Expression of mTORC1/2-related proteins in primary and brain metastatic lung adenocarcinoma
Ildikó Krencz1, Anna Sebestyén2, Katalin Fábián3
11st Department of Pathology and Experimental Cancer Research, Semmelweis University, 1085 Budapest, Hungary.
Abstract:
Brain metastases (BMs) are common complications of adenocarcinomas (ADCs) of the lung and are associated with a poor prognosis. Although an increasing amount of data indicates that dysregulated activity of mammalian target of rapamycin (mTOR) can influence the metastatic potential of various tumors, the role of mTOR complexes in the development of BMs from ADCs of the lung is largely unknown. To estimate mTOR activity, we studied the expression of mTOR-related proteins (mTORC1: p-mTOR, p-S6; mTORC2: p-mTOR, Rictor) in primary (n=67) and brain metastatic (n=67) lung ADCs, including 15 paired tissue samples, using immunohistochemistry and tissue microarrays. Correlation with clinicopathological parameters was also analyzed. Increased p-mTOR, p-S6, and Rictor expressions were observed in 34%, 33%, and 37% of primary ADCs and in 79%, 70%, and 66% of BMs, respectively. Expression of these markers was significantly higher in BMs as compared with primary carcinomas (P<.0001, P<.0001, P<.001). Rictor expression was significantly higher in primary ADCs of the paired cases with BMs as compared with primary ADCs without BMs (67% versus 28%; P<.01). No other statistically significant correlations were found between mTOR activity and clinicopathological parameters. The increased mTORC1/C2 activity in a subset of pulmonary ADCs and the higher incidence of increased mTORC1/C2 activity in BMs suggest that the immunohistochemistry panel for characterizing mTOR activity and its potential predictive and prognostic role warrants further investigations.
Insights
Increased activity of the mammalian target of rapamycin (mTOR) pathway, specifically mTORC1 and mTORC2, is linked to brain metastases in lung adenocarcinomas. This suggests mTOR pathway alterations play a role in lung cancer brain metastasis development.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Brain metastases (BMs) are frequent in lung adenocarcinomas (ADCs), leading to poor prognoses.
- The mammalian target of rapamycin (mTOR) pathway's role in tumor metastasis is recognized, but its specific involvement in lung ADC BMs is unclear.
Purpose of the Study:
- To investigate the activity of mTOR complexes (mTORC1 and mTORC2) in primary lung ADCs and their corresponding brain metastases.
- To correlate mTOR activity markers with clinicopathological parameters in lung ADC.
Main Methods:
- Immunohistochemistry and tissue microarrays were used to assess the expression of mTOR-related proteins (p-mTOR, p-S6, Rictor) in 67 primary lung ADCs and 67 BMs.
- Analysis included 15 paired primary and metastatic samples.
- Clinicopathological correlations were performed.
Main Results:
- Significantly higher expression of p-mTOR, p-S6, and Rictor was found in BMs compared to primary lung ADCs (P<.0001, P<.0001, P<.001).
- Rictor expression was significantly elevated in primary ADCs from patients with BMs versus those without (67% vs. 28%, P<.01).
- No significant correlations were observed between mTOR activity and other clinicopathological parameters.
Conclusions:
- Increased mTORC1 and mTORC2 activity is prevalent in lung ADC brain metastases.
- Elevated mTOR activity, particularly Rictor expression in primary tumors, may be associated with the development of brain metastases.
- Further research into mTOR pathway markers for predicting and prognosticating lung ADC BMs is warranted.
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