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High frequency of loss of PTEN expression in human solid salivary adenoid cystic carcinoma and its implication for
1Department of Oral Pathology, College of Stomatology, Dalian Medical University, Dalian, China.
Abstract:
Salivary gland tumor (SGT) is one of the least studied cancers due to its rarity and heterogeneous histological types. Here, we reported that loss of PTEN expression was most frequently found in the poorly differentiated, high grade solid adenoid cystic carcinomas. Loss of PTEN expression correlated with activation of mTOR by increased phosphorylated S6 ribosome protein. We further functionally studied the role of PTEN in a pair of human SACC cell lines, SACC-83 and SACC-LM. Reduced PTEN level was correlated with the metastasis potential. When we knocked down PTEN in the SACC-83 cell line, we observed increased proliferation and enhanced migration/invasion in vitro, and increased tumor size in vivo. We further tested the therapeutical effect by applying a PI3K/mTOR inhibitor NVP-BEZ235 to both SACC cell lines. Decreased cell proliferation, increased apoptosis, as well as reduced cell migration/invasion were observed in both cell lines upon the NVP-BEZ235 treatment. Moreover, the NVP-BEZ235 treatment in a SGT xenograft mouse model significantly reduced primary tumor size and lung metastasis. Taken together, our results demonstrated that PTEN is a potent tumor suppressor in human SGTs, and targeting PI3K/mTOR pathway may be effective in the targeted therapy for human SGT patients with loss of PTEN expression.
Insights
Loss of PTEN expression in salivary gland tumors promotes cancer growth and metastasis. Targeting the PI3K/mTOR pathway with NVP-BEZ235 shows therapeutic potential for these rare cancers.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Salivary gland tumors (SGTs) are rare and heterogeneous, making them difficult to study.
- PTEN (Phosphatase and tensin homolog) is a known tumor suppressor, but its role in SGTs is not well understood.
- Aberrant activation of the PI3K/mTOR pathway is implicated in various cancers.
Purpose of the Study:
- To investigate the role of PTEN expression in salivary gland adenoid cystic carcinomas (SACC).
- To explore the functional consequences of PTEN loss on SACC progression and metastasis.
- To evaluate the therapeutic efficacy of a PI3K/mTOR inhibitor in SGT models.
Main Methods:
- Analysis of PTEN expression in SGT patient samples, correlating with histological grade.
- Functional studies using human SACC cell lines (SACC-83, SACC-LM) with PTEN knockdown.
- In vitro assays for proliferation, migration, and invasion; in vivo studies using xenograft models.
- Treatment with PI3K/mTOR inhibitor NVP-BEZ235 in cell lines and mouse models.
Main Results:
- Loss of PTEN expression was frequent in poorly differentiated, high-grade SGTs and correlated with PI3K/mTOR pathway activation.
- Reduced PTEN levels enhanced SACC cell proliferation, migration, invasion in vitro, and tumor growth in vivo.
- NVP-BEZ235 treatment decreased proliferation, increased apoptosis, and reduced migration/invasion in SACC cell lines.
- In vivo, NVP-BEZ235 significantly reduced primary tumor size and lung metastasis in SGT xenografts.
Conclusions:
- PTEN acts as a crucial tumor suppressor in human SGTs, particularly in aggressive subtypes.
- Loss of PTEN promotes SGT progression and metastasis, likely through PI3K/mTOR pathway activation.
- Targeting the PI3K/mTOR pathway with inhibitors like NVP-BEZ235 represents a promising therapeutic strategy for SGT patients with PTEN loss.
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