Quantification of cellular volume and sub-cellular density fluctuations: comparison of normal peripheral blood cells and circulating tumor cells identified in a breast cancer patient
Kevin G. Phillips, Anand Kolatkar, Kathleen J. Rees, Rachel Rigg, Dena Marrinucci, Madelyn Luttgen, Kelly Bethel, Peter Kuhn, Owen J. T. McCarty
Abstract
Cancer metastasis, the leading cause of cancer-related deaths, is facilitated in part by the hematogenous transport of circulating tumor cells (CTCs) through the vasculature. Clinical studies have demonstrated that CTCs circulate in the blood of patients with metastatic disease across the major types of carcinomas, and that the number of CTCs in peripheral blood is correlated with overall survival in metastatic breast, colorectal, and prostate cancer. While the potential to monitor metastasis through CTC enumeration exists, the basic physical features of CTCs remain ill defined and moreover, the corresponding clinical utility of these physical parameters is unknown. To elucidate the basic physical features of CTCs we present a label-free imaging technique utilizing differential interference contrast (DIC) microscopy to measure cell volume and to quantify sub-cellular mass-density variations as well as the size of subcellular constituents from mass-density spatial correlations. DIC measurements were carried out on CTCs identified in a breast cancer patient using the high-definition (HD) CTC detection assay. We compared the biophysical features of HD-CTC to normal blood cell subpopulations including leukocytes, platelets (PLT), and red blood cells (RBCs). HD-CTCs were found to possess larger volumes, decreased mass-density fluctuations, and shorter-range spatial density correlations in comparison to leukocytes. Our results suggest that HD-CTCs exhibit biophysical signatures that might be used to potentially aid in their detection and to monitor responses to treatment in a label-free fashion. The biophysical parameters reported here can be incorporated into computational models of CTC-vascular interactions and in vitro flow models to better understand metastasis.
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