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Molecular mechanisms of melanoma metastasis
1Department of Cell Biology, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Abstract:
The molecular changes associated with the transition of melanoma cells from radial growth phase to vertical growth phase (metastatic phenotype) are not very well defined. Expression of the tyrosine-kinase receptor c-KIT progressively decreases during local tumor growth and invasion of human melanomas. To provide direct evidence that c-KIT plays a role in metastasis of human melanoma, we transfected the c-KIT gene into c-KIT-negative, highly metastatic human melanoma cells and subsequently analyzed their tumorigenic and metastatic potential in nude mice. Enforced c-KIT expression significantly inhibited tumor growth and metastasis. Exposure of c-KIT-positive melanoma cells in vitro and in vivo to stem cell factor (SCF), the ligand for c-KIT, triggered apoptosis of these cells but not of normal melanocytes. These results suggest that the loss of c-KIT receptor may allow malignant melanoma cells to escape SCF/c-KIT-mediated apoptosis, thus contributing to tumor growth and eventually metastasis. The expression of c-KIT and other genes associated with malignant melanoma (such as MCAM/MUC18) is highly regulated by the transcription factor AP-2. The AP-2 protein is not expressed in malignant melanoma cells. Therefore, loss of AP-2 expression might be a crucial event in the progression of human melanoma.
Insights
Loss of c-KIT receptor in melanoma cells promotes tumor growth and metastasis. Restoring c-KIT expression inhibits melanoma progression and triggers cancer cell death, suggesting c-KIT
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Melanoma progression involves poorly understood molecular changes from radial to vertical growth phases.
- Decreased expression of tyrosine-kinase receptor c-KIT correlates with tumor growth and invasion in human melanomas.
Purpose of the Study:
- To investigate the role of c-KIT in human melanoma metastasis.
- To determine if enforced c-KIT expression affects melanoma cell tumorigenicity and metastatic potential.
Main Methods:
- Transfection of the c-KIT gene into c-KIT-negative, highly metastatic human melanoma cells.
- Analysis of tumorigenic and metastatic potential in nude mouse models.
- In vitro and in vivo exposure of c-KIT-positive melanoma cells to stem cell factor (SCF).
Main Results:
- Enforced c-KIT expression significantly inhibited tumor growth and metastasis in mice.
- Exposure to SCF induced apoptosis in c-KIT-positive melanoma cells, but not normal melanocytes.
- Loss of AP-2 transcription factor expression may be critical for melanoma progression.
Conclusions:
- Loss of c-KIT receptor function may enable melanoma cells to evade SCF/c-KIT-mediated apoptosis, driving tumor growth and metastasis.
- Restoring c-KIT expression presents a potential therapeutic strategy for melanoma.
- The transcription factor AP-2 plays a significant role in regulating melanoma-associated gene expression and progression.