title: Remnant living cells that escape cell loss in late-stage tumors exhibit cancer stem cell-like characteristics.
abstract: A balance between cell proliferation and cell loss is essential for tumor progression. Although up to 90% of cells are lost in late-stage carcinomas, the progression and characteristics of remnant living cells in tumor mass are unclear. Here we used molecular imaging to track the progression of living cells in a syngeneic tumor model, and ex vivo investigated the properties of this population at late-stage tumor. The piggyBac transposon system was used to stably introduce the dual reporter genes, including monomeric red fluorescent protein (mRFP) and herpes simplex virus type-1 thymidine kinase (HSV1-tk) genes for fluorescence-based and radionuclide-based imaging of tumor growth in small animals, respectively. Iodine-123-labeled 5-iodo-2'-fluoro-1-beta-D-arabinofuranosyluracil was used as a radiotracer for HSV1-tk gene expression in tumors. The fluorescence- and radionuclide-based imaging using the single-photon emission computed tomography/computed tomography revealed that the number of living cells reached the maximum at 1 week after implantation of 4T1 tumors, and gradually decreased and clustered near the side of the body until 4 weeks accompanied by enlargement of tumor mass. The remnant living cells at late-stage tumor were isolated and investigated ex vivo. The results showed that these living cells could form mammospheres and express cancer stem cell (CSC)-related biomarkers, including octamer-binding transcription factor 4, SRY (sex-determining region Y)-box 2, and CD133 genes compared with those cultured in vitro. Furthermore, this HSV1-tk-expressing CSC-like population was sensitive to ganciclovir applied for the suicide therapy. Taken together, the current data suggested that cells escaping from cell loss in late-stage tumors exhibit CSC-like characteristics, and HSV1-tk may be considered a theranostic agent for targeting this population in vivo.
authors.affiliation: Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan, ROC.
authors.forename: Y L
authors.initials: YL
authors.lastname: Chen
authors.forename: S Y
authors.initials: SY
authors.lastname: Wang
authors.forename: R S
authors.initials: RS
authors.lastname: Liu
authors.forename: H E
authors.initials: HE
authors.lastname: Wang
authors.forename: J C
authors.initials: JC
authors.lastname: Chen
authors.forename: S H
authors.initials: SH
authors.lastname: Chiou
authors.forename: C A
authors.initials: CA
authors.lastname: Chang
authors.forename: L T
authors.initials: LT
authors.lastname: Lin
authors.forename: D T W
authors.initials: DT
authors.lastname: Tan
authors.forename: Y J
authors.initials: YJ
authors.lastname: Lee
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D006023:Glycoproteins / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D064847:Multimodal Imaging; D018365:Neoplasm, Residual; D009369:Neoplasms / Q000000981:diagnostic imaging; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D049268:Positron-Emission Tomography; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D014057:Tomography, X-Ray Computed; D014162:Transfection; D014184:Transplantation, Homologous
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D006023:Glycoproteins; D050814:Octamer Transcription Factor-3; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D055748:SOXB1 Transcription Factors