| 1. |
- Bäck, Tom, 1964, et al.
(författare)
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Targeted alpha therapy with astatine-211-labeled anti-PSCA A11 minibody shows antitumor efficacy in prostate cancer xenografts and bone microtumors
- 2020
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Ingår i: Ejnmmi Research. - : Springer Science and Business Media LLC. - 2191-219X. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Purpose Targeted alpha therapy (TAT) is a promising treatment for micrometastatic and minimal residual cancer. We evaluated systemic alpha-radioimmunotherapy (alpha-RIT) of metastatic castration-resistant prostate cancer (mCRPC) using the alpha-particle emitter At-211-labeled to the anti-PSCA A11 minibody. A11 is specific for prostate stem cell antigen (PSCA), a cell surface glycoprotein which is overexpressed in more than 90% of both localized prostate cancer and bone metastases. Methods PC3-PSCA cells were implanted subcutaneously (s.c.) and intratibially (i.t) in nude mice. Efficacy of alpha-RIT (two fractions-14-day interval) was studied on s.c. macrotumors (0, 1.5 and 1.9 MBq) and on i.t. microtumors (100-200 mu m; 0, 0.8 or 1.5 MBq) by tumor-volume measurements. The injected activities for therapies were estimated from separate biodistribution and myelotoxicity studies. Results Tumor targeting of At-211-A11 was efficient and the effect on s.c. macrotumors was strong and dose-dependent. At 6 weeks, the mean tumor volumes for the treated groups, compared with controls, were reduced by approximately 85%. The separate myelotoxicity study following one single fraction showed reduced white blood cells (WBC) for all treated groups on day 6 after treatment. For the 0.8 and 1.5 MBq, the WBC reductions were transient and followed by recovery at day 13. For 2.4 MBq, a clear toxicity was observed and the mice were sacrificed on day 7. In the long-term follow-up of the 0.8 and 1.5 MBq-groups, blood counts on day 252 were normal and no signs of radiotoxicity observed. Efficacy on i.t. microtumors was evaluated in two experiments. In experiment 1, the tumor-free fraction (TFF) was 95% for both treated groups and significantly different (p < 0.05) from the controls at a TFF of 66%). In experiment 2, the difference in TFF was smaller, 32% for the treated group versus 20% for the controls. However, the difference in microtumor volume in experiment 2 was highly significant, 0.010 +/- 0.003 mm(3) versus 3.79 +/- 1.24 mm(3) (treated versus controls, respectively), i.e., a 99.7% reduction (p < 0.001). The different outcome in experiment 1 and 2 is most likely due to differences in microtumor sizes at therapy, or higher tumor-take in experiment 2 (where more cells were implanted). Conclusion Evaluating fractionated alpha-RIT with At-211-labeled anti-PSCA A11 minibody, we found clear growth inhibition on both macrotumors and intratibial microtumors. For mice treated with multiple fractions, we also observed radiotoxicity manifested by progressive loss in body weight at 30 to 90 days after treatment. Our findings are conceptually promising for a systemic TAT of mCRPC and warrant further investigations of At-211-labeled PSCA-directed vectors. Such studies should include methods to improve the therapeutic window, e.g., by implementing a pretargeted regimen of alpha-RIT or by altering the size of the targeting vector.
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| 2. |
- Gustavsson, Helene, 1977, et al.
(författare)
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ADAMTS1, a putative anti-angiogenic factor, is decreased in human prostate cancer.
