Carcinogenesis involves the chemical and structural alteration of biomolecules in cells. Aberrant methylation of DNA is a well-known carcinogenic mechanism and a common chemical modification of DNA. Terahertz waves can directly observe changes in DNA because the characteristic energies lie in the same frequency region. In addition, terahertz energy levels are not high enough to damage DNA by ionization. Here, we present terahertz molecular resonance fingerprints of DNA methylation in cancer DNA. Methylated cytidine, a nucleoside, has terahertz characteristic energies that give rise to the molecular resonance of methylation in DNA. Molecular resonance is monitored in aqueous solutions of genomic DNA from cancer cell lines using a terahertz time-domain spectroscopic technique. Resonance signals can be quantified to identify the types of cancer cells with a certain degree of DNA methylation. These measurements reveal the existence of molecular resonance fingerprints of cancer DNAs in the terahertz region, which can be utilized for the early diagnosis of cancer cells at the molecular level.

We demonstrated that tumors in freshly excised whole brain tissue could be differentiated clearly from normal brain tissue using a reflection-type terahertz (THz) imaging system. THz binary images of brain tissues with tumors indicated that the tumor boundaries in the THz images corresponded well to those in visible images. Grey and white-matter regions were distinguishable owing to the different distribution of myelin in the brain tissue. THz images corresponded closely with magnetic resonance imaging (MRI) results. The MRI and hematoxylin and eosin-stained microscopic images were investigated to account for the intensity differences in the THz images for fresh and paraffin-embedded brain tissue. Our results indicated that the THz signals corresponded to the cell density when water was removed. Thus, THz imaging could be used as a tool for label-free and real-time imaging of brain tumors, which would be helpful for physicians to determine tumor margins during brain surgery.

This paper demonstrates the principle of the nanoparticle-contrast-agent-enabled terahertz imaging (CATHI) technique, which yields a dramatic sensitivity of the differential signal from cancer cells with nanoparticles. The terahertz (THz) reflection signal increased beam by 20% in the cancer cells with nanoparticles of gold nano-rods (GNRs) upon their irradiation with a infrared (IR) laser, due to the temperature rise of water in cancer cells by surface plasma ploritons. In the differential mode, the THz signal from the cancer cells with GNRs was 30 times higher than that from the cancer cells without GNRs. As the high sensitivity is achieved by the surface plasmon resonance through IR laser irradiation, the resolution of the CATHI technique can be as good as a few microns and THz endoscopy becomes more feasible.

Cancer imaging using terahertz (THz) electromagnetic waves has the potential to overcome the drawbacks of existing cancer imaging techniques because of the unique properties of THz radiation. It is nonionizing, highly sensitive to water molecules, and suitable for the observation of many biomolecular characteristics based on low-energy vibrational modes. Consequently, it is advantageous to use THz cancer imaging for detection, especially of superficial carcinomas in soft tissues. However, there are three primary challenges facing this type of cancer imaging that must be addressed before it can be applied medically: the limited penetration depth in hydrated tissues, the difficulty of obtaining molecular resonance fingerprints of cancers, and the low image contrast between tissues. These challenges can be overcome by applying several state-of-the-art techniques; the penetration depth has been enhanced sufficiently to observe cancer lesions deep inside tissues by using freezing and penetration-enhancing agents: the biochemical modification of DNA can be utilized to track the resonance fingerprints of carcinogenesis at the genomic DNA level; and nanoparticles can increase the THz imaging contrast if they are employed similarly to how they are used in magnetic resonance imaging. These solutions are important to enable THz cancer imaging to be performed in clinical settings.

DNA methylation is a pivotal epigenetic modification of DNA that regulates gene expression. Abnormal regulation of gene expression is closely related to carcinogenesis, which is why the assessment of DNA methylation is a key factor in cancer research. Terahertz radiation may play an important role in active demethylation for cancer therapy because the characteristic frequency of the methylated DNA exists in the terahertz region. Here, we present a novel technique for the detection and manipulation of DNA methylation using terahertz radiation in blood cancer cell lines. We observed the degree of DNA methylation in blood cancer at the characteristic resonance of approximately 1.7 THz using terahertz time-domain spectroscopy. The terahertz results were cross-checked with global DNA methylation quantification using an enzyme-linked immunosorbent assay. We also achieved the demethylation of cancer DNA using high-power terahertz radiation at the 1.7-THz resonance. The demethylation degrees ranged from 10% to 70%, depending on the type of cancer cell line. Our results show the detection of DNA methylation based on the terahertz molecular resonance and the manipulation of global DNA methylation using high-power terahertz radiation. Terahertz radiation may have potential applications as an epigenetic inhibitor in cancer treatment, by virtue of its ability to induce DNA demethylation, similarly to decitabine.