PI3K in cancer-stroma interactions: bad in seed and ugly in soil.

Over the past decade the phosphoinositide-3 kinase (PI3K) signaling pathway emerged as an important player for tumor initiation and growth and, currently, PI3K inhibition constitutes a promising therapeutic approach for solid and hematological tumors. Beside its role in tumor cell evolution, PI3K signaling also provides integral functions for noncancerous cells that reside in healthy tissues surrounding the tumor, also referred as tumor microenvironment (TME). This review will address how PI3K signaling participates to the tumorigenic process and discuss the interaction between tumor cells and the surrounding TME, with particular focus on the role of PI3Ks in tumor-associated immune responses, tumor angiogenesis and metastasis formation.

The proline-rich tyrosine kinase Pyk2 regulates platelet integrin αIIbß3 outside-in signaling.

BACKGROUND: The proline-rich tyrosine kinase Pyk2 is a focal adhesion kinase expressed in blood platelets, and is activated downstream of G-protein coupled receptors as well as integrin α2ß1. OBJECTIVE: In this study we have investigated the involvement of Pyk2 in integrin αIIbß3 outside-in signaling in human and murine platelets. METHODS: We analyzed the stimulation of intracellular signaling pathways in platelets from Pyk2 knockout mice adherent to immobilized fibrinogen. RESULTS: Pyk2 was rapidly phosphorylated and activated in human and murine platelets adherent to fibrinogen through integrin αIIbß3. Activation of Pyk2 was Src-dependent, but did not require phospholipase Cγ2 activity. Platelets from Pyk2 knockout mice showed a defective ability to adhere and spread on fibrinogen, in association with a dramatic reduction of phosphatidylinositol 3-kinase (PI3K) activation and Akt phosphorylation. Pharmacological and genetic analysis demonstrated that integrin αIIbß3 engagement selectively stimulated the ß-isoform of PI3K (PI3Kß), and that, as for Pyk2, PI3Kß activation required Src family kinases activity, but not phospholipase Cγ2. In fibrinogen-adherent platelets, both Pyk2 and PI3Kß were necessary for stimulation of the small GTPase Rap1b, a regulator of cell adhesion and spreading. Integrin αIIbß3 engagement triggered the association of the PI3Kß regulatory subunit p85 with the adaptor protein c-Cbl, which was mediated by the p85 SH3 domain, and was independent of c-Cbl tyrosine phosphorylation. However, p85-associated c-Cbl was tyrosine phosphorylated by activated Pyk2 in fibrinogen adherent platelets. CONCLUSIONS: These results identify a novel pathway of integrin αIIbß3 outside-in signaling and recognize the tyrosine kinase Pyk2 as a major regulator of platelet adhesion and spreading on fibrinogen.

PI3K keeps the balance between metabolism and cancer.

Epidemiological studies have established a positive correlation between cancer and metabolic disorders, suggesting that aberrant cell metabolism is a common feature of nearly all tumors. To meet their demand of building block molecules, cancer cells switch to a heavily glucose-dependent metabolism. As insulin triggers glucose uptake, most tumors are or become insulin-dependent. However, the effects of insulin and of other similar growth factors are not only limited to metabolic control but also favor tumor growth by stimulating proliferation and survival. A key signaling event mediating these metabolic and proliferative responses is the activation of the phosphatidylinositol-3 kinases (PI3K) pathway. In this review, we will thus discuss the current concepts of tumor metabolism and the opportunity of PI3K-targeted therapies to exploit the "sweet tooth" of cancer cells.

Present and future of PI3K pathway inhibition in cancer: perspectives and limitations.

Phosphoinositide 3-kinases (PI3Ks) control key signaling pathways in cancer cells, leading to cell proliferation, survival, motility and angiogenesis. In several human cancers, activation of PI3Ks results from gain-of-function or over-expression of PI3Ks and/or hyperactivity of up- or downstream players in the pathway. As inhibition of PI3Ks and downstream targets such as mammalian target of rapamycin (mTOR) has been shown to reduce tumor growth in vitro and in preclinical models, several small molecule inhibitors of PI3Ks are currently undergoing clinical trial as novel agents in cancer therapy. These drugs include inhibitors targeting all class I PI3Ks (α, ß, γ, δ isoforms), compounds blocking selective PI3K isoforms and dual inhibitors active on both PI3Ks and mTOR. Herein, we summarize the pharmacology and preliminary clinical data of the main PI3K inhibitors undergoing clinical trial. We will also review the preclinical studies documenting the major effects of systemic PI3K inhibition on non-cancer tissues, which have shed light on potential side effects, caveats and limitations for PI3K blockade in patients.