Frequent Activation of the mTOR Pathway in Pancreatic Ductal Adenocarcinoma
AM Bellizzi, OH Iwenofu, XP Zhou, M Bloomston, WL Frankel. Ohio State University, Columbus, OH
Background: Mammalian target of rapamycin (mTOR) is a serine-threonine kinase critical to cell growth and proliferation. Activation of the PI3K/Akt/mTOR pathway has been described in various tumors. Previous studies have demonstrated loss of PTEN function (a tumor suppressor interacting with the pathway) and Akt amplification (a kinase directly upstream of mTOR) in a fraction of pancreatic ductal adenocarcinomas (PDAs). We utilized immunohistochemistry for PTEN, p-Akt, and p-S6rp (a major downstream effector of mTOR) to assess the status of the mTOR pathway in a group of PDAs.
Design: Tissue microarrays were constructed from 49 tumors; duplicate cores were taken from each. Slides were stained with antibodies to PTEN, p-Akt, and p-S6rp. Cases were scored as follows: PTEN (intact: 5% staining, lost), p-Akt (positive: 5% staining, negative), p-S6rp (0, 1+: modest intensity 5%, 2+: strong intensity 5%). Ducts in normal pancreas (NL, 12 cases) and chronic pancreatitis (CP, 27 cases) served as controls.
Results: A large number of the PDAs demonstrated loss of PTEN (41% of cases), while p-Akt was generally negative (84%). The majority of cases stained for p-S6rp (75%, 1+ in 33, 2+ in 3). PTEN was uniformly intact in NL and CP; p-Akt expression was frequent. While p-S6rp immunoreactivity was only noted in 1 NL control (8%), 1+ positivity was seen in 62% of CP. Results are summarized in the table.
mTOR Pathway Protein ExpressionData refers to number of cases
|PDA||intact: 29||positive: 8||0: 12|
|lost: 20||negative: 41||1+: 33|
|NL||intact: 10||positive: 12||0: 11|
|lost: 0||negative: 0||1+: 1|
|CP||intact: 27||positive: 18||0: 10|
|lost: 0||negative: 9||1+: 16|
Conclusions: mTOR pathway activation, as evidenced by p-S6rp immunoreactivity, is frequent in PDA. In most cases this appears to be independent of p-Akt status. Interestingly, p-S6rp expression was also noted in most cases of chronic pancreatitis, highlighting the possible importance of this pathway in both neoplastic and inflammatory processes. Given evidence of pathway activation and the existence of specific anti-mTOR therapeutics, mTOR may represent a logical target for directed biologic therapy.
Category: Liver & Pancreas
Wednesday, March 11, 2009 9:30 AM
Poster Session V # 230, Wednesday Morning