Table 1.
Most studied profibrotic mediators secreted by small intestinal neuroendocrine neoplasms (SI-NENs) and their implications as potential therapeutic targets related to mesenteric fibrosis (MF).
| Fibrotic Factors | Specific Invovement in MF | Potential Therapeutic Agent Targenting MF | Relevant Studies |
|---|---|---|---|
| Serotonin | -mitogenic effect in stroma cells -cyclin E induction -potentiates the effects of PDGF, β-FGF, EGF and insulin -decreased expression of serotonin degrading enzymes in the stroma |
-SSAs -5-HT synthesis inhibitors and receptor antagonists -Tyrosine kinase inhibitors |
[12] [14] [22] [23] [24] [25] [26] [27] |
| TGF-β | -chemotactic for fibroblasts and macrophages -cell proliferation -production of extracellular matrix and stimulation of growth factor secretion by fibroblasts |
-SSAs -Tyrosine kinase inhibitors -ACE inhibitors -Tamoxifen |
[28] [29] [30] [31] [32] [33,34,35] [36] |
| CTGF | -promoter of mitosis, chemotaxis -stimulator of apoptosis, angiogenesis, synthesis of collagens, fibronectin and α5-integrin -transcriptional activation through TGF-β1 and other mediators acting in turn as downstream mediator on fibroblasts -SMAD, PKC and ras/MEK/ERK (kinase) pathways necessary for the TGFβ1-mediated induction of the CTGF promoter |
-SSAs -Tyrosine kinase inhibitors |
[37] [38] [30] [10,39,40,41] |
| PDGF | -mitogenic properties on fibroblasts -PDGF a-receptor seen on clusters of tumour cells and occasionally on adjacent stroma -PDGF β -receptor seen only in the stroma -cyclin D1 expression via the MAPK/ERK pathway |
-Tyrosine kinase inhibitor (imatinib) | [42] [43] [13] [44] |
| IGF-1 | -cell proliferation -mitogenic effect on fibroblasts -serotonin-IGF-1 axis activation |
-5-HT synthesis inhibitors and receptor antagonists | [45] [46] [36] [37] [47] [48] |
| EGF | -cell proliferation and differentiation -highly expressed in SI-NENs |
-Tyrosine kinase inhibitors | [46] |
| TGF-α | -interaction with EGF EGFR receptor activation -highly expressed in SI-NENs |
-Tyrosine kinase inhibitor | [46] [49] [47] |
| FGF | -potent stimulant of endothelial cell growth -cell proliferation and stroma formation |
-Tyrosine kinase inhibitors | [12] [28] [36] [43] |
| VEGF | -secreted by CAFs to induce tumour cell proliferation | -Tyrosine kinase inhibitors | [46] [50] [6] |
| NGF | -regulatory effects on angiogenesis -highly expressed in mesenteric angiopathy |
-Tyrosine kinase inhibitors | [36] |
| VAP-1 | -higly expressed in SI-NEN stroma | -Pyridazone inhibitors -hVAP-1-targeted inhibitors |
[51] [52] |
| BMP | -members of the TGF-β superfamily -cell growth and differentiation -promoter of angiopathy |
-small molecule inhibitor of BMP signaling, K02288 -Statins |
[51] [53] [54,55] |
Abbreviations: 5-HT: serotonin; ACE: angiotensin-converting enzyme; BMP: bone morphogenic protein; CAFs: cancer-associated fibroblasts; CTGF, connective tissue growth factor; EGF: epidermal growth factor; EGFR: epidermal growth factor receptor; ERK: extracellular-signal-regulated kinase; FGF2, fibroblast growth factor 2; β-FGF: fibroblast growth factor beta; hVAP-1: human vascular adhesion protein-1; IGF-1: Insulin-like growth factor 1; K02288: bone morphogenetic protein (BMP) type I receptor inhibitor; MAPK: Mitogen-activated protein kinase; MEK: Mitogen-activated protein; MF: mesenteric fibrosis; PDGF: platelet-derived growth factor; PKC: Protein kinase C; SI-NEN, small intestinal neuroendocrine neoplasm; SMAD: an acronym from the fusion of Caenorhabditis elegans Sma genes and the Drosophila Mad, Mothers against decapentaplegic; SSAs: somatostatin analogues; TGFα: transforming growth factor alpha; TGFβ, transforming growth factor beta.