Intracellular Autofluorescence: a Biomarker for Epithelial Cancer Stem Cells

Overview

Journal Nat Methods

Specialties Biomedical Engineering
Pathology

Date 2014 Sep 29

PMID 25262208

Citations 118

Authors

Irene Miranda-Lorenzo

Jorge Dorado

Enza Lonardo

Sonia Alcala

Alicia G Serrano

Jenifer Clausell-Tormos

Michele Cioffi

Diego Megias

Sladjana Zagorac

Anamaria Balic

Manuel Hidalgo

Mert Erkan

Joerg Kleeff

Aldo Scarpa

Bruno Sainz Jr

Christopher Heeschen

Affiliations

Soon will be listed here.

Abstract

Cancer stem cells (CSCs) are thought to drive tumor growth, metastasis and chemoresistance. Although surface markers such as CD133 and CD44 have been successfully used to isolate CSCs, their expression is not exclusively linked to the CSC phenotype and is prone to environmental alteration. We identified cells with an autofluorescent subcellular compartment that exclusively showed CSC features across different human tumor types. Primary tumor-derived autofluorescent cells did not overlap with side-population (SP) cells, were enriched in sphere culture and during chemotherapy, strongly expressed pluripotency-associated genes, were highly metastatic and showed long-term in vivo tumorigenicity, even at the single-cell level. Autofluorescence was due to riboflavin accumulation in membrane-bounded cytoplasmic structures bearing ATP-dependent ABCG2 transporters. In summary, we identified and characterized an intrinsic autofluorescent phenotype in CSCs of diverse epithelial cancers and used this marker to isolate and characterize these cells.

Citing Articles

Detection of Cancer Stem Cells from Patient Samples.

Hakala S, Hamalainen A, Sandelin S, Giannareas N, Narva E Cells. 2025; 14(2).

PMID: 39851576 PMC: 11764358. DOI: 10.3390/cells14020148.

Identification and analysis of pancreatic intraepithelial neoplasia: opportunities and challenges.

Pian L, Song M, Wang T, Qi L, Peng T, Xie K Front Endocrinol (Lausanne). 2025; 15():1401829.

PMID: 39839479 PMC: 11746065. DOI: 10.3389/fendo.2024.1401829.

Medicinal plants as a potential resource for the discovery of novel structures towards cancer drug resistance treatment.

Nguyen M, Nguyen T, Le T, Le T, Chau N, Le T Heliyon. 2024; 10(20):e39229.

PMID: 39492898 PMC: 11530815. DOI: 10.1016/j.heliyon.2024.e39229.

Intricate relationship between cancer stemness, metastasis, and drug resistance.

Dakal T, Bhushan R, Xu C, Gadi B, Cameotra S, Yadav V MedComm (2020). 2024; 5(10):e710.

PMID: 39309691 PMC: 11416093. DOI: 10.1002/mco2.710.

Gasdermin C promotes Stemness and Immune Evasion in Pancreatic Cancer via Pyroptosis-Independent Mechanism.

Wu R, Li J, Aicher A, Jiang K, Tondi S, Dong S Adv Sci (Weinh). 2024; 11(42):e2308990.

PMID: 39297408 PMC: 11558074. DOI: 10.1002/advs.202308990.

References

Campbell L, Polyak K . Breast tumor heterogeneity: cancer stem cells or clonal evolution?. Cell Cycle. 2007; 6(19):2332-8. DOI: 10.4161/cc.6.19.4914. View

Burkert J, Otto W, Wright N . Side populations of gastrointestinal cancers are not enriched in stem cells. J Pathol. 2008; 214(5):564-73. DOI: 10.1002/path.2307. View

Al-Hajj M, Wicha M, Benito-Hernandez A, Morrison S, Clarke M . Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A. 2003; 100(7):3983-8. PMC: 153034. DOI: 10.1073/pnas.0530291100. View

. Retraction: Marker-independent identification of glioma-initiating cells. Nat Methods. 2013; 10(10):1035. DOI: 10.1038/nmeth1013-1035c. View

