Cancer and Metastasis Reviews

, Volume 38, Issue 1–2, pp 259–295 | Cite as

Exosomes, metastases, and the miracle of cancer stem cell markers

  • Zhe WangEmail author
  • Margot ZöllerEmail author


Cancer-initiating cells (CIC) are the driving force in tumor progression. There is strong evidence that CIC fulfill this task via exosomes (TEX), which modulate and reprogram stroma, nontransformed cells, and non-CIC. Characterization of CIC, besides others, builds on expression of CIC markers, many of which are known as metastasis-associated molecules. We here discuss that the linkage between CIC/CIC-TEX and metastasis-associated molecules is not fortuitously, but relies on the contribution of these markers to TEX biogenesis including loading and TEX target interactions. In addition, CIC markers contribute to TEX binding- and uptake-promoted activation of signaling cascades, transcription initiation, and translational control. Our point of view will be outlined for pancreas and colon CIC highly expressing CD44v6, Tspan8, EPCAM, claudin7, and LGR5, which distinctly but coordinately contribute to tumor progression. Despite overwhelming progress in unraveling the metastatic cascade and the multiple tasks taken over by CIC-TEX, there remains a considerable gap in linking CIC biomarkers, TEX, and TEX-initiated target modulation with metastasis. We will try to outline possible bridges, which could allow depicting pathways for new and expectedly powerful therapeutic interference with tumor progression.


Cancer-initiating cell biomarkers Metastasis Exosome biogenesis and targeting Exosome message transfer Gastrointestinal cancer 



A-ISC active ISC, AML acute myeloid leukemia, ASC adult stem cells, BMC bone marrow cells, CAF cancer-associated fibroblasts, ceRNA competing endogenous RNA, CIC cancer-initiating cells/cancer stem cells, CoCa colorectal cancer, DC dendritic cells, DS deep sequencing, EBV Epstein–Barr virus, EC endothelial cells, ECM extracellular matrix, EE early endosome, EMT epithelial–mesenchymal transition, ERM ezrin, radixin, moesin, ESC embryonic stem cells, ESCRT endosomal sorting complex required for transport, EV extracellular vesicles, Exo exosome, GAG glycosaminoglycan, GEM glycolipid-enriched membrane domains, GPCR G protein-coupled receptor, HCC hepatocellular carcinoma, hiPSC human-induced pluripotent SC, ICD intracellular domain, ILV intraluminal vesicle, ISC intestinal SC, kd knockdown, ko knockout, LDL low-density lipoprotein, LN laminin, lnc long nc, LNC lymph node cells, macrophage, MHC major histocompatibility complex, miRNA microRNA, MS mass spectrometry, MVB multivesicular body, nc noncoding, NK natural killer cells, NSCLC nonsmall cell lung carcinoma, PaCa pancreatic cancer, PSC pluripotent SC, R receptor, RA retinoic acid, RISC RNA-induced silencing complex, ROS reactive oxygen species, RTK receptor tyrosine kinase, Q-ISC quiescent ISC, SC stem cells, TEM tetraspanin- and glycolipid-enriched membrane microdomain, TEX tumor exosomes, TF transcription factor, TJ tight junction

Funding information

This work was supported by the National Natural Science Foundation of China (ZW, NSFC. 81702877) and the German Cancer Research Aid (MZ, 110836). The funding had no impact on the design of the study and on collection, analysis and interpretation of data, and on writing the manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Deep sequencing

ENA database accession No: PRJEB25446

Supplementary material

10555_2019_9793_MOESM1_ESM.docx (97 kb)
ESM 1 (DOCX 97 kb)


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of OncologyThe First Affiliated Hospital of Guangdong Pharmaceutical UniversityGuangzhouChina
  2. 2.Pancreas SectionUniversity Hospital of SurgeryHeidelbergGermany

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