Editors' ChoiceCancer

Integrins Initiating Cancer

Sci. Signal.  03 Jun 2014:
Vol. 7, Issue 328, pp. ec146
DOI: 10.1126/scisignal.2005545

The integrin αVβ3 is a surface protein involved in adhesion between the cell and the extracellular matrix, a process typically activated by when the integrin binds ligands, which are generally extracellular matrix proteins. High αVβ3 abundance in various cancers is associated with metastasis and poor prognosis. Seguin et al. discovered a ligand-independent role for αVβ3 in the development of tumor-initiating cells (also known as cancer stem cells) in various cancers; these cells are thought to contribute to relapse after an initial response to chemotherapy. Cell sorting of patient-derived lung and pancreatic xenografts revealed that the β3-positive subpopulation had more tumor-initiating cells than the β3-negative subpopulation. The β3-positive cells from patient-derived xenografts were resistant to various receptor tyrosine kinase inhibitors, including erlotinib, and experiments with xenografts indicated that sensitivity to erlotinib was conferred by knockdown of β3 and resistance was conferred by ectopic expression of β3. In xenograft-bearing mice, the acquisition of resistance induced by sustained administration of erlotinib correlated with increased abundance of αVβ3. Cell sorting of erlotinib-resistant xenografts revealed that the β3-positive subpopulation had increased capacity for self-renewal and tumor initiation and increased abundance of a stem marker compared with the β3-negative subpopulation. Erlotinib resistance occurred in cancer cells treated with integrin antagonists or those expressing a form of the β3 integrin subunit that cannot bind ligands, which led the authors to investigate a ligand-independent mechanism for the effects of αVβ3. The kinase KRAS, which activates the Ral guanosine triphosphatase family, associated with αVβ3 through the lectin galectin-3, and knockdown of KRAS, galectin-3, or RalB prevented the acquisition of erlotinib resistance and the increased self-renewal capacity of cells with αVβ3. RalB activates the kinase TBK1 and the transcription factor NF-κB, and RNA interference directed against TBK1 or the NF-κB subunit c-Rel in various cancer cells conferred sensitivity to erlotinib. Thus, αVβ3 mediates the resistance of tumor-initiating cells to tyrosine kinase inhibitors through the activation of NF-κB in a ligand-independent manner (see Kannan et al.).

L. Seguin, S. Kato, A. Franovic, M. F. Camargo, J. Lesperance, K. C. Elliott, M. Yebra, A. Mielgo, A. M. Lowy, H. Husain, T. Cascone, L. Diao, J. Wang, I. I. Wistuba, J. V. Heymach, S. M. Lippman, J. S. Desgrosellier, S. Anand, S. M. Weis, D. A. Cheresh, An integrin β3–KRAS–RalB complex drives tumour stemness and resistance to EGFR inhibition. Nat. Cell Biol. 16, 457–468 (2014).[PubMed]

N. Kannan, L. V. Nguyen, C. J. Eaves, Integrin β3 links therapy resistance and cancer stem cell properties. Nat. Cell Biol. 16, 397–399 (2014). [PubMed]