Let-7 Expression Defines Two Differentiation Stages of Cancer

The early phases of carcinogenesis resemble embryonic development, often involving the reexpression of embryonic mesenchymal genes. The NCI60 panel of human tumor cell lines can genetically be subdivided into two superclusters (SCs) that correspond to CD95 Type I and II cells. SC1 cells are characterized by a mesenchymal and SC2 cells by an epithelial gene signature, suggesting that SC1 cells represent less differentiated, advanced stages of cancer. miRNAs are small 20- to 22-nucleotide-long noncoding RNAs that inhibit gene expression at the posttranscriptional level. By performing miRNA expression analysis on 10 Type I and 10 Type II cells, we have determined that SC1 cells express low and SC2 cells high levels of the miRNA let-7, respectively, suggesting that let-7 is a marker for less advanced cancers. Expression of the let-7 target high-mobility group A2 (HMGA2), an early embryonic gene, but not of classical epithelial or mesenchymal markers such as E-cadherin or vimentin, inversely correlated with let-7 expression in SC1 and SC2 cells. Using ovarian cancer as a model, we demonstrate that expression of let-7 and HMGA2 is a better predictor of prognosis than classical markers such as E-cadherin, vimentin, and Snail. These data identify loss of let-7 expression as a marker for less differentiated cancer

Magnetic Particle Imaging-Guided Thermal Simulations for Magnetic Particle Hyperthermia

Magnetic particle hyperthermia (MPH) enables the direct heating of solid tumors with alternating magnetic fields (AMFs). One challenge with MPH is the unknown particle distribution in tissue after injection. Magnetic particle imaging (MPI) can measure the nanoparticle content and distribution in tissue after delivery. The objective of this study was to develop a clinically translatable protocol that incorporates MPI data into finite element calculations for simulating tissue temperatures during MPH. To verify the protocol, we conducted MPH experiments in tumor-bearing mouse cadavers. Five 8–10-week-old female BALB/c mice bearing subcutaneous 4T1 tumors were anesthetized and received intratumor injections of Synomag®-S90 nanoparticles. Immediately following injection, the mice were euthanized and imaged, and the tumors were heated with an AMF. We used the Mimics Innovation Suite to create a 3D mesh of the tumor from micro-computerized tomography data and spatial index MPI to generate a scaled heating function for the heat transfer calculations. The processed imaging data were incorporated into a finite element solver, COMSOL Multiphysics®. The upper and lower bounds of the simulated tumor temperatures for all five cadavers demonstrated agreement with the experimental temperature measurements, thus verifying the protocol. These results demonstrate the utility of MPI to guide predictive thermal calculations for MPH treatment planning