Mammalian target of rapamycin signaling activation patterns in neuroendocrine tumors of the lung

Righi, Luisella; Volante, Marco; Rapa, Ida; Tavaglione, Veronica; Inzani, Frediano; Pelosi, Giuseppe; Papotti, Mauro

doi:10.1677/erc-10-0157

Cited by 81 publications

(65 citation statements)

References 40 publications

(44 reference statements)

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“…Our results agreed with the conclusions of the study conducted on 218 clinically malignant BP-NETs by Righi et al, who revealed a statistically significant higher expression level of p-mTOR in well-differentiated neuroendocrine tumors compared to high-grade carcinomas (29).…”

Section: Lesion Type P-akt Expression (No Of Patients) P-mtor Expressupporting

confidence: 93%

“…Other studies have also investigated the p-AKT/p-mTOR pathway in BP-NETs, but their analysis of the percentage of immunoreactive tumor cells was combined with the staining intensity of the cells (26)(27)(28)(29). We decided to analyze our cases using only the percentage of positive cells, as our experience has indicated that the scoring system is highly subjective.…”

Section: Lesion Type P-akt Expression (No Of Patients) P-mtor Expresmentioning

confidence: 99%

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Expression of p-AKT and p-mTOR in a large series of bronchopulmonary neuroendocrine tumors

Alì

Boldrini

Capodanno

et al. 2011

Experimental and Therapeutic Medicine

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Abstract. Bronchopulmonary neuroendocrine tumors (BP-NETs) are separated into four subgroups: typical carcinoid tumor (TC), atypical carcinoid tumor (AC), large-cell neuroendocrine carcinoma (LCNEC) and small-cell lung carcinoma (SCLC). The signaling pathway involving AKT/ mammalian target of rapamycin (mTOR) is crucial to the regulation of cell growth, proliferation and survival, and is frequently activated in human cancers. Consequently, mTOR is considered an attractive target for anticancer agents. The present study aimed to evaluate the expression of phosphorylated AKT and mTOR in a series of BP-NETs, and to analyze the correlations with clinicopathological parameters. p-AKT and p-mTOR levels were determined by immunohistochemistry in a series of 210 BP-NETs, including 85 SCLCs, 17 LCNECs, 26 ACs, 75 TCs and 7 tumorlets. Higher p-AKT and p-mTOR expression levels were identified in the majority of tumorlets and carcinoids in comparison to the LCNECs (P=0.0001) and SCLCs (P=0.0002). Furthermore, a significant association was observed between p-mTOR expression and tumor size (T) in SCLCs (P=0.04) and LCNECs (P=0.03): T3-T4 tumors exhibited significantly lower p-mTOR expression compared to T1-T2 tumors. In conclusion, most of the BP-NETs examined in this study expressed p-AKT and p-mTOR, suggesting that the AKT/mTOR pathway plays an important role in these tumors. Additionally, our results confirm that low-to intermediate-grade tumors are more closely associated to each other than to high-grade tumors, despite sharing common classification and a common origin from neuroendocrine cells. These findings improve our knowledge of the biological characterization of these tumors and indicate new therapeutic opportunities for the treatment of BP-NETs.

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Section: Lesion Type P-akt Expression (No Of Patients) P-mtor Expressupporting

confidence: 93%

Section: Lesion Type P-akt Expression (No Of Patients) P-mtor Expresmentioning

confidence: 99%

Expression of p-AKT and p-mTOR in a large series of bronchopulmonary neuroendocrine tumors

Alì

Boldrini

Capodanno

et al. 2011

Experimental and Therapeutic Medicine

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“…However, an association of the activated mTOR pathway with a better patient prognosis has been reported (Noske et al 2008, Anagnostou et al 2009) as well. In one study on bronchial NETs, no prognostic impact of mTOR pathway components was reported (Righi et al 2010). We found that although mTOR expression itself was not associated with differences in patient prognosis, the detection of activated S6K confers a poor prognosis in stage IV midgut NETs.…”

