Effects of Marine Phospholipids Extract on the Lipid Levels of Metastatic and Nonmetastatic Prostate Cancer Patients.

High intake of omega-3 fatty acids (n-3 FAs) from fish has shown to reduce metastatic progression of prostate cancer. This clinical trial investigated the influence of high n-3 FA intake (marine phospholipids, MPL) on the FA composition of blood lipids, lysophosphatidylcholine (LPC), and on lipoproteins in prostate cancer patients and elderly men without prostate cancer. MPL supplementation resulted in a significant increase of n-3 FAs (eicosapentaenoic and docosahexaenoic acid) in blood lipids, while arachidonic acid (n-6 FA) decreased significantly. Low density lipoprotein (LDL) and high density lipoprotein (HDL) increased significantly, but the LDL increase was observed only in subjects with an inactive tumour. Similarly, LPC plasma concentration increased significantly only in patients without tumour. The missing increase of LDL and LPC after MPL supplementation in patients with actively growing (metastasizing) prostate cancer suggests that tumour cells have an elevated demand for LDL and LPC. Due to the MPL-induced increase of n-3 FAs in these blood lipids, it can be assumed that especially actively growing and metastasizing prostate cancer cells are provided with elevated amounts of these antimetastatic n-3 FAs. A hypothetic model explaining the lower incidence of metastatic progression in prostate cancer patients with high fish consumption is presented.

Anti-metastatic effects of liposomal gemcitabine in a human orthotopic LNCaP prostate cancer xenograft model.

Fatal outcomes of prostate carcinoma (PCa) mostly result from metastatic spread rather than from primary tumor burden. Here, we monitored growth and metastatic spread of an orthotopic luciferase/GFP-expressing LNCaP PCa xenograft model in SCID mice by in vivo imaging and in vitro luciferase assay of tissues homogenates. Although the metastatic spread generally shows a significant correlation to primary tumor volumes, the susceptibility of various tissues to metastatic invasion was different in the number of affected animals as well as in absolute metastatic burden in the individual tissues. Using this xenograft model we showed that treatment with liposomal gemcitabine (GemLip) inhibited growth of the primary tumors (83.9 +/- 6.4%; P = 0.009) as well as metastatic burden in lymph nodes (95.6 +/- 24.0%; P = 0.047), lung (86.5 +/- 10.5%; P = 0.015), kidney (88.4 +/- 9.2%; P = 0.045) and stomach (79.5 +/- 6.6%; P = 0.036) already at very low efficient concentrations (8 mg/kg) as compared to conventional gemcitabine (360 mg/kg). Our data show that this orthotopic LNCaP xenograft PCa model seems to reflect the clinical situation characterized by the fact that at time of diagnosis, prostate neoplasms are biologically heterogeneous and thus, it is a useful model to investigate new anti-metastatic therapies.

Liposomal gemcitabine (GemLip)-efficient drug against hormone-refractory Du145 and PC-3 prostate cancer xenografts.

BACKGROUND: Gemcitabine (Gemc) is an efficient chemotherapeutic drug in various cancer types (e.g., pancreas) but has only limited effects on hormone-refractory prostate cancer (HRPCa). Since HRPCa cells are highly sensitive to even low doses of Gemc in vitro, the lack of clinical effects might be due to rapid degradation of Gemc by deaminases combined with impaired accumulation in tumor tissue and PCa cells. Liposomal formulation (GemLip) is expected to protect the entrapped cytotoxic substance from enzymatic degradation and furthermore augment its accumulation within tumor tissues due to an enhanced permeability of the tumor vessels. METHODS: Anti-tumoral and anti-metastatic activity of GemLip and Gemc were investigated in two luciferase-expressing, human hormone-refractory PC-3 and Du145 HRPCa xenograft models in immunodeficient mice. Tumor growth was monitored by in vivo luminescence imaging (orthotopic) or callipering (subcutaneous). Anti-metastatic effects of treatment were determined by in vitro luciferase assay of the tissues. RESULTS: Tumor growth of subcutaneous Du145 xenografts was significantly inhibited only by GemLip (8 mg/kg: P = 0.014 and 6 mg/kg: P = 0.011) but not by conventional Gemc (360 mg/kg). In contrast, growth of orthotopic PC-3 xenografts was significantly inhibited by both, GemLip (P = 0.041) and Gemc (P = 0.002). The drugs furthermore strongly reduced spleen and liver metastases in this model. CONCLUSIONS: As shown by the very low efficient concentration of GemLip, liposomal entrapment of Gemc greatly enhances its activity. GemLip has, even at very low doses, a significant anti-tumoral and anti-metastatic therapeutic effect in HRPCa xenografts in vivo and was beneficial even when the conventional Gemc failed.

Development of novel chimeric transmembrane proteins for multimodality imaging of cancer cells.

Tracking the migration of cancer cells is essential to understanding the metastatic process. In order to facilitate the tracking of metastatic progression, we have generated transgenic cancer cell lines that express novel chimeric proteins composed of truncated human type II transmembrane proteins fused in-frame to a red fluorescence protein. These chimeric proteins have been engineered to display the fluorescence domain on the surface of cells. The three novel chimeric proteins exhibited high transient expression in several cancer cell lines. Membrane expression was well characterized in MCF-7 cell lines that stably express the chimeric proteins. Indirect immunocytochemistry of non-premeablized cells demonstrated co-localization of endogenous red and green fluorescence labeled secondary antibody bound on the cell surfaces. Immunoblots of total protein prepared from membrane, cytosolic and nuclear fractions indicated that the chimeric proteins were mainly associated with the membrane fraction. Further evidence of the membrane expression of these proteins was confirmed by confocal microscopy. Moreover, the chimeric protein was detected on the cell surface by T2-weighted magnetic resonance imaging using anti-red fluorescence protein antibody and superparamagnetic iron oxide particles in vitro and by optical imaging in vivo. The development of this non-mammalian cell surface marker, that can be detected by multi-modality imaging, will find utility in non-invasive longitudinal tracking of biological processes including metastatic progression, solid tumor treatment regimes and the fate of cells used in cell therapies such as islet or stem cells.

Noninvasive optical tracking of red fluorescent protein-expressing cancer cells in a model of metastatic breast cancer.

We have evaluated the use of the Xenogen IVIS 200 imaging system for real-time fluorescence protein-based optical imaging of metastatic progression in live animals. We found that green fluorescent protein-expressing cells (100 x 10(6)) were not detectable in a mouse cadaver phantom experiment. However, a 10-fold lower number of tdTomato-expressing cells were easily detected. Mammary fat pad xenografts of stable MDA-MB-231-tdTomato cells were generated for the imaging of metastatic progression. At 2 weeks postinjection, barely palpable tumor burdens were easily detected at the sites of injection. At 8 weeks, a small contralateral mammary fat pad metastasis was imaged and, by 13 weeks, metastases to lymph nodes were detectable. Metastases with nodular composition were detectable within the rib cage region at 15 weeks. 3-D image reconstructions indicated that the detection of fluorescence extended to approximately 1 cm below the surface. A combination of intense tdTomato fluorescence, imaging at > or = 620 nm (where autofluorescence is minimized), and the sensitivity of the Xenogen imager made this possible. This study demonstrates the utility of the noninvasive optical tracking of cancer cells during metastatic progression with endogenously expressed fluorescence protein reporters using detection wavelengths of > or = 620 nm.