PI3K-AKT-mTOR-signaling and beyond: the complex network in gastroenteropancreatic neuroendocrine neoplasms

Abstract

Gastroenteropancreatic neuroendocrine neoplasms are heterogeneous in their clinical behavior and require therapies specially tailored according to staging, grading, origin and expression of peptide receptors. Despite extensive scientific efforts, the therapy options are still not satisfactory. The main reasons are due to the lack of a broad mechanistic knowledge, an insufficient classification of specific diagnostic sub-groups, and predictive markers. GEP-NEN tumors evade early diagnosis because of slow asymptomatic growth behavior and are frequently not detected until metastasized. How signaling networks contribute to tumor progression and how these networks interact remains unclear in large parts. In this review we summarize the knowledge on the growth factor responsive non-angiogenetic pathways in sporadic GEP-NENs, highlight promising mechanistic research approaches, and describe important therapy targets.

Keywords: Gastroenteropancreatic neuroendocrine neoplasms; biotherapy; growth factors; inhibitor.; kinases; molecular biology; signal transduction.

Figure 1

PI3K signaling feedbacks: PI3K signaling is highly activated and de-regulated in GEP‑NENs. Several feedback loops contribute to this effect , . RTK activation by ligand binding triggers a phosphorylation cascade onto IRS-1 and PI3K. The latter phosphorylates PIP2 and thereby activates PDK-1 and Akt at T308. Akt in turn inhibits TSC2 by phosphorylation, which leads to mTOR activation. The mTOR complex 1 activates translation via eIF4A and p70S6K and cell cycle progression, whereas mTORC2 relieves a feedback loop by fully-activating Akt at S273. S6K promotes a negative feedback onto IRS‑1 and thereby counteracts mTORC1 inhibition. The two major negative regulators, PTEN and TSC2 are frequently down regulated in GEP-NENs which lead to a highly deregulated Akt activation , .

Figure 2

Paradoxical activation of Raf downstream signaling following treatment with ATP-competitive Raf inhibitors lead to an enhanced proliferation of B-Raf wild type cells in vitro and in vivo (adapted from Cichowski et al. 327): a) mutant B-Raf constitutively activates MAPK signaling in cancer cells; b) ATP-competitive inhibition of mutant B-Raf counteracts ERK activation and leads to tumor growth reduction; c) ATP-competitive wild type Raf inhibition in normal cells results in increased ERK activation and proliferation in vitro, and in hyperplasia in normal tissues of mice in vivo ; d) and e) sustained RTK or Ras dependent upstream signaling activates MAPK signaling under ATP-competitive wild type Raf inhibition , , .

Figure 3

Summary of growth factor-induced cellular mechanisms and inhibitory effects of somatostatin signaling in GEP-NENs. The major receptors of interest are RTKs, SSTRs and their Co-receptors. Cell adhesion molecules are of minor research interest but might have an interesting potential. Whereas RTK activate downstream PI3K and mitogen activated signaling that triggers gene regulation and secretion, SSTRs activate G-protein coupled signaling which has a predominant regulatory effect onto growth factor signaling cascades in GEP-NENs. Beside the main questions, which crosstalks are relevant for GEP-NEN cancerogenesis and how to inhibit their key mediators, the effect of paradoxical activation has not been clinically evaluated. Trafficking, intercellular and cell-matrix interactions have been analyzed only in a small number of publications , , but might have a high potential for therapeutic and prognostic issues. Ligand binding factors and receptor agonists and antagonists are of high research interest and the focus is on dual receptor targeting to develop a more subgroup specific therapy approach -. Italic: major fields of interest in current research and remaining open questions.

Figure 4

Major crosstalks between the PI3K and the MAPK cascades. The PI3K and the MAPK pathway are highly interconnected and can be activated by the same RTKs, dependent on the triggering ligand. Direct Ras-GTP interaction with PI3 Kinases can trigger Ras-activated PI3K signaling -. The KSR scaffold is also a potent regulator of key PI3K signaling mediators. Several cross-activations and -inhibitions have been assessed to date. For instance, Akt can inhibit Ras function , , - and Rsk can interfere with TSC2 -. Furthermore, both pathways converge on the same downstream targets, such as the FOXO proteins, GSK3, Myc or p70S6K -, and thus promote cancer associated-phenotypes.