Human Tumor Cell Proliferation Evaluated Using Manganese-Enhanced MRI

Abstract

BackgroundTumor cell proliferation can depend on calcium entry across the cell membrane. As a first step toward the development of a non-invasive test of the extent of tumor cell proliferation in vivo, we tested the hypothesis that tumor cell uptake of a calcium surrogate, Mn2+ [measured with manganese-enhanced MRI (MEMRI)], is linked to proliferation rate in vitro.Methodology/Principal FindingsProliferation rates were determined in vitro in three different human tumor cell lines: C918 and OCM-1 human uveal melanomas and PC-3 prostate carcinoma. Cells growing at different average proliferation rates were exposed to 1 mM MnCl2 for one hour and then thoroughly washed. MEMRI R1 values (longitudinal relaxation rates), which have a positive linear relationship with Mn2+ concentration, were then determined from cell pellets. Cell cycle distributions were determined using propidium iodide staining and flow cytometry. All three lines showed Mn2+-induced increases in R1 compared to cells not exposed to Mn2+. C918 and PC-3 cells each showed a significant, positive correlation between MEMRI R1 values and proliferation rate (p≤0.005), while OCM-1 cells showed no significant correlation. Preliminary, general modeling of these positive relationships suggested that pellet R1 for the PC-3 cells, but not for the C918 cells, could be adequately described by simply accounting for changes in the distribution of the cell cycle-dependent subpopulations in the pellet.Conclusions/SignificanceThese data clearly demonstrate the tumor-cell dependent nature of the relationship between proliferation and calcium influx, and underscore the usefulness of MEMRI as a non-invasive method for investigating this link. MEMRI is applicable to study tumors in vivo, and the present results raise the possibility of evaluating proliferation parameters of some tumor types in vivo using MEMRI.

Manganese-Enhanced MRI Reveals Early-Phase Radiation-Induced Cell Alterations In Vivo

“…The Ki-67 (Fig. 5) and MEMRI observations agreed well with a previous report (18) and suggested that the Mn 2þ accumulation in tumors, when evaluated during the early phase (24 hours) after irradiation, reflects cell-cycle alteration and a subsequent decrease in cell proliferation rather than apoptotic alterations.…”

“…In previous work, it was reported that Mn 2þ uptake in the tumor is linked to the proliferation rate of tumor cells (18). In our study, the number of Ki-67-positive cells (potential marker of tumor growth activity; refs.…”

“…Some previous studies have shown that MEMRI can enhance some types of tumors in vivo, such as salivary gland and eye (choroidal) tumors (16,17). In particular, Braun and colleagues showed that the uptake of Mn 2þ by tumors depends on the cellproliferation rate (18). Thus, we conducted a MnCl 2 loading study to investigate whether Mn 2þ is accumulated in tumor cells that have undergone G 2 -M cell-cycle arrest due to radiation exposure.…”

“…There are several reports, discussing the factors associated with Mn enhancement and tumor uptake. The tumor cell uptake of Mn 2þ is linked to the proliferation rate in vitro of human tumor cells (18). In addition, Mn 2þ is considered to be a cell viability indicator in myocardial infarction (19,20).…”

Modeling Human Choroidal Melanoma Xenograft Growth in Immunocompromised Rodents to Assess Treatment Efficacy

“…14 The faster growth of the C918 tumors is consistent with the finding that C918 cells have a higher proliferation rate in vitro than OCM-1 cells. 26 Second, the modeling also permits the calculation of tumor growth rate at any time point (equation 2). For example, in Rat 54 ( Fig.…”