Quantification of nanoscale nuclear refractive index changes during the cell cycle

Intrigued by our recent finding that the nuclear refractive index is significantly increased in malignant cellsand histologically normal cells in clinical histology specimensderived from cancer patients, we sought to identifypotential biological mechanisms underlying the observedphenomena. The cell cycle is an ordered series of eventsthat describes the intervals of cell growth, DNA replication,and mitosis that precede cell division. Since abnormal cellcycles and increased proliferation are characteristic of manyhuman cancer cells, we hypothesized that the observed increasein nuclear refractive index could be related to anabundance or accumulation of cells derived from cancerpatients at a specific point or phase(s) of the cell cycle.Here we show that changes in nuclear refractive index offixed cells are seen as synchronized populations of cells thatproceed through the cell cycle, and that increased nuclearrefractive index is strongly correlated with increased DNAcontent. We therefore propose that an abundance of cellsundergoing DNA replication and mitosis may explain theincrease in nuclear refractive index observed in both malignantand histologically normal cells from cancer patients.Our findings suggest that nuclear refractive index may bea novel physical parameter for early cancer detection andrisk stratification.