PubMedCrossRef
18.
Xiao W, Wang Y, Lau EY, Luo J, Yao N, Shi C, Meza L, Tseng H, Maeda Y, Kumaresan P, et al. The use of one-bead one-compound combinatorial library technology to discover high-affinity alphavbeta3 integrin and cancer targeting arginine-glycine-aspartic acid ligands with a built-in handle. Mol Cancer Ther. 2010;9(10):2714–23.PubMedPubMedCentralCrossRef
19.
Peng L, Liu R, Marik J, Wang X, Takada Y, Lam KS. Combinatorial chemistry identifies high-affinity peptidomimetics against alpha4beta1 integrin for in vivo tumor imaging. Nat Chem Biol. 2006;2(7):381–9.PubMedCrossRef
20.
Xiao W, Li T, Bononi FC, Lac D, Kekessie IA, Liu Y, Sanchez E, Mazloom A, Ma AH, Lin J, et al. Discovery and characterization of a high-affinity and high-specificity peptide ligand LXY30 for in vivo targeting of alpha3 integrin-expressing human tumors. EJNMMI Res. 2016;6(1):18.PubMedPubMedCentralCrossRef
21.
Darlak K, Wiegandt Long D, Czerwinski A, Darlak M, Valenzuela F, Spatola AF, Barany G. Facile preparation of disulfide-bridged peptides using the polymer-supported oxidant CLEAR-OX. J Pept Res. 2004;63(3):303–12.PubMedCrossRef
22.
Li T, Ling Y-H, Huang C-K, Pan Q, Perez-Soler R. Establishment and characterization of an erlotinib-resistant clone derived from the EGFRL858R NSCLC cell line H3255. Proc Am Asso Cancer Res. 2006;47 Abstr# 3768.
23.
Carney RP, Hazari S, Rojalin T, Knudson A, Gao T, Tang Y, Liu R, Viitala T, Yliperttula M, Lam KS. Targeting tumor-associated exosomes with integrin-binding peptides. Adv Biosyst. 2017;1(5).
24.
Lotvall J, Hill AF, Hochberg F, Buzas EI, Di Vizio D, Gardiner C, Gho YS, Kurochkin IV, Mathivanan S, Quesenberry P, et al. Minimal experimental requirements for definition of extracellular vesicles and their functions: a position statement from the International Society for Extracellular Vesicles. J Extracell Vesicles. 2014;3:26913.PubMedCrossRef
25.
Thery C, Witwer KW, Aikawa E, Alcaraz MJ, Anderson JD, Andriantsitohaina R, Antoniou A, Arab T, Archer F, Atkin-Smith GK, et al. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J Extracell Vesicles. 2018;7(1):1535750.PubMedPubMedCentralCrossRef
26.
Chen G, Huang AC, Zhang W, Zhang G, Wu M, Xu W, Yu Z, Yang J, Wang B, Sun H, et al. Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response. Nature. 2018;560(7718):382–6.PubMedPubMedCentralCrossRef
27.
Wang Y, Chen X, Tian B, Liu J, Yang L, Zeng L, Chen T, Hong A, Wang X. Nucleolin-targeted extracellular vesicles as a versatile platform for biologics delivery to breast cancer. Theranostics. 2017;7(5):1360–72.PubMedPubMedCentralCrossRef
28.
Li H, Ma W, Yoneda KY, Moore EH, Zhang Y, Pu LL, Frampton GM, Molmen M, Stephens PJ, Li T. Severe nivolumab-induced pneumonitis preceding durable clinical remission in a patient with refractory, metastatic lung squamous cell cancer: a case report. J Hematol Oncol. 2017;10(1):64.PubMedPubMedCentralCrossRef
29.
Hoshino A, Costa-Silva B, Shen TL, Rodrigues G, Hashimoto A, Tesic Mark M, Molina H, Kohsaka S, Di Giannatale A, Ceder S, et al. Tumour exosome integrins determine organotropic metastasis. Nature. 2015;527(7578):329–35.PubMedPubMedCentralCrossRef
30.
Morello V, Cabodi S, Sigismund S, Camacho-Leal MP, Repetto D, Volante M, Papotti M, Turco E, Defilippi P. β1 integrin controls EGFR signaling and tumorigenic properties of lung cancer cells. Oncogene. 2011;30(39):4087–96.PubMedCrossRef
31.
