| 1. |
- Damber, Jan-Erik, 1949, et al.
(författare)
-
The anti-tumour effect of low-dose continuous chemotherapy may partly be mediated by thrombospondin
- 2006
-
Ingår i: Cancer Chemother Pharmacol. - : Springer Science and Business Media LLC. - 0344-5704 .- 1432-0843. ; 58:3, s. 354-360
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Tumour growth is dependent on angiogenesis. Antiangiogenic chemotherapy, i.e. continuous or metronomic low-dose chemotherapy, is a method for administrating cytostatics at a low and well-tolerated concentration without prolonged breaks. The target is the genetically stable endothelial cells playing a pivotal role in angiogenesis within the tumour. Different mediators could mediate the antiangiogenic effect of metronomic chemotherapy. One of these mediators could be thrombospondin (TSP). TSP is a potent inhibitor of angiogenesis and might therefore be important in controlling tumour growth. This study was designed to evaluate the effects of low-dose continuous or moderate-dose bolus chemotherapy on tumour growth and on tumour expression of TSP. Materials and methods: Rats bearing a malignant prostate tumour (Dunning AT-1) not expressing TSP were treated systemically with cyclophosphamide, doxorubicin or paclitaxel and the combination of cyclophosphamide and doxorubicin. Tumour growth and body weight were measured during the treatment. CD36, one of TSP’s main receptors, was also analysed. The expression pattern of TSP-1, TSP-2 and CD36 was investigated using immunohistochemistry and Western blot analyses. Q-PCR was used to analyse TSP-1 mRNA expression. Results: Low-dose cyclophosphamide and paclitaxel re-induced the expression of TSP in the tumours. However, following a bolus dose of doxorubicin, tumours showed no expression of TSP. Both cyclophosphamide and doxorubicin treatments decreased the tumour weight by more than 60% compared with vehicle controls. When cyclophosphamide and doxorubicin were combined the tumour weight was reduced by 47%, while paclitaxel reduced the tumour weight by 18% compared to the vehicle controls. Conclusions: Systemic low-dose continuous treatment of a rat prostate cancer model with cyclophosphamide and paclitaxel induced the expression of TSP in tumour tissue and inhibited tumour growth. These findings support the hypothesis that the anti-tumour effect of low-dose metronomic chemotherapy, at least with certain chemotherapeutics, is partly mediated by induction of endogenous antiangiogenic factors.
|
|
| 2. |
- Jennbacken, Karin, 1978, et al.
(författare)
-
Expression of vascular endothelial growth factor C (VEGF-C) and VEGF receptor-3 in human prostate cancer is associated with regional lymph node metastasis.
- 2005
-
Ingår i: Prostate. - : Wiley. ; 65:2, s. 110-116
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND Vascular endothelial growth factor C (VEGF-C) and its receptor, VEGFR-3, have been implicated as important factors in the formation of lymphatic vessels and recent evidence suggests that tumor lymphangiogenesis promotes lymphatic metastasis. METHODS The expression of VEGF-C and VEGFR-3 was examined in 22 human prostate cancer specimens with immunohistochemistry. A semi-quantitative scoring system was used for evaluation of staining. RESULTS Expression of VEGF-C was stronger in prostate cancer areas in comparison to adjacent benign glands. In addition, patients with lymph node metastases had a significantly higher expression of VEGF-C than patients without lymph node metastases. Interestingly, VEGFR-3 was expressed in malignant prostate epithelial cells and its expression was significantly higher in the lymph node positive group compared to the lymph node negative group. CONCLUSIONS The results of the present study indicate that increased expression of VEGF-C and VEGFR-3 play a role in prostate cancer progression and in metastasis to regional lymph nodes. © 2005 Wiley-Liss, Inc.
|
|
| 3. |
- Jennbacken, Karin, 1978, et al.
(författare)
-
Prostate cancer progression into androgen independency is associated with alterations in cell adhesion and invasivity.
- 2006
-
Ingår i: Prostate. - : Wiley. ; 66:15, s. 1631-1640
-
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.
|
|
| 4. |
- Jennbacken, Karin, 1978, et al.
(författare)
-
The prostatic environment suppresses growth of androgen-independent prostate cancer xenografts: an effect influenced by testosterone.
- 2009
-
Ingår i: The Prostate. - : Wiley. - 1097-0045 .- 0270-4137. ; 69:11, s. 1164-75
-
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.
|
|
| 5. |
- Johansson, Mikael, et al.
