The term cholangiocarcinoma (CCA) defines a class of epithelial malignancies originating from bile ducts. Although it has been demonstrated that CCA patients with perineural invasion (PNI) have a worse prognosis, the biological features of this phenomenon are yet unclear. Our data show that in human intrahepatic CCA specimens with documented PNI, nerve-infiltrating CCA cells display positivity of the epithelial marker cytokeratin 7, lower with respect to the rest of the tumor mass. In an in vitro 3D model, CCA cells move towards a peripheral nerve explant allowing contact with Schwann cells (SCs) emerging from the nerve. Here, we show that SCs produce soluble factors that favor the migration, invasion, survival and proliferation of CCA cells in vitro. This effect is accompanied by a cadherin switch, suggestive of an epithelial–mesenchymal transition. The influence of SCs in promoting the ability of CCA cells to migrate and invade the extracellular matrix is hampered by a specific TGFβ receptor 1 (TGFBR1) antagonist. Differential proteomic data indicate that the exposure of CCA cells to SC secreted factors induces the upregulation of key oncogenes and the concomitant downregulation of some tumor suppressors. Taken together, these data concur in identifying SCs as possible promoters of a more aggressive CCA phenotype, ascribing a central role to TGFβ signaling in regulating this process.

Autophagy is an evolutionary conserved mechanism that allows for the degradation of long-lived proteins and entire organelles which are driven to lysosomes for digestion. Different kinds of stressful conditions such as starvation are able to induce autophagy. Lithium and rapamycin are potent autophagy inducers with different molecular targets. Lithium stimulates autophagy by decreasing the intracellular myo-inositol-1,4,5-triphosphate levels, while rapamycin acts through the inhibition of the mammalian target of rapamycin (mTOR). The correlation between autophagy and cell death is still a matter of debate especially in transformed cells. In fact, the execution of autophagy can protect cells from death by promptly removing damaged organelles such as mitochondria. Nevertheless, an excessive use of the autophagic machinery can drive cells to death via a sort of self-cannibalism. Our data show that lithium (used within its therapeutic window) stimulates the overgrowth of the rat Pheochromocytoma cell line PC12. Besides, lithium and rapamycin protect PC12 cells from toxic compounds such as thapsigargin and trimethyltin. Taken together these data indicate that pharmacological activation of autophagy allows for the survival of Pheochromocytoma cells in stressful conditions such as high-density cultures and exposure to toxins.

In recent years, a long list of relevant studies has highlighted the engagement of the nervous system in the fine-tuning of tumor development and progression. Several authors have shown that different types of nerve fibres (sympathetic, parasympathetic/vagal or somatosensory fibres) may contribute to tumor innervation affecting cancer initiation, progression and metastasis. A large presence of nerve fibres is frequently observed in tumors with respect to the corresponding healthy tissues. In this regard, it is worth noting that in some cases a reduced innervation may associate with slow tumor growth in a tissue-specific manner. Current studies have begun to shed light over the role played in this specific process by Schwann cells (SCs), the most abundant glial cells of the peripheral nervous system. SCs observed in cancer tissues share strong similarities with repair SCs that appear after nerve injury. A large body of research indicates that SCs may have a role in shaping the microenvironment of tumors by regulating the immune response and influencing their invasiveness. In this review, we summarize data relevant to the role of peripheral innervation in general, and of SCs in particular, in defining the progression of different tumors: melanoma that originate in the skin with mainly sensory innervation; pancreatic and liver-derived tumors (e.g., pancreatic adenocarcinoma and cholangiocarcinoma) with mainly autonomous innervation. We conclude by summarizing data regarding hepatocarcinoma (with anatomical predominance of small autonomic nerve fibres) in which the potential relationship between innervation and tumor progression has been little explored, and largely remains to be defined.