Nerve fibers in the tumor microenvironment in neurotropic cancer-pancreatic cancer and cholangiocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) and cholangiocarcinoma (CCA) are both deadly cancers and they share many biological features besides their close anatomical location. One of the main histological features is neurotropism, which results in frequent perineural invasion. The underlying mechanism of cancer cells favoring growth by and through the nerve fibers is not fully understood. In this review, we provide knowledge of these cancers with frequent perineural invasion. We discuss nerve fiber crosstalk with the main different components of the tumor microenvironment (TME), the immune cells, and the fibroblasts. Also, we discuss the crosstalk between the nerve fibers and the cancer. We highlight the shared signaling pathways of the mechanisms behind perineural invasion in PDAC and CCA. Hereby we have focussed on signaling neurotransmitters and neuropeptides which may be a target for future therapies. Furthermore, we have summarized retrospective results of the previous literature about nerve fibers in PDAC and CCA patients. We provide our point of view in the potential for nerve fibers to be used as powerful biomarker for prognosis, as a tool to stratify patients for therapy or as a target in a (combination) therapy. Taking the presence of nerves into account can potentially change the field of personalized care in these neurotropic cancers.

Fig. 1. Histology of perineural invasion in neurotropic cancer.

Histology slide of PDAC (a) and CCA (b) in Hematoxylin and Eosin (H&E) showing PNI, which is one of the shared pathological characteristics of both cancers. a PDAC slide with extended PNI and an almost identical histomorphology as CCA. b CCA with tumor cells massively invading the perineural space, surrounded by desmoplastic stroma and few small tumor glands in the stroma.

Fig. 2. A schematic overview of normal pancreas and liver innervation by the PSNS (in purple) and the SNS (in pink).

SNS innervation of the liver and pancreas is derived from the lateral horn of the spinal cord (liverT7-T12, pancreas C8-L3) across through sympathetic chain primarily via the splanchnic nerve to prevertebral ganglia including the celia and superior ganglion entering hepatic plexus. The PSNS supporting the liver and pancreas originates from the brainstem (dorsal motor nucleus of the n. vagus in the medulla) and activates parasympathetic postganglionic neurons in the liver or the pancreatic ganglia [–31].

Fig. 3. A bidirectional crosstalk between nerves and cancer in pancreas and liver.

Nerve fibers as branches of neuron infiltrate the TME and control cancer cells initiation, growth and metastasis mainly through three interactions pathways: a Direct contact in a synapse pathway, neuron as presynaptic cell via secretion of neurotransmitters and neuropeptides such as acetylcholin act on neurotransmitter receptors such as acetylcholin receptors on postsynaptic cell to regulate epithelial proliferation, stem cell activity, both nerve and liver or pancreatic cancer cells can be as pre- or post-synaptic cells in this communication. b Paracrine pathway, within TME, addition to direct influence, nerves communication with cancer can be mediated by regulation of tumor-related stroma cells. And the paracrine signals (neurotrophic growth factors) derived by cancer cell promote nerve axonogenesis or neurogenesis in TME. c Systemic pathway, nervous system can influence cancer cells activities through regulation the function of immune system mediated by elevated systemic circulating catecholamines. PNI can also be a consequence of circulating signals from cancer cells [42, 59].