- 2009
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Ingår i: BJU international. - 1464-410X .- 1464-4096. ; 104:11, s. 1786-90
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To investigate the expression of 'ADAM metallopeptidase with thrombospondin type I motif, 1' (ADAMTS1) in human prostate cancer, and to study its relationship to microvessel density (MVD) and metastasis. ADAMTS1 has been described as an anti-angiogenic and antitumour factor, but its function in prostate cancer is unknown. PATIENTS AND METHODS: ADAMTS1 expression was evaluated by immunohistochemistry in specimens obtained by transurethral resection of the prostate from patients with hormone-naïve and hormone-refractory prostate tumours, including adjacent benign tissue. A semiquantitative scoring system was used for evaluating the staining. MVD was quantified by counting the number of CD34-positive blood vessels. RESULTS: ADAMTS1 was strongly expressed in the luminal epithelial cells in benign prostate glands, whereas expression was significantly lower in prostate cancer cells. There was no obvious difference between hormone-naïve and hormone-refractory tumours, and ADAMTS1 expression did not correlate with Gleason score. However, in hormone-refractory tumours from patients with metastatic disease, the expression of ADAMTS1 was significantly lower than in tumours from patients without metastases. Furthermore, the MVD was higher in hormone-refractory than in hormone-naïve tumours and benign tissue, and MVD correlated with Gleason score. There was no association between ADAMTS1 and MVD in the hormone-naïve tumours, while hormone-refractory tumours with low ADAMTS1 expression had a higher MVD than those with moderate/high expression. CONCLUSION: ADAMTS1 expression is decreased in prostate cancer, and might be involved in the early steps of prostate cancer development. Further, ADAMTS1 might have an anti-angiogenic and antimetastatic role in hormone-refractory prostate cancer, where low ADAMTS1 expression is associated with a high MVD and metastasis.
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| 3. |
- Gustavsson, Helene, 1977, et al.
(författare)
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ADAMTS1 alters blood vessel morphology and TSP1 levels in LNCaP and LNCaP-19 prostate tumors.
- 2010
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Ingår i: BMC cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Decreased expression of the angiogenesis inhibitor ADAMTS1 (ADAM metallopeptidase with thrombospondin type 1 motif, 1) has previously been reported during prostate cancer progression. The aim of this study was to investigate the function of ADAMTS1 in prostate tumors.
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| 4. |
- Gustavsson, Helene, 1977, et al.
(författare)
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Altered expression of genes regulating angiogenesis in experimental androgen-independent prostate cancer.
- 2008
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Ingår i: Prostate. - : Wiley. - 1097-0045. ; 68:2, s. 161-170
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND The aim of this study was to investigate how the expression of genes regulating angiogenesis is altered when prostate cancer cells progress into androgen-independency. METHODS A gene array specific for angiogenesis was used to compare the human prostate cancer cell line LNCaP (androgen-dependent) with its more angiogenic and tumorigenic subline LNCaP-19 (androgen-independent). Results were verified with real-time RT-PCR, and further investigations were focused on the angiogenesis inhibitor a disintegrin and metalloproteinase with thrombospondin motifs 1 (ADAMTS1). Expression of ADAMTS1 was investigated in vitro as well as in subcutaneous tumors with real-time RT-PCR and Western blotting. Microvessel density (MVD), versican proteolysis and protein levels of TIMP-2 and TIMP-3, known as ADAMTS1 inhibitors, were also analyzed in tumor xenografts. RESULTS The gene array revealed decreased expression of ADAMTS1, ephrin-A5, fibronectin 1, and neuropilin 1 in LNCaP-19 compared to LNCaP, while expression of midkine and VEGF were increased. Further studies showed that mRNA and protein levels of ADAMTS1 were significantly lower in LNCaP-19 compared to LNCaP, both in vitro and in subcutaneous tumors. The amount of ADAMTS1 correlated negatively with MVD, but no relation was found between ADAMTS1 and versican proteolysis. CONCLUSIONS Expression of several genes associated with angiogenesis was altered during transition into androgen-independency. Among these, a significant decrease was found for ADAMTS1, whose expression inversely correlated with MVD. Its role in progression of prostate cancer needs further investigation, but this inhibitor of angiogenesis could be an interesting candidate for future anti-angiogenic therapy.
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| 5. |
- Hagberg Thulin, Malin, et al.
(författare)
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Osteoblasts stimulate the osteogenic and metastatic progression of castration-resistant prostate cancer in a novel model for in vitro and in vivo studies.
