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Needles in a haystack: capturing elusive cancer cells

A new paper from Mark Howarth and graduate students Jayati Jain and Gianluca Veggiani has demonstrated how isolation of rare cells can be improved, by successfully trapping cells expressing very low levels of two important cancer biomarkers (1).

Antibody interaction for capture of HER2-positive cancer cells (from PDB 1 N8Z)

Antibody interaction for capture of HER2-positive cancer cells (from PDB 1 N8Z) (Click to enlarge)

Sorting and isolating specific cells from a complex mixture of cells, proteins and fluids is an essential aspect of many research and clinical applications. One example of particular interest is the detection and isolation of circulating tumour cells shed from malignant tumours into the bloodstream. The number of the cells present can be used to differentiate between healthy and diseased states and to monitor cancer progression and response to therapy.  

An emerging successful technique for isolating cancer cells is through the use of nanoscaled magnetic beads that are coated with antibodies against cancer cell biomarkers. However, a major challenge facing this application is its inefficiency in isolating low biomarker expressing cells, which include the most potent ones - cancer stem cells.

Research in the Howarth lab has focused on the individual components of the cell-magnetic bead interaction to address this problem. Using cancer biomarkers HER2 and EpCAM which are over-expressed in many cancer types, the group investigated how antibody affinity, antibody-bead linkage and cell membrane dynamics affect the efficiency of magnetic beads in isolating low biomarker expressing cells.

Using mutations to generate antibodies with varying affinity, they found that improving the antibody affinity dramatically improved the isolation of cells expressing lower biomarker levels. When they explored the role of cellular factors in binding, they found that high cholesterol content in the cell membrane enhanced the cell’s chances of magnetic capture.

Optimising these factors together, the group saw a dramatic improvement in the isolation of cells expressing very low levels of HER2 or EpCAM compared with the standard approach. This optimisation of cell isolation still needs to be tested on blood samples from cancer patients, but in the future, the findings may help in the diagnosis and monitoring of particular cancer types, where previous methods have struggled to capture circulating tumour cells.

Reference

  1. Cholesterol loading and ultrastable protein interactions determine the level of tumor marker required for optimal isolation of cancer cells. Jain J, Veggiani G, Howarth M. Cancer Res. 2013 Feb 1. [Epub ahead of print]

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