Given the recent identification of the mTOR pathway as a possible target for cancer therapy, the expression pattern of phosphorylated mTOR (p-mTOR) pathway components has attracted vivid scientific interest in several neoplasms, including primary cutaneous T cell lymphomas. However, published information examining crosstalk between AKT/mTOR cascade and interconnected signaling pathways in mycosis fungoides (MF) is limited.
We analysed immunohistochemically 54 skin biopsies (21 tumour and 33 plaque stage) from 50 patients with MF, for whom clinical information was available. Paraffin embedded tissue was stained for p-mTOR, its upstream p-AKT, its downstream effectors p-p70S6K and p-4E-BP1, as well as for p-ERK1/2 (extracellular signal-related kinase 1/2), the transcription factor Notch-1 and a member of the mammalian family of signal transducer activator of transcription, namely p-STAT-3. For statistical analysis only the predominant pattern i.e. cytoplasmic for p-mTOR, p-AKT, and NOTCH1 and nuclear for p-STAT3, p-p70S6K, p-4E-BP1 and p-ERK1/2 was taken into account. A Histo-score (H-score) based on the percentage of stained neoplastic cells (labelling index-LI) multiplied by staining intensity for each protein was calculated and was correlated with clinicopathological features and cancer-free (CSS), disease-free (DFS) and progression-free (PFS) survival.
p-p70S6K expression was recorded in all cases, whereas the rate of positivity for the remaining molecules ranged from 52.8% to 67.3%. p-mTOR was coexpressed with p-p70S6K in 67.3% of cases, but coexpression with other molecules was less common (27.4–38.5%). Notch-1 displayed higher H-scores in tumours than in plaques (p=0.0475), as previously demonstrated. The same applied to p-p70S6K, but this correlation was of borderline significance. Significant correlations were recorded between p-4E-BP1 and p-p70S6K (p=0.0019), p-ERK and p4E-BP1 (p=0.0588), as well as between Notch-1 and p-p70S6K (p=0.0001) and p-4E-BP1 (p=0.0003). The latter two correlations remained when plaques and tumours were analysed separately. Interestingly, p-STAT3 showed a weak positive correlation with p-AKT in the entire cohort, but when analysis was restricted to plaques this relationship became statistically significant (p=0.0419). Notch1, p-4E-BP1 and p-p70S6K expression were associated with advanced stage. In univariate survival analysis increased p-p70S6K (p=0.0174) and p-AKT (p=0.0198) H-scores as well as p-4E-BP-1 immunopositivity adversely affected CSS but not DFS in plaques, along with CD30 expression (p=0.0004). In particular, blood clonality affected both DFS and CSS, as well as time to disease progression (p=0.0009, p=0.0031 and p=0.0216 respectively). The CSS time was also substantially shortened for subjects with simultaneous overexpression of p-AKT and p-p70S6K along with p-4E-BP1 immunopositivity (p= 0.0001). On the contrary in the subgroup of tumours decreased p-STAT3 H-score was only parameter that adversely affected CSS in tumour stage (p=0.0394), with the presence of blood clonality attaining marginal significance in this regard.
Activation of AKT-mTOR components appears to have an intimate liaison with NOTCH1, p-ERK and p-STAT-3 and seems to be implicated in disease progression and in the acquisition of a more aggressive phenotype. Phosphorylation of several key components of this pathway, namely AKT, p70S6K and 4E-BP1 in MF, single or in combinations emerge as potential markers of prognostic value in plaque stage, whereas in tumours p-STAT-3 is brought forward as a favourable prognostic marker.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.