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INVITED REVIEW AND COMMENTARY |
From the Department of Surgery, Division of Thoracic Surgery (Dr V. Donnenberg), and the Department of Medicine, Division of Hematology Oncology (Dr A. Donnenberg), University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pennsylvania.
The failure to eradicate cancer may be as fundamental as a misidentification of the target. Current therapies succeed at eliminating bulky disease but often miss a tumor reservoir that is the source of disease recurrence and metastasis. Recent advances in the understanding of tissue development and repair cause us to revisit the process of drug resistance as it applies to oncogenesis and tumor heterogeneity. The cancer stem cell hypothesis states that the cancer-initiating cell is a transformed tissue stem cell, which retains the essential property of self-protection through the activity of multiple drug resistance (MDR) transporters. This resting constitutively drug-resistant cell remains at low frequency among a heterogeneous tumor mass. In the context of this hypothesis, the authors review the discovery of MDR transporters in cancer and normal stem cells and the failure of MDR reversal agents to increase the therapeutic index of substrate antineoplastic agents.
Key Words: Cancer stem cell • multiple drug resistance • chemotherapy • oncogenesis
Address for reprints: Vera S. Donnenberg, PhD, Hillman Cancer Research Center, 5117 Centre Avenue, Suite 2.42, Pittsburgh, PA 15213.
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