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

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Abstract

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.

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Abbreviations

PCa:

Prostate carcinoma

GemLip:

Liposomal gemcitabine

Gemc:

Gemcitabine

SCID:

Severe combined immunodeficiency disease

dFdC:

2′,2′-Difluoro-2′-deoxycytidine

RLU:

Relative light units

ph/s:

Photons per second

MTD:

Maximal tolerable dose

EPR:

Enhanced permeability and retention effect

GFP:

Green fluorescent protein

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Acknowledgments

This work was supported by the Dietmar Hopp Stiftung GmbH and the Kirstins Weg, Stiftung e.V.

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Author notes

  1. Alena Sukolinskaya

    Present address: N.N. Alexandrov National Cancer Center of Belarus, Minsk, Belarus

Authors and Affiliations

  1. Department of Clinical Research, Tumor Biology Center, Freiburg, Germany

    Peter Jantscheff, Vittorio Ziroli, Jessica Kluth, Alena Sukolinskaya, Lenka A. Taylor & Ulrich Massing

  2. ProQinase GmbH, Freiburg, Germany

    Norbert Esser & Ralph Graeser

  3. Clinic of Medical Oncology & Department of Clinical Research, Tumor Biology Center, Freiburg, Germany

    Clemens Unger

  4. Clinical Research, Department of Lipids & Liposomes, Tumor Biology Center, Breisacher Str.117, 79106, Freiburg, Germany

    Peter Jantscheff

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  1. Peter Jantscheff
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Correspondence to Peter Jantscheff.

Electronic supplementary material

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10585_2009_9288_MOESM1_ESM.tif

Supplementary Fig. 1 Effect of “orthotopic Co-culture” on CEACAM6 expression of LNCaP cells in vitro. GFP-luciferase fusion protein expressing, CEACAM-negative LNCaP cells were co-cultured in an “orthotopic PCa spheroid in vitro system“with ~ 1-2 mm3 spheroids of normal or PCa prostate tissue (P) for 4 - 21 days in 6-well plates. From individual spheroids epithelial Primary Spheroid Outgrowing Cells (PSOCs) were released into the culture. FACS scatter plots (A) show neither PSOCs from a pure spheroid culture (P90/2), nor GFP expressing, FL1-positive LNCaP cells (LNCaP), do significantly stain with a CEACAM6 specific antibody (9A6). In contrast, two co-cultures of spheroids, PSOCs, and LNCaP (P88/4 ortho and P90/2 ortho) display a striking shift of 10-35% LNCaP cells to CEACAM6 positive cells (right upper quadrant). Histograms (B) gating the GFP-expressing, FL-1 positive LNCaP cells only show a general shift of antigen expression of co-cultered cells (solid and dashed lines) compared to untreated LNCaP cells (black histogram). This shift of antigen expression (also CEACAM 1 is enhanced) was confirmed by staining of co-cultered LNCaP cells with pan-CEACAM (D14-HD11) or anti-CEACAM1 antibodies. In contrast to the “orthotopic Co-culture“DHT-treatment did not change antigen expression (not shown). Whether such changes are also involved in carrier-free implantation of LNCaP cells into mouse prostate tissue was not subject of the present study, but the efficient outgrow of the primary tumors and the strong metastatic spread accompanied by this mode of implantation support such assumptions. The use of luciferase/GFP fusion protein transduced LNCaP cells in the present model, however, will render the possibility to analyze these parameters in the next step [1]. Expression of the two markers not only allows highly sensitive detection of metastatic lesion in different tissues by luciferase in vivo and in vitro (Tab. 1, Fig. 6) but will also give the opportunity to analyze expression of distinct cell surface markers in GFP-expressing metastatic cells by cell flow cytometry in vitro [1]. Additionally it offers the possibility to isolate individual metastatic cells from small tissue-restricted metastases by FACS-sorting and to compare their cellular properties with parental and primary tumor cells (TIFF 3574 kb)

10585_2009_9288_MOESM2_ESM.tif

Supplementary Fig. 2 Tumor localization and delayed re-appearance of tumor growth (1 and 3 no treatment). (A) The figure shows inverted images from 5 min exposure at 10x10 binning before (1, 2) and after (3, 4) treatment (before treatment = time point of randomization; after treatment = final imaging). Three animals were analysed in each imaging set. Strong expansion of tumors (i.e. of luminescence signals) was seen in the vehicle control group (NaCl: iii and iv), whereas the GemLip 8 mg/kg (v) or Gemcitabine 360mg/kg treated groups (iii and vi) showed similar or reduced tumor signals after treatment. Also all other animals with primary imaging signals -despite of exclusion by randomization because of too weak or too strong signals- were also followed up on tumor development. The figure shows one animal (i) which was excluded by randomization from the experiment since it did not show any signal at this time point (1). An imageable tumor, however, developed only at the end of the observation period (3). (B) Figure shows orthotopic tumor localization on the right or left anterior prostate gland (arrows) by the overlay of imaging (5 min exposure at 10x10 binning) on light photographs of SCID mice (overlay corresponding to inverted images in A-4) (TIFF 1110 kb)

10585_2009_9288_MOESM3_ESM.docx

Tab 1supp. Reduction of percentage of animals with metastatic lesions and mean RLU values in different organs of orthotopic PCa models treated with GemLip or Gemc (DOCX 18 kb)

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Jantscheff, P., Ziroli, V., Esser, N. et al. Anti-metastatic effects of liposomal gemcitabine in a human orthotopic LNCaP prostate cancer xenograft model. Clin Exp Metastasis 26, 981–992 (2009). https://doi.org/10.1007/s10585-009-9288-1

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