Identification of CD146 as a marker enriched for tumor-propagating capacity reveals targetable pathways in primary human sarcoma.

Abstract

Tumor-propagating cells (TPCs) are believed to drive cancer initiation, progression and recurrence. These cells are characterized by enhanced tumorigenicity and self-renewal. The ability to identify such cells in primary human sarcomas relies on the dye exclusion ability of tumor side population (SP) cells. Here, we performed a high-throughput cell surface antigen screen and found that CD146 is enriched in the SP population. In vivo serial transplantation assays showed that CD146+ cells are highly tumorigenic, capable of self-renewal and thus enriches for the TPC population. In addition, depletion of SP cells from the CD146+ population show that CD146+ cells and SP cells are a distinct and overlapping TPC populations. Gene expression profiling of CD146+ and SP cells revealed multiple pathways commonly upregulated in both of these populations. Inhibition of one of these upregulated pathways, Notch signaling, significantly reduced tumor growth and self-renewal. Our data demonstrate that CD146 is an effective cell surface marker for enriching TPCs in primary human sarcomas. Targeting differentially activated pathways in TPCs may provide new therapeutic strategies for treating sarcoma.

• Authors: Qingxia Wei, Yuning J Tang, Veronique Voisin, Shingo Sato, Makoto Hirata, Heather Whetstone, Ilkyu Han, Laurie Ailles, Gary D Bader, Jay Wunder, Benjamin A Alman
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 37 Pg. 40283-94 (Nov 24 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26517673 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers, Tumor
• CD146 Antigen
• Dipeptides
• N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester

Topics

• Animals
• Biomarkers, Tumor (genetics, metabolism)
• CD146 Antigen (genetics, metabolism)
• Dipeptides (pharmacology)
• Flow Cytometry
• Gene Expression Profiling (methods)
• Gene Expression Regulation, Neoplastic
• Humans
• Mice, Inbred NOD
• Mice, Knockout
• Mice, SCID
• Neoplastic Stem Cells (metabolism)
• Osteosarcoma (genetics, pathology)
• Reverse Transcriptase Polymerase Chain Reaction
• Sarcoma (genetics, pathology)
• Side-Population Cells (metabolism)
• Signal Transduction (drug effects, genetics)
• Transplantation, Heterologous
• Tumor Cells, Cultured