Abstract
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 p110α, p110β, p110γ, and p110δ. Although for many years attention has been mainly focused on p110α recent evidence supports the conclusion that p110β, p110γ, and p110δ can also have a role in cancer. Amongst these, accumulating evidence now indicates that p110γ 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 p110γ 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 p110γ 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 p110γ 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 p110γ can regulate invasion of myeloid cells into tumors and tumor angiogenesis. Finally p110γ has also been directly involved in regulation of cancer cell migration. Taken together these data indicate that p110γ plays multiple roles in regulation of several processes that are critical for tumor progression and metastasis. This review will discuss the role of p110γ 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.
Highlights
Gastrointestinal cancers comprise a group of cancers that affect the gastrointestinal tract and include esophageal, stomach, liver, pancreatic and colorectal cancer
The aim of this review is to summarize the evidence indicating that the phosphoinositide 3-kinase (PI3K) isoform p110γ plays a key role in gastrointestinal cancers
CONCLUDING REMARKS Given the predominant expression of p110γ in hematopoietic cells the interest of oncologists on this specific lipid kinase has been mainly focused on hematological malignancies
Summary
Gastrointestinal cancers comprise a group of cancers that affect the gastrointestinal tract and include esophageal, stomach, liver, pancreatic and colorectal cancer. The prospect for patients with liver and pancreatic cancer is dismal. The 5 year survival rate for pancreatic ductal adenocarcinomas (PDAC) is the lowest among all cancers (Li et al, 2004). In 2011 hepatocellular carcinoma (HCC) was estimated as the second and sixth leading cause of cancer-related death in men and women respectively (Jemal et al, 2011). There have been great advances in survival rates for many types of cancers over the past few decades but hardly any Abbreviations: EC, endothelial cells; GPCR, G-protein coupled receptor; HCC, hepatocellular carcinoma; LPA, lysophosphatidic acid; mTOR, mechanistic target of rapamycin; PDAC, pancreatic cancer adenocarcinoma; PI3K, phosphoinositide 3-kinase; RTK, receptor tyrosine kinase; S1P, sphingosine-1-phosphate
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have