The phosphoinositide-3 kinase (PI3K) signaling pathway is one of the most frequently deregulated signaling cascades in tumor initiation and progression. PI3K enzymes are crucial effectors of a broad range of extracellular stimuli and mediate activation of signal transduction events regulating cell survival, morphology and migration of malignant and non-malignant cells.

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.

PI3K signaling and tumor-associated immune response

Immune cells and mediators are fundamental components of TME. Depending on the cell type involved, the immune response can have either pro- or anti-tumorigenic functions. Notably, cytotoxic T lymphocytes, T helper and NK cells are able to recognize and destroy tumor cells as well as circulating tumor metastases, a process known as immune surveillance. Their presence in the TME is thus largely recognized as a factor of good prognosis. Conversely, cells normally involved in chronic inflammation, such as monocytes, granulocytes and mast cells, provide the tumor with growth factors, angiogenic factors and enzymes for extracellular matrix (ECM) remodeling, which favor tumor progression and relapse.

PI3K signaling in tumor angiogenesis

The ability of tumors to grow and invade strictly relies on the formation of new blood vessels that provide the adequate supply of nutrients and oxygen. Tumor neovascularization is coordinated by a plethora of cell types that either reside in or are recruited to TME. Tumor cells provide the first cue for neoangiogenesis, as they secrete pro-angiogenic factors, such as the vascular endothelial growth factor (VEGF), that activate naturally quiescent endothelial cells. New blood vessels thereby originate from pre-existing vascular structures as a result of intensive proliferation and migration of activated endothelial cells. In addition, tumor infiltrating bone marrow-derived cells, including monocytes, mast cells and endothelial progenitor cells, can directly promote angiogenesis and vasculogenesis.

PI3K signaling in ECM remodeling

Cellular components of the TME are immersed in the ECM, a complex network of macromolecules that is intensively modified and remodeled during cancer progression. Pathogenic remodeling of ECM in the TME is mainly due to CAFs, that secrete ECM components and ECM-modifying enzymes. CAFs appear to constitute a heterogeneous population of cells and their origin is still debated. The most widely accepted view is that CAFs are early developmental precursors that respond to signals derived from cancer cells. Among these signals, some are PI3K-mediated, such as the hepatocyte growth factor, the epidermal growth factor (EGF) and the basic fibroblast growth factor. It is thus conceivable that PI3K inhibition may prevent CAFs expansion and consequent setting of a tumor-supporting ECM.

PI3K signaling in metastasis

Tumor inflammation, neo-angiogenesis and matrix remodeling are interconnected processes that eventually contribute to the end-stage of tumorigenesis represented by tumor dissemination. Beside intense TME remodeling, metastasis is a multi-stage process involving cancer cell motility out of the primary tumor, intravasation into the circulatory system, transit in the blood or lymph, extravasation and proliferation at a new distant site. In cancers of epithelial origin, these processes are favored by epithelial-to-mesenchymal transition (EMT), a developmental regulatory program that relinquishes tumor cells from intrinsic polarization and adhesion to the ECM, eventually facilitating the rise of satellite lesions. EMT is coordinated by a set of pleiotropically acting transcriptional factors, such as Snail, Slug, Twist and Zeb1/2.

PI3K inhibitors: attack on multiple fronts

The various roles of PI3K-mediated signaling in the cross-talk between the tumor and its microenvironment clearly indicate a therapeutic potential. However, the identification of strategies aimed at blocking oncogenic PI3K signaling without affecting important systemic functions is still a challenge. Inhibition of all PI3Ks causes a potent blockade of the pathway and thus appears attractive, as it can concomitantly hit the tumor in its weak points. However, systemic toxicity of pan-PI3K inhibitors represents a major drawback. As different PI3K isoforms have different expression patterns and activation mechanisms, inhibition of specific PI3K isoforms in defined tumors appears a way to circumvent toxicity issues.