Extra-pancreatic invasion induces lipolytic and fibrotic changes in the adipose microenvironment, with released fatty acids enhancing the invasiveness of pancreatic cancer cells.
Extra-pancreatic invasion induces lipolytic and fibrotic changes in the adipose microenvironment, with released fatty acids enhancing the invasiveness of pancreatic cancer cells.
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DOI：
10.18632/oncotarget.15430
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发表时间：
2017-03-14
期刊：
影响因子：
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通讯作者：
Nakamura M
中科院分区：
文献类型：
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作者：
Okumura T;Ohuchida K;Sada M;Abe T;Endo S;Koikawa K;Iwamoto C;Miura D;Mizuuchi Y;Moriyama T;Nakata K;Miyasaka Y;Manabe T;Ohtsuka T;Nagai E;Mizumoto K;Oda Y;Hashizume M;Nakamura M
胰腺癌的进展涉及肿瘤微环境的组成部分，包括星状细胞、免疫细胞、内皮细胞和细胞外基质。虽然胰腺周围脂肪是参与胰腺外浸润的主要基质成分，但其在胰腺癌局部浸润和转移中的作用尚不清楚。本研究利用基因工程小鼠（Pdx1-Cre; LSL-KrasG12D; Trp53R172H/+）和体外器官型脂肪侵袭模型，研究了脂肪组织在胰腺癌进展中的作用。喂食高脂肪食物的老鼠比喂食标准食物的老鼠有更大的原发性胰腺肿瘤和更高的远端器官转移率。在器官型脂肪侵袭模型中，胰腺癌细胞簇更小，形状更长，纤维化增加。脂肪组织来源的条件培养基增强了胰腺癌细胞的侵袭性和对吉西他滨的耐药性，并诱导癌细胞的形态改变，增加了其细胞质中脂滴的数量。脂肪组织衍生的条件培养基中油酸、棕榈油酸和亚油酸的浓度高于正常培养基，这些脂肪酸显著增强了癌细胞的迁移。与癌细胞共培养时，成熟脂肪细胞体积较小，培养基中脂肪酸浓度较高。这些发现表明，胰腺周围脂肪组织的脂溶性和纤维化改变通过脂肪细胞释放的脂肪酸增强了局部侵袭和转移。抑制癌细胞对脂肪酸的摄取可能是一种针对癌细胞与基质细胞相互作用的新疗法。
Pancreatic cancer progression involves components of the tumor microenvironment, including stellate cells, immune cells, endothelial cells, and the extracellular matrix. Although peripancreatic fat is the main stromal component involved in extra-pancreatic invasion, its roles in local invasion and metastasis of pancreatic cancer remain unclear. This study investigated the role of adipose tissue in pancreatic cancer progression using genetically engineered mice (Pdx1-Cre; LSL-KrasG12D; Trp53R172H/+) and an in vitro model of organotypic fat invasion. Mice fed a high fat diet had significantly larger primary pancreatic tumors and a significantly higher rate of distant organ metastasis than mice fed a standard diet. In the organotypic fat invasion model, pancreatic cancer cell clusters were smaller and more elongated in shape and showed increased fibrosis. Adipose tissue-derived conditioned medium enhanced pancreatic cancer cell invasiveness and gemcitabine resistance, as well as inducing morphologic changes in cancer cells and increasing the numbers of lipid droplets in their cytoplasm. The concentrations of oleic, palmitoleic, and linoleic acids were higher in adipose tissue-derived conditioned medium than in normal medium, with these fatty acids significantly enhancing the migration of cancer cells. Mature adipocytes were smaller and the concentration of fatty acids in the medium higher when these cells were co-cultured with cancer cells. These findings indicate that lipolytic and fibrotic changes in peripancreatic adipose tissue enhance local invasiveness and metastasis via adipocyte-released fatty acids. Inhibition of fatty acid uptake by cancer cells may be a novel therapy targeting interactions between cancer and stromal cells.