- 2014
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Ingår i: Clinical & experimental metastasis. - : Springer Science and Business Media LLC. - 1573-7276 .- 0262-0898. ; 31:3, s. 269-283
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Tidskriftsartikel (refereegranskat)abstract
- Castration-resistant prostate cancer (CRPC) is strongly associated with sclerotic bone metastases and poor prognosis. Models that mimic human CRPC are needed to identify the mechanisms for prostate cancer (PC) growth in bone and to develop new therapeutic strategies. We characterize a new model, LNCaP-19, and investigate the interaction between tumor cells and osteoblasts in the sclerotic tumor response of CRPC. Osteogenic profiling of PC cell lines (LNCaP-19, LNCaP, C4-2B4, and PC-3) was performed by gene expression arrays and mineral staining. Conditioned medium from MC3T3-E1 was used for osteoblast stimulation of CRPC cells. The capacity of LNCaP-19 cells to induce sclerotic lesions was assessed in intratibial xenografts and verified by serum markers, histological analysis and bone mineral density (BMD) measurements. The CRPC cell line LNCaP-19 expresses a pronounced osteogenic profile compared to its parental androgen-dependent cell line LNCaP. Osteoblast-derived factors further increase the expression of genes known to enhance metastatic progressionof PC. LNCaP-19 forms sclerotic tumors in tibia of castrated mice as evident by increased total BMD (P<0.01). There was a strong correlation between serum osteocalcin and BMD (total: R (2) 0.811, P<0.01, trabecular: R (2) 0.673, P<0.05). For the first time we demonstrate that a CRPC cell line generated in vitro has osteogenic capacity and that osteomimicry can be an inherent feature of these cells. Osteoblast-derived factors further promote the osteogenic and metastatic phenotype in CRPC cells. Altogether, our model demonstrates that both tumor cells and osteoblasts are mediators of the bone forming process of CRPC.
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| 6. |
- Jennbacken, Karin, 1978, et al.
(författare)
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Inhibition of metastasis in a castration resistant prostate cancer model by the quinoline-3-carboxamide tasquinimod (ABR-215050)
- 2012
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Ingår i: The Prostate. - : Wiley. - 0270-4137 .- 1097-0045. ; 72:8, s. 913-924
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND Tasquinimod (ABR-215050) is an orally active quinoline-3-carboxamide analog that has completed phase II clinical trial in patients with castration resistant prostate cancer, showing promising inhibiting effects on the occurrence of metastasis and delayed disease progression. Its mechanism of action is not fully elucidated, but previous studies show anti-angiogenic effects and strong interaction with the S100A9 protein. METHODS This study was performed to evaluate if tasquinimod inhibits prostate cancer metastasis, by using both orthotopic and intratibial xenograft models. Animals were treated with tasquinimod, and tumor growth characteristics as well as molecular markers for metastasis and angiogenesis were analyzed. RESULTS The results show that formation of lung and lymph node metastases from orthotopic castration resistant prostate tumors was inhibited by tasquinimod treatment. Importantly, establishment of tumors in the bone after intratibial implantation was suppressed by tasquinimod. In addition, establishment and growth of subcutaneous tumors were affected. Both in primary tumors and serum from treated mice an upregulation of thrombospondin 1 was observed. Further, downregulation of the hypoxia driven genes VEGF, CXCR4, and LOX was detected in the primary tasquinimod-treated tumors and decreased expression of chemotactic ligand SDF-1 was demonstrated in the lungs. Thus, these molecular changes could contribute to the anti-angiogenic and anti-metastatic effects of tasquinimod. CONCLUSIONS In conclusion, this study and clinical data show that tasquinimod interferes with the metastatic process, presumably by inhibition of tumor establishment. Therefore, tasquinimod is an interesting treatment option for patients with prostate cancer prone to metastasis. Prostate 72:913924, 2012. (C) 2011 Wiley Periodicals, Inc.
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| 7. |
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| 8. |
- Jennbacken, Karin, 1978, et al.
(författare)
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Prostate cancer progression into androgen independency is associated with alterations in cell adhesion and invasivity.