Bill HM, Knudsen B, Moores SL, Muthuswamy SK, Rao VR, Brugge JS, Miranti CK. Epidermal growth factor receptor-dependent regulation of integrin-mediated signaling and cell cycle entry in epithelial cells. Mol Cell Biol. 2004;24(19):8586–99.PubMedPubMedCentralCrossRef
32.
Schwartz MA, Ginsberg MH. Networks and crosstalk: integrin signalling spreads. Nat Cell Biol. 2002;4(4):E65–8.PubMedCrossRef
33.
Kanda R, Kawahara A, Watari K, Murakami Y, Sonoda K, Maeda M, Fujita H, Kage M, Uramoto H, Costa C, et al. Erlotinib resistance in lung cancer cells mediated by integrin beta1/Src/Akt-driven bypass signaling. Cancer Res. 2013;73(20):6243–53.PubMedCrossRef
34.
Bartolazzi A, Cerboni C, Flamini G, Bigotti A, Lauriola L, Natali PG. Expression of alpha 3 beta 1 integrin receptor and its ligands in human lung tumors. Int J Cancer. 1995;64(4):248–52.PubMedCrossRef
35.
Boelens MC, van den Berg A, Vogelzang I, Wesseling J, Postma DS, Timens W, Groen HJ. Differential expression and distribution of epithelial adhesion molecules in non-small cell lung cancer and normal bronchus. J Clin Pathol. 2007;60(6):608–14.PubMedCrossRef
36.
Guo L, Zhang F, Cai Y, Liu T. Expression profiling of integrins in lung cancer cells. Pathol Res Pract. 2009;205(12):847–53.PubMedCrossRef
37.
Yoshimasu T, Sakurai T, Oura S, Hirai I, Tanino H, Kokawa Y, Naito Y, Okamura Y, Ota I, Tani N, et al. Increased expression of integrin alpha3beta1 in highly brain metastatic subclone of a human non-small cell lung cancer cell line. Cancer Sci. 2004;95(2):142–8.PubMedCrossRef
38.
Liu R, Li X, Xiao W, Lam KS. Tumor-targeting peptides from combinatorial libraries. Adv Drug Deliv Rev. 2016.
39.
40.
Zhou C, Yuan Z, Ma W, Qi L, Mahavongtrakul A, Li Y, Li H, Gong J, Fan RR, Li J, et al. Clinical utility of tumor genomic profiling in patients with high plasma circulating tumor DNA burden or metabolically active tumors. J Hematol Oncol. 2018;11(1):129.PubMedPubMedCentralCrossRef
41.
Frampton GM, Fichtenholtz A, Otto GA, Wang K, Downing SR, He J, Schnall-Levin M, White J, Sanford EM, An P, et al. Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat Biotechnol. 2013;31(11):1023–31.PubMedPubMedCentralCrossRef
42.
43.
Schrock AB, Welsh A, Chung JH, Pavlick D, Bernicker EH, Creelan BC, Forcier B, Ross JS, Stephens PJ, Ali SM, et al. Hybrid capture-based genomic profiling of circulating tumor DNA from patients with advanced non-small cell lung cancer. J Thorac Oncol. 2018.
44.
45.
Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361(10):947–57.PubMedCrossRef
46.
Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, Gemma A, Harada M, Yoshizawa H, Kinoshita I, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010;362(25):2380–8.PubMedCrossRef
47.
Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, Seto T, Satouchi M, Tada H, Hirashima T, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol. 2010;11(2):121–8.PubMedCrossRef
48.
Schwer AL, Gaspar LE. Update in the treatment of brain metastases from lung cancer. Clin Lung Cancer. 2006;8(3):180–6.PubMedCrossRef
49.
Shirakihara T, Kawasaki T, Fukagawa A, Semba K, Sakai R, Miyazono K, Miyazawa K, Saitoh M. Identification of integrin alpha3 as a molecular marker of cells undergoing epithelial-mesenchymal transition and of cancer cells with aggressive phenotypes. Cancer Sci. 2013;104(9):1189–97.PubMedCrossRefPubMedCentral
Metadata
Title
High-affinity peptide ligand LXY30 for targeting α3β1 integrin in non-small cell lung cancer
Authors
Wenwu Xiao
Weijie Ma
Sixi Wei
Qianping Li
Ruiwu Liu
Randy P. Carney
Kevin Yang
Joyce Lee
Alan Nyugen
Ken Y. Yoneda
Kit S. Lam
Tianhong Li
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Journal of Hematology & Oncology / Issue 1/2019
Electronic ISSN: 1756-8722
DOI
https://doi.org/10.1186/s13045-019-0740-7

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