(författare)
-
Tumor blood flow and the cytotoxic effects of estramustine and its constituents in a rat glioma model
- 1997
-
Ingår i: Neurosurgery. - : Oxford University Press. - 0148-396X .- 1524-4040. ; 41:1, s. 237-244
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Estramustine (EaM) is a conjugate of nor-nitrogen mustard (NNM) and 17 beta-estradiol (E2) that has cytotoxic and radiosensitizing effects on experimental malignant glioma. Its mechanism of action is only partly understood. To further investigate the mechanism in vivo, the effects on tumor blood flow (TBF) and tumor growth were analyzed.METHODS: TBF was measured by radioactive microspheres, and tumor growth was measured by weight. Apoptosis was evaluated by in situ end labeling and gel electrophoresis. The effects of the constituents NNM and E2 were also evaluated.RESULTS: EaM increased TBF to 153.8 ml/100 g/min after 3 days and to 153.9 ml/100 g/min after 10 days of treatment, compared with 94.0 ml/100 g/min in untreated controls. Cerebral blood flow did not change after EaM treatment. NNM increased TBF but also showed a tendency to increase cerebral blood flow. E2 increased TBF, whereas cerebral blood flow was unchanged. EaM resulted in a rapid reduction in tumor weight from 230 mg in untreated animals to 146 mg after 3 days of treatment. EaM induced an early transient fragmentation of deoxyribonucleic acid in glioma but not in the normal brain. Neither NNM nor E2 affected tumor weight.CONCLUSION: EaM increases TBF in the BT4C rat glioma model with a concomitant rapid antitumoral effect. The increase in TBF could partially be induced by an estrogen-like action of EaM, but the rapid cytotoxic effect of the drug is obviously attributed to the intact EaM compound. This cytotoxic effect might be attributable to the induction of programmed cell death.
|
|
| 6. |
- Nilsson, Jonas, et al.
(författare)
-
Cloning, characterization and expression of human LIG1
- 2001
-
Ingår i: Biochemical and Biophysical Research Communications - BBRC. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 284:5, s. 1155-1161
-
Tidskriftsartikel (refereegranskat)abstract
- Growth factor receptors are frequently amplified and over-expressed in various human cancers. Recently, a Drosophila cell surface protein, Kekkon-1, was found to participate in an epidermal growth factor (EGF) driven negative feedback loop. Kekkon-1 is induced by EGF, binds to the EGF-receptor, and inhibits receptor-mediated signaling. Here, we have searched for human genes with homologies to Kekkon-1 and identified human LIG1. The gene is the human homologue of mouse Lig-1 and is located on chromosome band 3p14, a region frequently deleted in various human cancers. It is predicted to encode a transmembrane cell-surface protein with extracellular leucine-rich repeats and immunoglobulin-like domains. LIG1 mRNA was detected in all tissues analyzed. The highest and lowest relative expression levels were found in brain and spleen, respectively, and differed by more than 200-fold. Taken together, our data are compatible with a role for LIG1 as a growth and tumor suppressor in human tissues.
|
|
| 7. |
- Vallbo, Christina, 1964, et al.
(författare)
-
The expression of thrombospondin-1 in benign prostatic hyperplasia and prostatic intraepithelial neoplasia is decreased in prostate cancer.
- 2004
-
Ingår i: BJU Int. - : Wiley. ; 93:9, s. 1339-1343
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE To evaluate the immunohistochemical expression of thrombospondin (TSP), a potent inhibitor of angiogenesis, in human benign prostatic hyperplasia (BPH) and prostate cancer. MATERIALS AND METHODS The expression of TSP-1, TSP-2 and CD36 receptor was assessed in 73 tissue specimens using immunohistochemistry; specimens were from 32 patients with BPH, seven with prostatic intraepithelial neoplasia (PIN) and 34 with cancer. RESULTS Immunohistochemistry showed that all 39 patients with BPH and PIN had TSP-1-positive glands. In contrast, none of the 34 patients with cancer had positive TSP-1 staining in the cancer tissue. All 73 patients were positive for TSP receptor CD36 and negative for TSP-2. CONCLUSIONS TSP is expressed in BPH, down-regulated in PIN and absent in prostate cancer tissue. This may indicate that TSP is important in prostate cancer progression. Further studies are needed to understand the significance of these findings for the malignant transformation of the prostate gland.
|
|
| 8. |
- Vallbo, Christina, 1964, et al.
(författare)
-
Thrombospondins, metallo proteases and thrombospondin receptors messenger RNA and protein expression in different tumour sublines of the Dunning prostate cancer model
- 2005
-
Ingår i: Acta Oncol. - : Informa UK Limited. ; 44:3, s. 293-298
-
Tidskriftsartikel (refereegranskat)abstract
- Thrombospondin is a potent inhibitor of angiogenesis and might therefore be important in controlling tumour growth. TSP interacts with a number of proteases and receptors and in this way inhibits stimulation of angiogenesis. An earlier study showed that thrombospondin is expressed in benign prostatic hyperplasia (BPH) and high-grade prostatic intraepithelial neoplasia (PIN) but is absent in prostate cancer. The present study was therefore designed to evaluate the expression of thrombospondin 1 and 2 (TSP-1, TSP-2), TSP receptors CD36 and CD47, and matrix-metalloproteases 2 and 9 (MMP-, MMP-9) in a rat prostate cancer model. By using immunohistochemistry, Western blot, and real-time PCR the expression patterns of TSP-1, TSP-2, CD36, CD47, MMP-2, and MMP-9 were investigated in normal rat prostate tissue and five malignant Dunning sublines tissue. TSP-1 mRNA levels were decreased in all tumours compared with normal prostate. However, there was no difference in expression of TSP-2 and CD36 mRNA in these samples. MMP-2 was increased with malignancy, but no expression of MMP-9 was seen. The CD47 receptor did slightly increase with malignancy except for H3327. The results showed that thrombospondin is expressed in normal prostate but not in prostate tumours in a rat model. Simultaneously, MMP-2 expression increases with malignancy.
|
|
