Androgen receptor targets NFKB and TSPI to suppress prostate tumor growth in vivo

The androgen role in the maintenance of prostate epithelium is subject to conflicting opinions. While androgen ablation drives the regression of normal and cancerous prostate, testosterone may cause both proliferation and apoptosis. Several investigators note decreased proliferation and stronger response to chemotherapy of the prostate cancer cells stably expressing androgen receptor (AR), however no mechanistic explanation was offered. In this paper we demonstrate in vivo anti-tumor effect of the AR on prostate cancer growth and identify its molecular mediators. We analyzed the effect of AR on the tumorigenicity of prostate cancer cells. Unexpectedly, the AR-expressing cells formed tumors in male mice at a much lower rate than the AR-negative controls. Moreover, the AR-expressing tumors showed decreased vascularity and massive apoptosis. AR expression lowered the angiogenic potential of cancer cells, by increasing secretion of an anti-angiogenic protein, thrombospondin-1. AR activation caused a decrease in RelA, a subunit of the pro-survival transcription factor NF kappa B, reduced its nuclear localization and transcriptional activity. This, in turn, diminished the expression of its anti-apoptotic targets, Bcl-2 and IL-6. Increased apoptosis within AR-expressing tumors was likely due to the NF kappa B suppression, since it was restricted to the cells lacking nuclear (active) NF kappa B. Thus we for the first time identified combined decrease of NF kappa B and increased TSP1 as molecular events underlying the AR anti-tumor activity in vivo. Our data indicate that intermittent androgen ablation is preferable to continuous withdrawal, a standard treatment for early-stage prostate cancer. (C) 2007 Wiley-Liss, Inc.

Experimental verification of therapeutic doses for the superficially-placed tumor radiotherapy with heavy ions at HIRFL

Up to now, clinical trials of heavy-ion radiotherapy for superficially placed tumors have been carried out for six times and over 60 selected patients have been treated with 80—100 MeV/u carbon ions supplied by the Heavy Ion Research Facility in Lanzhou (HIRFL) at the Institute of Modern Physics, Chinese Academy of Sciences since November, 2006. A passive irradiation system and a dose optimization method for radiotherapy with carbon-ion beams have been developed. Experimental verification of longitudinally ...

Heavy-ion conformal irradiation in the shallow-seated tumor therapy terminal at HIRFL

Basic research related to heavy-ion cancer therapy has been done at the Institute of Modern Physics (IMP), Chinese Academy of Sciences since 1995. Now a plan of clinical trial with heavy ions has been launched at IMP. First, superficially placed tumor treatment with heavy ions is expected in the therapy terminal at the Heavy Ion Research Facility in Lanzhou (HIRFL), where carbon ion beams with energy up to 100 MeV/u can be supplied. The shallow-seated tumor therapy terminal at HIRFL is equipped with a passive beam delivery system including two orthogonal dipole magnets, which continuously scan pencil beams laterally and generate a broad and uniform irradiation field, a motor-driven energy degrader and a multi-leaf collimator. Two different types of range modulator, ripple filter and ridge filter with which Guassian-shaped physical dose and uniform biological effective dose Bragg peaks can be shaped for therapeutic ion beams respectively, have been designed and manufactured. Therefore, two-dimensional and three-dimensional conformal irradiations to tumors can be performed with the passive beam delivery system at the earlier therapy terminal. Both the conformal irradiation methods have been verified experimentally and carbon-ion conformal irradiations to patients with superficially placed tumors have been carried out at HIRFL since November 2006.

Capability verification of the beam delivery system in the superficially-placed tumor therapy terminal at HIRFL

The passive beam delivery system in the superficially-placed tumor therapy terminal at Heavy Ion Researc h Facility in Lanzhou (HIRFL), which includes two orthogonal dipole magnets as scanning system, a motor-driven energy degrader as range-shifter, series of ridge filters as range modulator and a multileaf collimator, is introduced in detail. The capacities of its important components and the whole system have been verified experimentally. The tests of the ridge filter for extending Bragg peak and the range shifter for energy adjustment show both work well. To examine the passive beam delivery system, a beam shaping experiment were carried out, simulating a three-dimensional (3D) conformal irradiation to a tumor. The encouraging experimental result confirms that 3D layer-stacking conformal irradiation can be performed by means of the passive system. The validation of the beam delivery system establishes a substantial basis for upcoming clinical trial for superficially-placed tumors with heavy ions in the therapy terminal at HIRFL.

Physical property measurement of therapeutic carbon ion beam in the shallow-seated tumor therapy terminal at HIRFL

For the first time the physical properties of therapeutic carbon-ion beam supplied by, the shallow-seated tumor therapy terminal at the Heavy Ion Research Facility in Lanzhou (HIRFL) are measured. For a 80.55MeV/u C-12 ion beam delivered to the therapy terminal, the homogeneity of irradiation fields is 73.48%, when the beam intensity varied in the range of 0.001-0.1nA (i.e. 1 X 10(6) - 1 X 10(8) particles per second). The stability of the beam intensity within a few minutes is estimated to be 80.87%. The depth-dose distribution of the beam at the isocenter of the therapy facility is measured, and the position of the high-dose Bragg peak is found to be located at the water-equivalent depth of 13.866mm. Based on the relationship between beam energy and Bragg peak position, the corresponding beam energy at the isocenter of the therapy terminal is evaluated to be 71.71MeV/u for the original 80.55MeV/u C-12 ion beam, which consisted basically with calculation. The readout of the previously-used air-free ionization chamber regarding absorbed dose is calibrated as well in this experiment. The results indicate that the performance of the therapy facility should be optimized further to meet the requirements of clinical trial.

In vivo growth-inhibition of S 180 tumor by mixture of 5-Fu and low molecular lambda-carrageenan from Chondrus ocellatus

POLYSACCHARIDES; ANTICOAGULANT; SURVIVAL

Aberrant expression of X-linked genes RbAp46, Rsk4, and Cldn2 in breast cancer

The consequence of activation status or gain/loss of an X-chromosome in terms of the expression of tumor suppressor genes or oncogenes in breast cancer has not been clearly addressed. In this study, we investigated the activation status of the X-chromosomes in a panel of human breast cancer cell lines, human breast carcinoma, and adjacent mammary tissues and a panel of murine mammary epithelial sublines ranging from low to high invasive potentials. Results show that most human breast cancer cell lines were homozygous, but both benign cell lines were heterozygous for highly polymorphic X-loci (IDS and G6PD). On the other hand, 60% of human breast carcinoma cases were heterozygous for either IDS or G6PD markers. Investigation of the activation status of heterozygous cell lines revealed the presence of only one active X-chromosome, whereas most heterozygous human breast carcinoma cases had two active X-chromosomes. Furthermore, we determined whether or not an additional active X-chromosome affects expression levels of tumor suppressor genes and oncogenes. Reverse transcription-PCR data show high expression of putative tumor suppressor genes Rsk4 and RbAp46 in 47% and 79% of breast carcinoma cases, respectively, whereas Cldn2 was down-regulated in 52% of breast cancer cases compared with normal adjacent tissues. Consistent with mRNA expression, immunostaining for these proteins also showed a similar pattern. In conclusion, our data suggest that high expression of RbAp46 is likely to have a role in the development or progression of human breast cancer. The activation status of the X-chromosome may influence the expression levels of X-linked oncogenes or tumor suppressor genes.