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Prostatic tumor regrowth after initially successful castration therapy may be related to a decreased apoptotic cell
M Landström1, J E Damber, A Bergh
1Department of Pathology, University of Umeå, Sweden.
Abstract:
Castration of rats transplanted with the androgen-sensitive Dunning R3327-PAP prostatic tumor results initially in a reduction of tumor growth, but after some time, some of the tumors start to grow again. The relapsed, androgen-insensitive PAP tumor shows a dedifferentiated morphology. In the present study, we examined whether this androgen-independent tumor regrowth was due to an increased cell proliferation rate or to a reduction of the number of tumor cells dying by apoptosis. Nine rats (with 18 tumors) were castrated and followed for 16 to 20 weeks. Six of the tumors increased their volume markedly (relapsed), while 12 remained relatively stable (nonrelapsed). The mitotic index and apoptotic index for epithelial cells were examined by light microscopy. Tumor growth rate correlated negatively both to the apoptotic index identified by morphological criteria (RS = -0.82; P < 0.0001) and to the apoptotic index identified by in situ end labeling (RS = -0.83; P < 0.0001). The tumor growth rate percentage did not correlate to the mitotic index, and it was negatively correlated (RS = -0.62; P < 0.01) to the number of cells immunostained for proliferating cell nuclear antigen. It is suggested that one initial event during the androgen-independent prostatic tumor regrowth in the PAP relapse model might be a reduction of the number of tumor cells being depleted by apoptosis, rather than an increase of cell proliferation rate.
Insights
Androgen-independent prostate tumor regrowth in rats is linked to reduced apoptosis (programmed cell death), not increased cell proliferation. This finding is crucial for understanding prostate cancer relapse after castration.
Area of Science:
- Oncology
- Cell Biology
- Urology
Background:
- Androgen-sensitive Dunning R3327-PAP prostatic tumors in rats initially regress after castration.
- Some tumors develop resistance, becoming androgen-insensitive and exhibiting dedifferentiated morphology.
- The mechanisms driving this relapse, whether increased proliferation or decreased apoptosis, require clarification.
Purpose of the Study:
- To investigate the cellular mechanisms behind androgen-independent prostate tumor regrowth in the Dunning R3327-PAP rat model.
- To determine if relapsed tumors exhibit increased cell proliferation or reduced apoptosis compared to non-relapsed tumors.
Main Methods:
- Castration of rats bearing Dunning R3327-PAP tumors.
- Monitoring tumor volume changes over 16–20 weeks to identify relapsed (markedly increased volume) and non-relapsed (stable volume) tumors.
- Analysis of mitotic and apoptotic indices in epithelial cells using light microscopy and in situ end labeling.
- Immunostaining for proliferating cell nuclear antigen (PCNA).
Main Results:
- Tumor growth rate strongly correlated negatively with apoptotic indices (morphological and in situ end labeling).
- Tumor growth rate did not correlate with the mitotic index.
- Tumor growth rate negatively correlated with PCNA-positive cells, indicating reduced proliferation in growing tumors.
- Relapsed tumors showed a reduced apoptotic index compared to non-relapsed tumors.
Conclusions:
- Androgen-independent prostate tumor regrowth in this model is primarily associated with a reduction in tumor cell apoptosis.
- An increase in cell proliferation rate is unlikely to be the initial event driving androgen-independent tumor regrowth.
- Targeting apoptosis pathways may be a therapeutic strategy for managing prostate cancer relapse.