Inhibition of Wnt-1 in human prostate cancer cells blocks prostate cancer cell proliferation, invasion, growth and skeletal metastasis in vitro and in vivo
Bibliographic record
Abstract
Proc Amer Assoc Cancer Res, Volume 47, 2006 3979 Prostate cancer is among the leading malignancies in men and is associated with a high incidence of skeletal metastases. Several studies have implicated the role of the Wnt/β-catenin pathway in a variety of malignancies including prostate cancer. In previous studies we have shown increased expression of Wnt-1 and β-catenin in highly invasive PC-3 human prostate cancer cells and in surgical biopsy specimens of prostate cancer patients with skeletal metastasis. In the current study, we evaluated the effects of inhibiting Wnt-1 in PC-3 cells using gene transfer technology. For these studies, full length cDNA encoding Wnt-1 was stably transfected into PC-3 cells in an antisense orientation. Three clones expressing the lowest levels of Wnt-1 (PC-3-Wnt-1-AS) were then selected These experimental cells exhibited a change in their morphology from spheroid to spindle shape and a decrease in cell adherence, proliferation and invasion as compared to the wild type cells and cells transfected with vector alone. These effects were associated with inhibition of E-cadherin, parathyroid hormone related peptide (PTHrP) and urokinase (uPA), genes which are involved in cell adhesion, proliferation and invasion respectively. The specificity of Wnt inhibition was confirmed by incubation of PC-3 cells with Wnt-1 antibody. In order to monitor the effect of Wnt-1 inhibition on tumor progression in vivo , male Balb c nu/nu mice were inoculated subcutaneously into the right flank with control and experimental cells. Animals inoculated with control cells developed primary tumors by 4 weeks post tumor cell inoculation and these continued to grow for the next 8 weeks. In contrast, animals inoculated with PC-3-Wnt-1-AS cells showed tumor development only at week 10 which exhibited a markedly slower rate of tumor growth. In order to evaluate the effect of Wnt-1 inhibition on experimental skeletal metastases, PC-3 and PC-3-Wnt-1-AS cells were inoculated into the tibia of male Fox Chase SCID mice. Radiological evidence of skeletal lesions was evident in tibias of 100% of animals inoculated with PC-3 cells. However only 10% of animals inoculated with PC-3-Wnt-1-AS cells showed any evidence of skeletal lesions as analyzed by X-ray, microCT and bone histomorphometric analyses. Furthermore immunohistochemical analysis of control and experimental primary tumors exhibited a marked inhibition of E-cadherin, PTHrP and uPA production in tumors from experimental animals inoculated with PC-3-Wnt-1-AS cells. The results obtained in these studies provide compelling evidence for the role of Wnt-1 and its signalling pathway in the establishment and progression of prostate cancer and its capacity to metastasize to the skeleton. Further elucidation of the role of this pathway will lead to the development of new strategies to block prostate cancer growth and metastasis in prostate cancer patients.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".