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CELL BIOLOGY
Intercellular transfer of P-glycoprotein mediates acquired multidrug resistance in tumor cells
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*Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218; and Nuclear Medicine Research Laboratory and Gene Transfer and Gene Expression Laboratory, Memorial Sloan–Kettering Cancer Center, New York, NY 10021
Edited by Joan Massagué, Memorial Sloan–Kettering Cancer Center, New York, NY, and approved December 6, 2004 (received for review March 30, 2004)
The overexpression of P-glycoprotein (P-gp) causes resistance to chemotherapy in many tumor types. Here, we report intercellular transfer of functional P-gp from P-gp-positive to P-gp-negative cells in vitro and in vivo. The expression of acquired P-gp is transient in isolated cells but persists in the presence of P-gp-positive cells or under the selective pressure of colchicine. The intercellular transfer of functional P-gp occurs between different tumor cell types and results in increased drug resistance both in vitro and in vivo. Most importantly, the acquired resistance permits tumor cells to survive potentially toxic drug concentrations long enough to develop intrinsic P-gp-mediated resistance. P-gp transfer also occurs to putative components of tumor stroma, such as fibroblasts, raising the possibility that multidrug resistance could be conferred by resistant tumor cells to critical stromal elements within the tumor mass. This is the first report, to our knowledge, that a protein transferred between cells retains its function and confers a complex biologic property upon the recipient cell. These findings have important implications for proteomic analyses in tumor samples and resistance to cancer therapy.
cell–cell communication | multidrug resistance phenotype
This paper was submitted directly (Track II) to the PNAS office.
Freely available online through the PNAS open access option.
Abbreviations: P-gp, P-glycoprotein; MDR, multidrug resistance; AqMDR, acquired resistance MDR; PE, phycoerythrin.
A.L. and B.M.M. contributed equally to this work.
¶ To whom correspondence should be addressed at: Memorial Sloan–Kettering Cancer Center, 1275 York Avenue, New York, NY 10021. E-mail: larsons{at}mskcc.org.
© 2005 by The National Academy of Sciences of the USA
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