Section: Discussionmentioning

confidence: 49%

“…These in vitro results are in line with our findings that mTOR expression as well as downstream activation of 4EBP1, eIF4E and S6K correlates with proliferation in GEP-NET. Most recently, in analogy to our work in GEP-NET, a large study on the expression of mTOR pathway components in lung NETs has been published in this journal (Righi et al 2010). The authors reported an overexpression of p-4EBP1 in high-grade tumours, in contrast to p-mTOR and p-S6K, which were strongly expressed in low-grade tumours.…”

Section: Discussionmentioning

confidence: 67%

mTOR expression and activity patterns in gastroenteropancreatic neuroendocrine tumours

Kasajima¹,

Pavel²,

Darb‐Esfahani³

et al. 2010

Endocrine Related Cancer

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Clinical trials indicate efficacy of drugs inhibiting the mammalian target of rapamycin (mTOR) in the treatment of gastroenteropancreatic neuroendocrine tumours (GEP-NET); however, information on detailed expression and activity patterns of mTOR in these tumours is sparse. We investigated the expression of mTOR and expression as well as phosphorylation of its downstream targets 4EBP1, S6K and eIF4E in a cohort of 99 human GEP-NET by immunohistochemistry. We correlated our findings with clinicopathological variables and patient prognosis. We found that 61, 93, 80, 69, 57 and 79% of GEP-NET were positive for mTOR, 4EBP1, cytoplasmic phospho-4EBP1 (p-4EBP1), nuclear p-4EBP1, phospho-S6K (p-S6K) and phospho-eIF4E (p-eIF4E) respectively. mTOR expression and activity were higher in foregut than in midgut tumours. In foregut tumours, expression of mTOR was higher when distant metastases were present (PZ0.035). Strong mTOR activity was associated with higher proliferative capacity. In patients with stage IV midgut tumours, strong p-S6K expression was associated with poor disease-specific survival (PZ0.048). In conclusion, mTOR shows considerable variations in expression and activity patterns in GEP-NET in dependence of tumour location and metastatic status. We hypothesise that these differences in mTOR expression and activity might possibly influence response to mTOR inhibitors.

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“…Recent in vitro studies indicate that somatostatin receptors are overexpressed in metastatic typical carcinoid tumors of the lung [8] and that the mTOR is found in most lung NETs with higher expression in typical and atypical carcinoids (see Figure 3). [19].…”

Section: Management Of Advanced/metastatic Diseasementioning

confidence: 99%

Update on Therapeutic Strategy in Lung Carcinoids

Pusceddu¹,

Vitali²,

Haspinger³

et al. 2013

JCT

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An estimated 25% to 30% of all neuroendocrine tumors (NETs) have their origin in the bronchial tree and into the lungs. Although lung NETs account for less than 1% of all pulmonary malignancies, the incidence of these neoplasms has risen precipitously since the mid 1970s. Currently, according to the 2004 World Health Organization categorization, these tumors are separated into 4 subtypes characterized by increasing biologic aggressiveness: low-grade typical carcinoid (TC), intermediate-grade atypical carcinoid (AC), high-grade large-cell neuroendocrine carcinoma (LCNEC) and small-cell carcinoma (SCLC). Surgery is the treatment of choice for typical and atypical carcinoid lung NETs with loco-regional disease. At diagnosis up to 64% of patients with atypical carcinoid lung NETs present with lymph node metastases, and 5-year survival ranges from 61% to 88%. In contrast, lymph node metastases are present in fewer than 15% of typical carcinoid lung NETs, and 5-year survival exceeds 90%. To date, there is no recognized standard of treatment for advanced carcinoid lung NETs. In recent years only two trials reported intriguing results regarding lung NETs: a phase 2 retrospective study of dacarbazine derivative temozolomide and the phase 3, RADIANT-2 trial in advanced NETs. Successful management requires a multidisciplinary team management. This review is restricted to typical/atypical NETs.

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Mammalian target of rapamycin signaling activation patterns in neuroendocrine tumors of the lung

Cited by 81 publications

References 40 publications

Expression of p-AKT and p-mTOR in a large series of bronchopulmonary neuroendocrine tumors

Expression of p-AKT and p-mTOR in a large series of bronchopulmonary neuroendocrine tumors

mTOR expression and activity patterns in gastroenteropancreatic neuroendocrine tumours

Update on Therapeutic Strategy in Lung Carcinoids

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