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Altered expression of G1 regulatory proteins in human soft tissue sarcomas
Jinyoung Yoo1, Sonya Y Park, Seok Jin Kang
1Department of Pathology, St Vincent's Hospital, Catholic University, South Korea.
Context:
Soft tissue sarcomas constitute a heterogeneous group of tumors for which tumorigenesis is not fully understood. Altered cell-cycle regulation may underlie the development and/or progression of human malignancies. However, data concerning the occurrence of cell-cycle aberrations in soft tissue sarcomas are very limited.
Objectives:
To detect the abnormal features of cell-cycle regulatory proteins in soft tissue sarcomas and to determine the potential role of these proteins in clinical behavior.
Design:
The p53 and Rb-cyclin D pathways were investigated by immunohistochemical studies of p53, mdm2, pRb, p16, cyclin D1, and cdk4 proteins, respectively.
Results:
Of the 67 sarcomas analyzed, nuclear accumulation of p53 was detected in 25 samples (37%), and overexpression of mdm2 was found in 16 samples (24%). Both p53 and mdm2 expression correlated with tumor grade. Abnormalities involving the Rb-cyclin D pathway were identified in all of the tumors by the altered expression of either pRb (72%) or p16 (94%). Fourteen (21%) and 64 (96%) cases demonstrated cyclin D1 or cdk4 expression, respectively. Overexpression of cyclin D1 showed an association with pRb and p53. There was no correlation between pRb, p16, cyclin D1, or cdk4 and tumor grade or relapse.
Conclusion:
Disturbance in the cell-cycle regulatory system involving the p53 pathway and the Rb-cyclin D pathway is relatively frequent in soft tissue sarcomas and may be a contributing factor in the tumorigenesis of these tumors. The alterations in the Rb-cyclin D pathway probably constitute an early event, whereas the abnormalities in the p53 pathway seem to be involved in tumor progression. It is noteworthy that cyclin D1 may play a key role in linking both pathways.
Insights
Cell-cycle regulatory protein abnormalities are frequent in soft tissue sarcomas, impacting tumorigenesis. The Rb-cyclin D pathway alterations appear early, while p53 pathway changes suggest roles in tumor progression.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Soft tissue sarcomas are a heterogeneous tumor group with poorly understood tumorigenesis.
- Altered cell-cycle regulation is implicated in human malignancies, but data in soft tissue sarcomas are limited.
Purpose of the Study:
- To identify abnormal cell-cycle regulatory proteins in soft tissue sarcomas.
- To correlate these protein abnormalities with clinical behavior.
Main Methods:
- Immunohistochemical analysis of p53, mdm2, pRb, p16, cyclin D1, and cdk4 proteins.
- Investigation of the p53 and Rb-cyclin D pathways in 67 soft tissue sarcomas.
Main Results:
- p53 nuclear accumulation (37%) and mdm2 overexpression (24%) correlated with tumor grade.
- Rb-cyclin D pathway abnormalities (pRb 72%, p16 94%) were found in all tumors.
- Cyclin D1 (21%) and cdk4 (96%) expression varied; cyclin D1 overexpression associated with pRb and p53.
Conclusions:
- Cell-cycle regulatory system disturbances, involving p53 and Rb-cyclin D pathways, are common in soft tissue sarcomas.
- Rb-cyclin D pathway alterations may be early events, while p53 pathway abnormalities are linked to tumor progression.
- Cyclin D1 may connect the p53 and Rb-cyclin D pathways.