Tumor-Initiating Cells of Various Tumor Types Exhibit Differential Angiogenic Properties and React Differently to Antiangiogenic Drugs

Author:

Benayoun Liat1,Gingis-Velitski Svetlana1,Voloshin Tali1,Segal Ehud2,Segev Rotem1,Munster Michal1,Bril Rotem1,Satchi-Fainaro Ronit2,Scherer Stefan J.3,Shaked Yuval1

Affiliation:

1. Department of Molecular Pharmacology, Rappaport Faculty of Medicine, Technion, Haifa, Israel

2. Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

3. Hoffmann La Roche, Basel, Switzerland

Abstract

Abstract Tumor-initiating cells (TICs) are a subtype of tumor cells believed to be critical for initiating tumorigenesis. We sought to determine the angiogenic properties of TICs in different tumor types including U-87MG (glioblastoma), HT29 (colon), MCF7 (breast), A549 (non-small-cell lung), and PANC1 (pancreatic) cancers. Long-term cultures grown either as monolayers (“TIC-low”) or as nonadherent tumor spheres (“TIC-high”) were generated. The TIC-high fractions exhibited increased expression of stem cell surface markers, high aldehyde dehydrogenase activity, high expression of p21, and resistance to standard chemotherapy in comparison to TIC-low fractions. Furthermore, TICs from U-87MG and HT29 but not from MCF7, A549, and PANC1 tumor types possess increased angiogenic activity. Consequently, the efficacy of vascular endothelial growth factor-A (VEGF-A) neutralizing antibody is limited only to those tumors that are dependent on VEGF-A activity. In addition, such therapy had little or reversed antiangiogenic effects on tumors that do not necessarily rely on VEGF-dependent angiogenesis. Differential angiogenic activity and antiangiogenic therapy sensitivity were also observed in TICs of the same tumor type, suggesting redundant angiogenic pathways. Collectively, our results suggest that the efficacy of antiangiogenic drugs is dependent on the angiogenic properties of TICs and, therefore, can serve as a possible biomarker to predict antiangiogenic treatment efficacy.

Funder

Israel Student Education Foundation, Fine, and Jacobs studentships

Israeli Ministry of Health, Israel Science Foundation, European Commission under FP7 program

Hoffmann La Roche

Publisher

Oxford University Press (OUP)

Subject

Cell Biology,Developmental Biology,Molecular Medicine

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