Targeting p110gamma in gastrointestinal cancers: attack on multiple fronts.
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Phosphoinositide 3-kinases (PI3Ks) regulate several cellular functions that are critical for cancer progression and development, including cell survival, proliferation and migration. Three classes of PI3Ks exist with the class I PI3K encompassing four isoforms of the catalytic subunit known as p110a, p110ß, p110?, and p110d. Although for many years attention has been mainly focused on p110a recent evidence supports the conclusion that p110ß, p110?, and p110d can also have a role in cancer. Amongst these, accumulating evidence now indicates that p110? is involved in several cellular processes associated with cancer and indeed this specific isoform has emerged as a novel important player in cancer progression. Studies from our laboratory have identified a specific overexpression of p110? in human pancreatic ductal adenocarcinoma (PDAC) and in hepatocellular carcinoma (HCC) tissues compared to their normal counterparts. Our data have further established that selective inhibition of p110? is able to block PDAC and HCC cell proliferation, strongly suggesting that pharmacological inhibition of this enzyme can directly affect growth of these tumors. Furthermore, increasing evidence suggests that p110? plays also a key role in the interactions between cancer cells and tumor microenvironment and in particular in tumor-associated immune response. It has also been reported that p110? can regulate invasion of myeloid cells into tumors and tumor angiogenesis. Finally p110? has also been directly involved in regulation of cancer cell migration. Taken together these data indicate that p110? plays multiple roles in regulation of several processes that are critical for tumor progression and metastasis. This review will discuss the role of p110? in gastrointestinal tumor development and progression and how targeting this enzyme might represent a way to target very aggressive tumors such as pancreatic and liver cancer on multiple fronts.
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