Abstract
Fucoxanthin (Fx) is a marine carotenoid with anti-inflammatory and anti-cancer properties in various animal models of carcinogenesis. However, there is currently no information on the effects of Fx in animal models of pancreatic cancer. We investigated the chemopreventive effects of Fx in C57BL/6J mice that received allogenic and orthotopic transplantations of cancer cells (KMPC44) derived from a pancreatic cancer murine model (Ptf1aCre/+; LSL-krasG12D/+). Using microarray, immunofluorescence, western blot, and siRNA analyses, alterations in cancer-related genes and protein expression were evaluated in pancreatic tumors of Fx-administered mice. Fx administration prevented the adenocarcinoma (ADC) development of pancreatic and parietal peritoneum tissues in a pancreatic cancer murine model, but not the incidence of ADC. Gene and protein expressions showed that the suppression of chemokine (C-C motif) ligand 21 (CCL21)/chemokine receptor 7 (CCR7) axis, its downstream of Rho A, B- and T-lymphocyte attenuator (BTLA), N-cadherin, αSMA, pFAK(Tyr397), and pPaxillin(Tyr31) were significantly suppressed in the pancreatic tumors of mice treated with Fx. In addition, Ccr7 knockdown significantly attenuated the growth of KMPC44 cells. These results suggest that Fx is a promising candidate for pancreatic cancer chemoprevention that mediates the suppression of the CCL21/CCR7 axis, BTLA, tumor microenvironment, epithelial mesenchymal transition, and adhesion.
Highlights
Pancreatic cancer (PC), a representative intractable cancer, is the seventh and fourth leading cause of cancer-related mortality worldwide and in the USA, respectively [1,2]
In the USA, it is expected that the mortality rate of PC will continue to rise for the 20 years and become the second leading cause of cancer death by 2040 [3]
Fx significantly altered the expression of 174 genes in pancreatic tumors
Summary
Pancreatic cancer (PC), a representative intractable cancer, is the seventh and fourth leading cause of cancer-related mortality worldwide and in the USA, respectively [1,2]. Oral ingestion of Fx could suppress obesity and diabetes, both of which are risk factors of pancreatic carcinogenesis, in human volunteers through decreases in body weight, waist circumference, and in blood triacylglycerol, C-reactive protein, and HbA1c levels [29,30]. Terasaki et al have shown that FxOH treatment induces apoptosis by attenuating chemokine, adhesion, PI3K/AKT, MAPK, and cell cycle signals in PDAC cells (KMPC44) established from PC tissue on Ptf1aCre/+; LSL-krasG12D3/+ofm17ice [28]. FxOH had an apoptotic potential in PDAC cells (HaPC-5) from N-nitrosobis(2-. Had an apoptotic potential in PDAC cells (HaPC-5) from N-nitrosobis(2aosinnhxdfooowpcrIamnreondaptchtyesieoulr)npapinmpirseraieanssvemesnae(uitBdlraOsibctnPuhlee)ed-ompiynna,odntkwuhcicenereeeadia,nnthatviidac-eimhsncetaflsistngaieocmarnetPmer, DdPmaAItt3oohCKrdey/mesaAluonuKdpdseTpial,n.rnaegTtnsihK-sdceiaMvsFneoxPcOeeoCrfnHf4ee4-[fctf2retc7esce]at.lostlesfHod.FfoHxFwxaoePinvnCeia-rn5,nfliclimeattlmalleslmation. The number of (B) Tub 1, (C) Tub 2, (D) Por, and (E) total ADCs in pancreatic and parietal peritoneum tissues. AAlltteerriinngg EEffffeecctt ooff FFxx oonn tthhee TTrraannssccrriippttoommee iinn TTuummoorrTTisisssuueeooffaaPPaannccrreeaatitcicCCaanncceerr Model MMooduesle Mouse. (≥1.5-fold) and downregulated (≤−1.5-fold) genes between groups 1 and 2
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