Nature 450, 1235-1239 (20 December 2007) | doi:10.1038/nature06385; Received 2 January 2007; Accepted 17 October 2007

Isolation of rare circulating tumour cells in cancer patients by microchip technology

Sunitha Nagrath1,3, Lecia V. Sequist2,3, Shyamala Maheswaran2, Daphne W. Bell2,4, Daniel Irimia1, Lindsey Ulkus2, Matthew R. Smith2, Eunice L. Kwak2, Subba Digumarthy2, Alona Muzikansky2, Paula Ryan2, Ulysses J. Balis1,4, Ronald G. Tompkins1, Daniel A. Haber2 & Mehmet Toner1

  1. Surgical Services and BioMEMS Resource Center, Massachusetts General Hospital, Harvard Medical School, and Shriners Hospital for Children, Boston, Massachusetts 02114, USA
  2. Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, USA
  3. These authors contributed equally to this paper.
  4. Present addresses: National Human Genome Research Institute/NIH Cancer Genetics Branch, Bethesda, Maryland 20892, USA (D.W.B.); Department of Pathology, University of Michigan Health System, Ann Arbor, Michigan 48109, USA (U.J.B.).

Correspondence to: Mehmet Toner1 Correspondence and requests for materials should be addressed to M.T. (Email: mtoner@hms.harvard.edu).

Viable tumour-derived epithelial cells (circulating tumour cells or CTCs) have been identified in peripheral blood from cancer patients and are probably the origin of intractable metastatic disease1, 2, 3, 4. Although extremely rare, CTCs represent a potential alternative to invasive biopsies as a source of tumour tissue for the detection, characterization and monitoring of non-haematologic cancers5, 6, 7, 8. The ability to identify, isolate, propagate and molecularly characterize CTC subpopulations could further the discovery of cancer stem cell biomarkers and expand the understanding of the biology of metastasis. Current strategies for isolating CTCs are limited to complex analytic approaches that generate very low yield and purity9. Here we describe the development of a unique microfluidic platform (the 'CTC-chip') capable of efficient and selective separation of viable CTCs from peripheral whole blood samples, mediated by the interaction of target CTCs with antibody (EpCAM)-coated microposts under precisely controlled laminar flow conditions, and without requisite pre-labelling or processing of samples. The CTC-chip successfully identified CTCs in the peripheral blood of patients with metastatic lung, prostate, pancreatic, breast and colon cancer in 115 of 116 (99%) samples, with a range of 5–1,281 CTCs per ml and approximately 50% purity. In addition, CTCs were isolated in 7/7 patients with early-stage prostate cancer. Given the high sensitivity and specificity of the CTC-chip, we tested its potential utility in monitoring response to anti-cancer therapy. In a small cohort of patients with metastatic cancer undergoing systemic treatment, temporal changes in CTC numbers correlated reasonably well with the clinical course of disease as measured by standard radiographic methods. Thus, the CTC-chip provides a new and effective tool for accurate identification and measurement of CTCs in patients with cancer. It has broad implications in advancing both cancer biology research and clinical cancer management, including the detection, diagnosis and monitoring of cancer10.


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