Pancreatic cancer pain and its correlation with changes in tumor vasculature, macrophage infiltration, neuronal innervation, body weight and disease progression

Abstract

To begin to understand the relationship between disease progression and pain in pancreatic cancer, transgenic mice that develop pancreatic cancer due to the expression of the simian virus 40 large T antigen under control of the rat elastase-1 promoter were examined. In these mice precancerous cellular changes were evident at 6 weeks and these included an increase in: microvascular density, macrophages that express nerve growth factor and the density of sensory and sympathetic fibers that innervate the pancreas, with all of these changes increasing with tumor growth. In somatic tissue such as skin, the above changes would be accompanied by significant pain; however, in mice with pancreatic cancer, changes in pain-related behaviors, such as morphine-reversible severe hunching and vocalization only became evident at 16 weeks of age, by which time the pancreatic cancer was highly advanced. These data suggest that in mice as well as humans, there is a stereotypic set of pathological changes that occur as pancreatic cancer develops, and while weight loss generally tracks disease progression, there is a significant lag between disease progression and behaviors indicative of pancreatic cancer pain. Defining the mechanisms that mask this pain in early and mid-stage disease and drive the pain in late-stage disease may aid in earlier diagnosis, survival, and increased quality of life of patients with pancreatic cancer.

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

“…The potential role of sensory neurons and their association with sympathetic and parasympathetic neurons remains to be defined. Mantyh and colleagues have documented in detail that autonomic nerves, especially sympathetic postganglionic fibers, are affected in cancer progression (5,(54)(55)(56). Moreover, both sympathetic and parasympathetic neurons release molecules that can activate sensory neurons; sympathetic postganglionic neurons release three molecules of ATP for every molecule of norepinephrine.…”

“…Like most abdominal organs, the pancreas is innervated by sensory fibers from both the nodose (via the vagal nerve) and spinal ganglia (via splanchnic nerves) (3)(4)(5)(6)(7). In rodent models of acute or chronic pancreatitis, blockade of primary afferents from both nodose and spinal ganglia can moderate or prevent inflammation (8,9) as well as associated pathology, even if done after the inciting injury (10,11).…”

Pancreatic innervation in mouse development and β-cell regeneration

“…Loss of the β-cell population does not affect the subcellular localization of CGRP, a molecule that is central to nociception-Changes in CGRP + pancreatic sensory innervation have been implicated in pancreatic cancer-associated pain (Lindsay et al 2005). Pancreatic pain has not been associated with β-cell loss itself--as occurs in type 1 diabetes and in synthetic diabetic mouse models such as non-obese diabetic or streptozotocin mice.…”

“…Observation of impaired glucose tolerance during high-stringency glucose tolerance tests after these animals were otherwise considered fully recovered (P. Heiser, personal communication) led us to hypothesize that autonomic islet innervation is affected, and that the recovery of some physiological aspect of autonomic innervation in these animals may not be complete after 60 days of recovery. Remodeling of pancreatic sensory neurons has been associated with pain in the context of pancreatic cancer (Lindsay et al 2005). In contrast, pancreatic pain has not been reported in association with diabetic phenotypes.…”

“…Since the pancreatic sympathetic neurons remain while VMAT2 immunoreactivity is lost, we conclude that the ability of postganglionic sympathetic neurons to accumulate noradrenaline may be compromised by the large-scale loss of β-cells in RIP-cmyc ER animals. However, the persistence of NPY localization indicates that the architecture of sympathetic neurons is maintained throughout changes in the β-cell population.Loss of the β-cell population does not affect the subcellular localization of CGRP, a molecule that is central to nociception-Changes in CGRP + pancreatic sensory innervation have been implicated in pancreatic cancer-associated pain (Lindsay et al 2005). Pancreatic pain has not been associated with β-cell loss itself--as occurs in type 1 diabetes and in synthetic diabetic mouse models such as non-obese diabetic or streptozotocin mice.…”