1. NCHU Institution Repository
  2. 農業暨自然資源學院
  3. 食品暨應用生物科技學系
Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/96063
標題: Effects of five selected polysaccharides on immunomodulatory functions and tumor immunotherapy in vitro and in vivo
五種多醣對免疫調節功能及癌症免疫療法之影響
作者: Hsiao-Chien Lin
林筱茜
關鍵字: 抗發炎;多醣;Th1/Th2免疫平衡;癌症免疫療法;異種移殖動物實驗模式;anti-inflammation;polysaccharides;Th1/Th2 immune balance;tumor immunotherapy;tumor xenografted animal models
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摘要: 
本研究篩選五種潛力多醣，包括甜蕎麥(CBPS)、苦蕎麥(BBPS)、芭樂籽(GSPS)、紅色台灣藜(RFLPS)及黃色台灣藜(YFLPS)多醣為材料，進行免疫調節研究，並以男性前列腺癌(PC-3)及女性乳腺癌(MCF-7)的癌症免疫療法為研究標的，進行動物體外(in vitro)及體內實驗(in vivo)。結果發現五種多醣添加於脾臟細胞使其細胞激素分泌傾向Th2免疫平衡，降低脂多醣(lipopolysaccharide, LPS)所誘導巨噬細胞分泌(interleukin (IL)-1β + IL-6 + tumor necrosis factor (TNF) -α)/IL-10細胞激素之比值，具有抗發炎潛力，其中以芭樂籽多醣最具抗發炎作用。對人類癌細胞株生長之影響方面，多醣處理之脾臟及腹腔巨噬細胞條件培養液顯著抑制PC-3及MCF-7細胞之生長，其中以MCF-7細胞株較為顯著，細胞激素與癌細胞存活率相關性分析發現，脾臟細胞(Th2/Th1)及巨噬細胞促發炎/抗發炎細胞激素比值增加與癌細胞存活率呈現負相關，推測五種多醣可能經由刺激脾臟細胞分泌IL-10，使免疫反應傾向Th2而抑制MCF-7細胞生長。另外，五種多醣藉由活化及增加巨噬細胞促發炎/抗發炎細胞激素比值來抑制PC-3和MCF-7細胞生長。
五種多醣經膠體過濾層析後，均含有二至三個區分物，區分物皆含有醣類及蛋白質，推測可能為蛋白多醣或醣蛋白。五種多醣及其區分物顯著增加脾臟細胞IL-10/IL-2細胞激素比值，使免疫反應傾向Th2免疫平衡，且降低脂多醣(LPS)所誘導巨噬細胞(IL-1β + IL-6 + TNF-α)/IL-10細胞激素之分泌比值，具有抗發炎潛力，其中以芭樂籽多醣膠體過濾第三區分物(GSF3)最具抗發炎作用。單獨添加五種多醣區分物均可顯著抑制PC-3及MCF-7細胞的生長；但僅GSF3脾臟細胞及巨噬細胞條件培養液顯著抑制癌細胞之生長，因此篩選出芭樂籽多醣進行癌症免疫療法試驗，進一步分析GSF3單醣組成及特性，發現GSF3為蛋白多醣，在單醣組成中含有半乳糖醛酸、葡萄糖、半乳糖及木糖成分。
選擇以BALB/c雄鼠為前列腺癌細胞異種移殖(cancer cell xenografted)動物實驗模式，結果發現餵食芭樂籽多醣4週對BALB/c雄鼠脾臟細胞及腹腔巨噬細胞細胞激素分泌，使其傾向Th2及M2免疫平衡，推測餵食芭樂籽多醣能經由其Th2免疫反應特性，改善前列腺癌BALB/c雄鼠體內過度傾向Th1免疫平衡，有助於抑制腫瘤細胞的生長並有助前列腺癌細胞之清除。
為了解芭樂籽多醣區分物3抗癌作用機制，以人類癌細胞株(PC-3及MCF-7細胞) 探討GSF3可能的抗癌機制，結果顯示，在細胞凋亡中發現直接添加GSF3可增加PC-3及MCF-7細胞表現Bax / Bcl-2 mRNA之比值；GSF3腹腔巨噬細胞條件培養液可增加PC-3細胞Fas mRNA表現量；GSF3脾臟細胞條件培養液可增加PC-3及MCF-7細胞Fas mRNA表現量，本研究推測GSF3處理可能經由提升Bax / Bcl-2基因表現比值及Fas基因表現，使癌細胞接受死亡訊號，進而使PC-3及MCF-7細胞走向凋亡。

Five potential polysaccharides from common buckwheat (CBPS), bitter buckwheat (BBPS), guava seed (GSPS), red formosa lambsquarters (RFLPS) and yellow formosa lambsquarters (YFLPS) were isolated for their immunomodulatory potential and tumor immunotherapy against human prostate cancer PC-3 cells and human breast cancer MCF-7 in vitro and in vivo. The results showed that all of five selected polysaccharides have a Th2-inclination property. Treatments with five selected polysaccharides in the presence of lipopolysaccharide (LPS) significantly decreased (IL-1β + IL-6 + TNF-α)/IL-10 cytokine secretion ratios by macrophages, suggesting that all of the selected polysaccharides, particularly GSPS, have anti-inflammatory potential. In the growth test of cancer cells, indirect addition of five selected polysaccharides using conditioned media of primary splenocytes (SCM) and peritoneal macrophages (MCM) markedly inhibited the growth of PC-3 and MCF-7 cells, particularly MCF-7 cells. The relationship between the growth of cancer cells and cytokine secretions by macrophages and splenocytes were analyzed. There is a negative correlation between the viability of human cancer cells and Th2/Th1 cytokine secretion levels in the corresponding SCM; there are negative correlations between viabilities of MCF-7 cells/PC-3 cells and pro-/anti-inflammatory cytokine secretion levels in the corresponding MCM. Our results suggest that five selected polysaccharides have a Th2-inclination property that may inhibit the growth of human breast cancer MCF-7 cells through increasing IL-10 secretion by primary splenocytes. In addition, five selected polysaccharides might inhibit the growth of human breast cancer PC-3 and MCF-7 cells through activating macrophages and increasing their secretion ratios of pro- /anti-inflammatory cytokines in a tumor microenvironment.
