Neuroplastic Changes Occur Early in the Development of Pancreatic Ductal Adenocarcinoma

Abstract

Perineural tumor invasion of intrapancreatic nerves, neurogenic inflammation, and tumor metastases along extrapancreatic nerves are key features of pancreatic malignancies. Animal studies show that chronic pancreatic inflammation produces hypertrophy and hypersensitivity of pancreatic afferents and that sensory fibers may themselves drive inflammation via neurogenic mechanisms. Whereas genetic mutations are required for cancer development, inflammation has been shown to be a precipitating event that can accelerate the transition of precancerous lesions to cancer. These observations led us to hypothesize that inflammation that accompanies early phases of PDAC would produce pathologic changes in pancreatic neurons and innervation. Using a lineage labeled genetically engineered mouse model of PDAC we found that pancreatic neurotrophic factor mRNA expression and sensory innervation increased dramatically when only pancreatic intraepithelial neoplasia (PanIN) were apparent. These changes correlated with pain-related decreases in exploratory behavior and increased expression of nociceptive genes in sensory ganglia. At later stages, cells of pancreatic origin could be found in the celiac and sensory ganglia along with metastases to the spinal cord. These results demonstrate that the nervous system participates in all stages of PDAC, including those that precede appearance of cancer.

Ablation of sensory neurons in a genetic model of pancreatic ductal adenocarcinoma slows initiation and progression of cancer

“…PNI is a common clinical feature of PDAC that coincides with tumor and metastasis formation (26). Interestingly, a similar correlation occurs in PKCT mice where cells of pancreatic origin migrate to the DRG during PanIN and early cancer stages (Fig.…”

“…It should be noted that the tumorigenic potential of these cells is unknown; however, spinal metastases are rare in patients with PDAC. At later disease stages, tumors can be found in both peripheral nerves and spinal cord in the PKC model (26), but at the time in which spinal inflammation is first observed, no obvious tumors were detected. Importantly, the migration of cells is not restricted to animal models.…”

“…The data presented here demonstrate that at the PanIN stage of PDAC in the PKC model, spinal cord inflammation and PNI of both the spinal cord and peripheral ganglia are already well under way. Stopczynski et al (26), showed that in the PanIN stage, sprouting of sensory fibers and increases in neurotrophic factors accompany an increase in mRNAs encoding CGRP, TRPV1, and TRPA1 in DRG, all hallmarks of pancreatic inflammation driven by increased activity in pancreatic sensory neurons, i.e., neurogenic inflammation. Growth-factor-related changes, as well as chemokine release, support PNI (44-47), a common clinical feature of several cancers including up to 100% of PDAC cases (48)(49)(50).…”

“…at 1-2 d of age (P2). More detailed information including the protocols for assessing spinal inflammation can be found in SI Methods (23,26,(71)(72)(73)(74)(75)(76)(77)(78)(79)(80)(81). …”

Molecular mechanisms of perineural spread of cutaneous carcinoma: a potential role for receptor tyrosine kinases and other biomarkers

“…(49) This ensures the nerve microenvironment remains intact as opposed to aforementioned models where PNI is facilitated or staged. These models have allowed effective study of tumour evolution in the context of the nervous system.…”