Abstract
Cancer cachexia represents a debilitating syndrome that diminishes quality of life and augments the toxicities of conventional treatments. Cancer cachexia is particularly debilitating in patients with pancreatic cancer (PC). Mechanisms responsible for cancer cachexia are under investigation and are largely derived from observations in syngeneic murine models of cancer which are limited in PC. We evaluate the effect of human PC cells on both muscle wasting and the systemic inflammatory milieu potentially contributing to PC-associated cachexia. Specifically, human PC xenografts were generated by implantation of pancreatic cancer cells, L3.6pl and PANC-1, either in the flank or orthotopically within the pancreas. Mice bearing orthotopic xenografts demonstrated significant muscle wasting and atrophy-associated gene expression changes compared to controls. Further, despite the absence of adaptive immunity, splenic tissue from orthotopically engrafted mice demonstrated elevations in several pro-inflammatory cytokines associated with cancer cachexia, including TNFα, IL1β, IL6 and KC (murine IL8 homologue), when compared to controls. Therefore, data presented here support further investigation into the complexity of cancer cachexia in PC to identify potential targets for this debilitating syndrome.
Highlights
With mortality rates largely unchanged over 50 years, pancreatic cancer (PC) is projected to be the second leading cause of cancer deaths by 2030 [1, 2]
Significant skeletal muscle wasting was evident in both L3.6pl flank and orthotopic tumor-bearing groups when compared to sham controls, as determined by tibialis anterior (TA) muscle weight and fiber cross sectional area (CSA) (Figure 1C–1D)
We observed atrophy in the triceps surae muscle group, which weighed 13% less in mice bearing L3.6pl flank tumors compared to sham controls (111±6.7 mg vs. 128±2.6 mg; P = 0.09) and 19% less in mice bearing L3.6pl orthotopic tumors compared to sham controls (102±4.3 mg vs. 126±2.6 mg; P < 0.01)
Summary
With mortality rates largely unchanged over 50 years, pancreatic cancer (PC) is projected to be the second leading cause of cancer deaths by 2030 [1, 2]. The muscle wasting observed in cachexia is associated with a wide array of molecular pathways, some of which are triggered by tumor and host-derived systemic inflammatory changes in advanced cancer [12]. Many of these pathways converge on the inappropriate activation of the ubiquitin-proteasome system (UPS), leading to increased degradation of muscle proteins and progressive loss of contractile machinery [13, 14]. Clinical trials have demonstrated that many of these targets in isolation, such as secreted cytokines, are not solely responsible for sustaining cancer-induced cachexia [4, 16] To complicate matters, it is unclear why severe cachexia is observed in some patients while others are relatively spared
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