Nerve-cancer interactions in the stromal biology of pancreatic cancer

Abstract

Interaction of cancer cells with diverse cell types in the tumor stroma is today recognized to have a fate-determining role for the progression and outcome of human cancers. Despite the well-described interactions of cancer cells with several stromal components, i.e., inflammatory cells, cancer-associated fibroblasts, endothelial cells, and pericytes, the investigation of their peculiar relationship with neural cells is still at its first footsteps. Pancreatic cancer (PCa) with its abundant stroma represents one of the best-studied examples of a malignant tumor with a mutually trophic interaction between cancer cells and the intratumoral nerves embedded in the desmoplastic stroma. Nerves in PCa are a rich source of neurotrophic factors like nerve growth factor (NGF), glial-cell-derived neurotrophic factor (GDNF), artemin; of neuronal chemokines like fractalkine; and of autonomic neurotransmitters like norepinephrine which can all enhance the invasiveness of PCa cells via matrix-metalloproteinase (MMP) upregulation, trigger neural invasion (NI), and activate pro-survival signaling pathways. Similarly, PCa cells themselves provide intrapancreatic nerves with abundant trophic agents which entail a remarkable neuroplasticity, leading to emergence of more routes for NI and cancer spread, to augmented local neuro-surveillance, neural sensitization, and neuropathic pain. The strong correlation of NI with PCa-associated desmoplasia suggests the potential presence of a triangular relationship between nerves, PCa cells, and other stromal partners like myofibroblasts and pancreatic stellate cells which generate tumor desmoplasia. Hence, although not a classical hallmark of human cancers, nerve-cancer interactions can be considered as an indispensable sub-class of cancer-stroma interactions in PCa. The present article provides an overview of the so far known nerve-cancer interactions in PCa and illustrates their ominous role in the stromal biology of human PCa.

Keywords: desmoplasia; neural invasion; neuropathic pain; neuroplasticity; neurotransmitters; neurotrophic factors; pancreatic cancer; stroma.

Figure 1

Nerve-cancer interactions in human pancreatic cancer (PCa). Neural cells and PCa cells undergo a mutually growth-supporting interaction. Nerve-derived molecules like neurotrophic factors, neurotransmitters, and chemokines are capable of enhancing PCa cell tumorigenicity in several aspects, including invasiveness, cancer cell chemotaxis, locomotion, proliferation, and cell survival via upregulation of numerous signaling pathways. In analogy, PCa cells secrete neuromodulatory agents which induce neuroplasticity, augment neural invasion, and neuropathic pain sensation. NGF, nerve growth factor; GDNF, glial-cell-derived neurotrophic factor; Nf-kappaB, nuclear factor kappa B; PI3-K, phosphoinositide-3-kinase; nAChR, nicotinic acetylcholine receptor; CREB, cAMP response element-binding; AKT, protein kinase B; MMP-2 and -9, matrix-metalloproteinase-2 and -9; FAK, focal adhesion kinase; Erk, extracellular signal-regulated kinase; MALT1, mucosa-associated lymphoid tissue lymphoma translocation gene 1; TRAF, tumor-necrosis-factor-receptor-associated factor; KIF14, kinesin family member 14 (KIF14); ARHGDIbeta, RHO-GDP dissociation inhibitor-β; GAP-43, growth-associated protein 43. Please refer to the manuscript for the respective references.

Figure 2

Neural invasion and neuroplasticity in the desmoplastic PCa stroma. Human PCa specimens contain hypertrophic nerves which are victims of neural invasion and frequently encountered in the desmoplastic tumor stroma. The asterisks demonstrate nerves surrounded by invading PCa cells in the activated perineural, immunolabeled tumor desmoplasia (A,B). This neural invasion is either present as perineural invasion (C) along their epi- or perineurium, or as endoneural invasion which destructs the neural integrity (D).

Figure 3

The hypothetic triangular relationship between nerves, PCa cells, and pancreatic stellate cells (PSC). PCa cells benefit not only from nerves, but also from PSCs which can – in their activated state – increase PCa cell growth, invasiveness, and tumor angiogenesis. Moreover, activated PSCs can provide neural cells with neurotrophic factors like NGF and neurotransmitters which can modulate neuronal activity. Conversely, there is yet insufficient evidence for a modulating activity of nerve-derived molecules upon PSC activity. Still, studies on hepatic stellate cells demonstrated that neurotransmitters including 5-hydroxytryptophan (5-HT), neuropeptide Y, gamma-amino butyric acid (GABA), and acetylcholine (ACh) can significantly increase the fibrogenic activity, proliferation, and calcium currents of stellate cells. Right upper image: myenteric plexus neurons treated with neurotrophic PCa tissue extracts, immunostained against the neuronal marker beta-III-tubulin. Lower image: rat pancreatic stellate cells immunostained against alpha smooth muscle actin. PDGF, platelet-derived growth factor; VEGF, vascular endothelial growth factor; MMP, matrix-metalloproteinase; ACh, acetylcholine; NGF, nerve growth factor; 5-HT, 5-hydroxytryptophan; NPY, neuropeptide Y; GABA, gamma-amino butyric acid; ECM, extracellular matrix; GDNF, glial-cell-derived neurotrophic factor. Please refer to the manuscript for the respective references.