Hermann P, Trabulo S, Sainz Jr B, Balic A, Garcia E, Hahn S . Multimodal Treatment Eliminates Cancer Stem Cells and Leads to Long-Term Survival in Primary Human Pancreatic Cancer Tissue Xenografts. PLoS One. 2013; 8(6):e66371. PMC: 3688976. DOI: 10.1371/journal.pone.0066371. View

Broadley K, Hunn M, Farrand K, Price K, Grasso C, Miller R . Side population is not necessary or sufficient for a cancer stem cell phenotype in glioblastoma multiforme. Stem Cells. 2011; 29(3):452-61. DOI: 10.1002/stem.582. View

Zhang S, Huang F, Huang Y, Zhong W, Yu Z . Characterization of a cancer stem cell-like side population derived from human pancreatic adenocarcinoma cells. Tumori. 2011; 96(6):985-92. View

van Herwaarden A, Schinkel A . The function of breast cancer resistance protein in epithelial barriers, stem cells and milk secretion of drugs and xenotoxins. Trends Pharmacol Sci. 2005; 27(1):10-6. DOI: 10.1016/j.tips.2005.11.007. View

Cicalese A, Bonizzi G, Pasi C, Faretta M, Ronzoni S, Giulini B . The tumor suppressor p53 regulates polarity of self-renewing divisions in mammary stem cells. Cell. 2009; 138(6):1083-95. DOI: 10.1016/j.cell.2009.06.048. View

10.

Clarke M, Dick J, Dirks P, Eaves C, Jamieson C, Jones D . Cancer stem cells--perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Res. 2006; 66(19):9339-44. DOI: 10.1158/0008-5472.CAN-06-3126. View

11.

White E . Deconvoluting the context-dependent role for autophagy in cancer. Nat Rev Cancer. 2012; 12(6):401-10. PMC: 3664381. DOI: 10.1038/nrc3262. View

12.

Santini D, Vincenzi B, Fratto M, Perrone G, Lai R, Catalano V . Prognostic role of human equilibrative transporter 1 (hENT1) in patients with resected gastric cancer. J Cell Physiol. 2010; 223(2):384-8. DOI: 10.1002/jcp.22045. View

13.

Sainz Jr B, Barretto N, Uprichard S . Hepatitis C virus infection in phenotypically distinct Huh7 cell lines. PLoS One. 2009; 4(8):e6561. PMC: 2720605. DOI: 10.1371/journal.pone.0006561. View

14.

Bell D . Characterization of the fluorescence of the antitumor agent, mitoxantrone. Biochim Biophys Acta. 1988; 949(1):132-7. DOI: 10.1016/0167-4781(88)90063-2. View

15.

Greenwood M, Yule G . On the Statistical Interpretation of some Bacteriological Methods employed in Water Analysis. J Hyg (Lond). 2010; 16(1):36-54. PMC: 2206908. DOI: 10.1017/s0022172400006501. View

16.

Iliopoulos D, Hirsch H, Wang G, Struhl K . Inducible formation of breast cancer stem cells and their dynamic equilibrium with non-stem cancer cells via IL6 secretion. Proc Natl Acad Sci U S A. 2011; 108(4):1397-402. PMC: 3029760. DOI: 10.1073/pnas.1018898108. View

17.

Balic A, Dorado J, Alonso-Gomez M, Heeschen C . Stem cells as the root of pancreatic ductal adenocarcinoma. Exp Cell Res. 2011; 318(6):691-704. DOI: 10.1016/j.yexcr.2011.11.007. View

18.

Beier D, Hau P, Proescholdt M, Lohmeier A, Wischhusen J, Oefner P . CD133(+) and CD133(-) glioblastoma-derived cancer stem cells show differential growth characteristics and molecular profiles. Cancer Res. 2007; 67(9):4010-5. DOI: 10.1158/0008-5472.CAN-06-4180. View

19.

Qin D, Xia Y, Whitesides G . Soft lithography for micro- and nanoscale patterning. Nat Protoc. 2010; 5(3):491-502. DOI: 10.1038/nprot.2009.234. View

20.

Hermann P, Huber S, Herrler T, Aicher A, Ellwart J, Guba M . Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell. 2008; 1(3):313-23. DOI: 10.1016/j.stem.2007.06.002. View