The purification of five selected polysaccharides using Sepharose 6B gel filtration showed that there were two or three fractions in each individual polysaccharide. The total protein and carbohydrate constituent ratios suggested that each individual fractions might be a proteopolysaccharide or glycoprotein. Five selected polysaccharides and its purified components significantly increased IL-10/IL-2 cytokine secretion ratios dose-dependently, suggesting that these polysaccharides and its purified components have a Th2-inclination property. Treatments with five selected polysaccharides and its purified components in the presence of LPS significantly decreased (IL-1β + IL-6 + TNF-α)/IL-10 cytokine secretion ratios by macrophages, suggesting that all of the five selected polysaccharides and its purified components, particularly GSF3, have anti-inflammatory potential. Direct addition of five selected polysaccharides and its purified components for 24 and 48 hours significantly inhibit PC-3 and MCF-7 cell growth. However, only GSF3 inhibited the growth of PC-3 and MCF-7 cells using SCM and MCM. Thus, GSPS was further selected to perform in animal studies for tumor immunotherapy. In addition, GSF3 was analyzed for its monosaccharides composition and property using a pre-column derivatization high-performance liquid chromatography (HPLC) method that was developed and optimized to characterize and quantify the monosaccharides. The results showed that GSF3 was a proteopolysaccharide. In monosaccharide composition, our study found that GSF3 is consisted of galacturonic acid, glucose, galactose and xylose.
BALB/c male mice were selected for prostate cancer cell xenografted animals to evaluate GSPS effects. Through a 4-week feeding experiment, GSPS significantly decreased Th1/Th2 cytokine secretion ratios of splenocytes and pro-/anti-inflammatory cytokine secretion ratios of peritoneal macrophages in BALB/c male mice xenografted with PC-3 cells, showing a Th2 and M2-inclination property in the experiment mice. Our results evidenced that GSPS intervention might inhibit PC-3 cell growth by improving Th1-skewed immune balance in the PC-3 xenografted BALB/c male mice, possibly via its potent Th2-inclination property.
In order to unravel possible and anti-tumor mechanisms of GSF3, GSF3 was selected to treat PC-3 and MCF-7 cells using direct addition or immunotherapy. The effects of GSF3 and conditioned media of immune cells cultured with GSF3 on pro-/anti-apoptotic and Fas genes expression were analyzed. The results showed that GSF3 direct addition increased pro-(Bax)/ anti-apoptotic (Bcl-2) mRNA expression ratios in PC-3 and MCF-7 cells. In addition, conditioned media of peritoneal macrophages cultured with GSF3 increased Fas mRNA expression in PC-3 cells, as wells as the conditioned media of splenocytes cultured with GSF3 increased Fas mRNA expressions in PC-3 and MCF-7 cells. Our results suggest that GSF3 treatments might induce apoptosis through increasing pro-(Bax)/ anti-apoptotic (Bcl-2) gene expression ratios and Fas gene expression via direct action or immunotherapy to achieve anticancer effects on PC-3 and MCF-7 cells.
URI: http://hdl.handle.net/11455/96063
Rights: 同意授權瀏覽/列印電子全文服務，2021-02-07起公開。
Appears in Collections:食品暨應用生物科技學系

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