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Molecular markers of the
mTOR pathway activation in human tumors: A baseline analysis
F. Rojo, C. Iglesias, J. Tabernero, J. Jimenez, S. Rodriguez, J. Bellmunt, S.
Ramon, J. Baselga
Vall d'Hebron University Hospital, Barcelona, Spain
Background. Activation of the PI3-K/Akt/mTOR signal transduction pathway
contributes to the development and progression of tumors by prevention of
apoptosis and deregulation of the cell cycle.
Dissecting the molecular events of this pathway may provide instrumental
knowledge with implications for the development of PI3K/Akt/mTOR inhibitors and
multi-signalling inhibitory strategies.
Methods. We have analysed 121 paraffin-embedded human malignant tumors:
25 gastric, 25 colon, 23 breast, 19 prostate, 19 glioblastoma and 10 pancreas,
with a complete immunohistochemistry profile including multiple phosphorylated
(p) downstream proteins: pAkt, p4EBP1, pp70S6K and pS6K.
The levels of expression were evaluated as percentage and intensity of stained
cells (Hscore).
Results. Globally, there was a significant correlation between the levels
of pAkt, p4EBP1, pp70S6K and pS6K (Spearman’s test, p<0.001).
pAkt expression was consistently high in all tumor types whereas the downstream
effectors presented higher expression in pancreatic, breast, prostatic and
glioblastoma than in gastric and colon tumors (table).
pAkt and downstream effectors were mainly detected in the infiltrating edge of
the tumor.
Interestingly, pAkt and downstream effectors where highly expressed in the
poor-differentiated areas of the tumor whereas in the well-differentiated areas
only pAkt was highly expressed.
Conclusions. Detection of p molecules of the Akt/mTOR pathway is feasible
in a variety of tumor types.
As new agents targeting the PI3-K/Akt/mTOR pathway are entering in the clinic,
our findings suggest that the level of in vivo activation of these
downstream proteins could be used to establish correlations with response.
Pharmacodynamic studies aimed to determine the degree of inhibition of this
pathway in the tumor might be relevant to establish the optimal biological dose
of these compounds.
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Global
n (%)
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Gastric
n (%)
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Colon
n (%)
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Breast
n (%)
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Prostate
n (%)
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Glioblastoma
n (%)
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Pancreas
n (%)
|
|
n
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121
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25
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25
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23
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19
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19
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10
|
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pAkt expression
|
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14 (56)
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15 (60)
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16 (69.5)
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19 (100)
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13 (68.4)
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8 (80)
|
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p4EBP1 expression
|
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4 (16)
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6 (24)
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15 (65.2)
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17 (89.4)
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13 (68.4)
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9 (90)
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pS6K expression
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7 (28)
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9 (36)
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15 (65.2)
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15 (78.9)
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10 (52.6)
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8 (80)
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pp70S6K expression
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4 (16)
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8 (32)
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15 (65.2)
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11 (57.8)
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8 (42.1)
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7 (70)
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Copyright 2004 American Society of Clinical Oncology All rights
reserved worldwide.
Source: http://www.asco.org/ac/1,1003,_12-002636-00_18-0026-00_19-003213,00.asp
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