Frequent Aberrant Activation of the PI3K/Akt/mTOR Pathway in Pancreatic Endocrine Tumors
XP Zhou, WL Frankel, M Bloomston, OH Iwenofu, AM Bellizzi. Ohio State University, Columbus, OH
Background: Mammalian target of rapamycin (mTOR), a serine-threonine kinase, functions in the regulation of apoptosis, proliferation, and cell growth. Signaling through the PI3K/Akt/mTOR pathway results in increased translation of key mRNAs governing cell cycle progression and metabolism. Aberrant activation of this pathway, either by signaling through growth factor receptors, activating mutations/amplification of kinases, or by loss of function of the tumor suppressor PTEN, has been described in a number of human cancers. Utilizing immunohistochemistry for PTEN, p-Akt, p-mTOR, and p-S6rp (a target of mTOR activation), we analyzed signaling through this cascade in a cohort of pancreatic endocrine tumors (PET).
Design: Tissue microarrays were constructed from formalin-fixed, paraffin-embedded blocks of 101 PET from our departmental archive and stained for PTEN, p-Akt, p-mTOR, and p-S6rp. Expression intensity was scored as 0 (absent), 1+ (modest), or 2+ (strong). Islets from 7 normal pancreata served as controls.
Results: The normal islets expressed PTEN (2+ in 4, 1+ in 3), with no demonstrable expression of p-Akt, p-mTOR, or p-S6rp. PTEN expression was detected in the majority of tumors (2+ in 77 and 1+ in 19). Twenty-three tumors showed modest (1+) p-Akt expression, which tended to inversely correlate with PTEN expression. Modest to high levels (1-2+) of p-mTOR expression were present in 79 tumors (2+ in 35, 1+ in 44), and modest to high levels of p-S6rp were detected in 37 (2+ in 8, 1+ in 29). Results are summarized in the table.
PI3K/Akt/mTOR Pathway Protein Expression* data represents number of cases expressing the protein at a given intensity
Conclusions: Aberrant activation of the PI3K/Akt/mTOR pathway was detected in the majority of PET. In most of these cases this activation appears to be downstream (p-mTOR or p-S6rp immunoreactivity) and not attributable to PTEN loss/p-Akt activation. Given these findings, mTOR may represent a rational therapeutic target in PET.
Category: Liver & Pancreas
Monday, March 9, 2009 9:30 AM
Poster Session I Stowell-Orbison/Autopsy Award # 216, Monday Morning