- 2006
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Ingår i: Prostate. - : Wiley. ; 66:15, s. 1631-1640
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Tidskriftsartikel (refereegranskat)abstract
- Background Mortality in prostate cancer is primarily due to failure to cure hormone refractory patients with metastatic disease. The present study focused on elucidating alterations in invasive properties, which are connected with progression into androgen independency. Methods Ability to grow without anchor, migration, cell adhesion properties and expression of invasive factors were investigated in LNCaP and its androgen-independent subline LNCaP-19. Also, invasive capacity into blood vessels was examined in subcutaneous tumors. Results Transition into an androgen-independent state was associated with ability to grow without anchor, increased migration, and alterations in cell adhesion properties. The tumor suppressor E-cadherin was downregulated and the proinvasive factors N-cadherin, MMP-9, and membrane type 1 (MT1)-MMP were upregulated in LNCaP-19. In addition, LNCaP-19 displayed a markedly increased invasivity into blood vessels. Conclusions The results show that LNCaP-19 mimics hormone refractory prostate cancer and therefore is an excellent tool for studies on androgen-independent cancer and invasion. This study shows that transition into an androgen-independent state correlates with several proinvasive alterations. Prostate 66: 1631-1640, 2006. © 2006 Wiley-Liss, Inc.
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| 9. |
- Jennbacken, Karin, 1978, et al.
(författare)
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The prostatic environment suppresses growth of androgen-independent prostate cancer xenografts: an effect influenced by testosterone.
- 2009
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Ingår i: The Prostate. - : Wiley. - 1097-0045 .- 0270-4137. ; 69:11, s. 1164-75
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Interactions between prostate cancer cells and their surrounding stroma play an important role in the growth and maintenance of prostate tumors. To elucidate this further, we investigated how growth of androgen-dependent (AD) LNCaP and androgen-independent (AI) LNCaP-19 prostate tumors was affected by different microenvironments and androgen levels. METHODS: Tumor cells were implanted subcutaneously and orthotopically in intact and castrated immunodeficient mice. Orthotopic tumor growth was followed by magnetic resonance imaging (MRI). Gene expression in the tumors was evaluated by means of microarray analysis and microvessel density (MVD) was analyzed using immunohistochemistry. RESULTS: The results showed that LNCaP-19 tumors grew more rapidly at the subcutaneous site than in the prostate, where tumors were obviously inhibited. Castration of the mice did not affect ectopic tumors but did result in increased tumor growth in the prostatic environment. This effect was reversed by testosterone treatment. In contrast to LNCaP-19, the LNCaP cells grew rapidly in the prostate and castration reduced tumor development. Gene expression analysis of LNCaP-19 tumors revealed an upregulation of genes, inhibiting tumor growth (including ADAMTS1, RGS2 and protocadherin 20) and a downregulation of genes, promoting cell adhesion and metastasis (including N-cadherin and NRCAM) in the slow-growing orthotopic tumors from intact mice. CONCLUSIONS: The results show that the prostatic environment has a varying impact on AD and AI tumor xenografts. Data indicate that the androgen-stimulated prostatic environment limits growth of orthotopic AI tumors through induction of genes that inhibit tumor growth and suppression of genes that promote cell adhesion and metastasis.
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| 10. |
- Tomic, Tajana Tesan, et al.
(författare)
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Castration resistant prostate cancer is associated with increased blood vessel stabilization and elevated levels of VEGF and Ang-2.
- 2012
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Ingår i: The Prostate. - : Wiley. - 1097-0045 .- 0270-4137. ; 72:7, s. 705-12
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Tidskriftsartikel (refereegranskat)abstract
- Angiogenesis is important for the progression of prostate cancer and may be a target for treatment in castration resistant (CR) disease. This study was performed to investigate blood vessel stabilization and expression of the pro-angiogenic factors vascular endothelial growth factor (VEGF) and Angiopoietin-2 (Ang-2) in CR and hormone naïve (HN) prostate cancer. The effect of androgen deprivation therapy (ADT) on these parameters was also studied.
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