Obesity-Induced Inflammation and Desmoplasia Promote Pancreatic Cancer Progression and Resistance to Chemotherapy.
Obesity-Induced Inflammation and Desmoplasia Promote Pancreatic Cancer Progression and Resistance to Chemotherapy.
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DOI：
10.1158/2159-8290.cd-15-1177
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发表时间：
2016-08
期刊：
影响因子：
28.2
通讯作者：
Jain RK
中科院分区：
文献类型：
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作者：
Incio J;Liu H;Suboj P;Chin SM;Chen IX;Pinter M;Ng MR;Nia HT;Grahovac J;Kao S;Babykutty S;Huang Y;Jung K;Rahbari NN;Han X;Chauhan VP;Martin JD;Kahn J;Huang P;Desphande V;Michaelson J;Michelakos TP;Ferrone CR;Soares R;Boucher Y;Fukumura D;Jain RK
目前尚不清楚肥胖如何影响胰腺导管腺癌（PDAC）患者的治疗结果。在正常胰腺中，肥胖会促进炎症和纤维化。我们在PDAC的小鼠模型中发现，肥胖还促进与肿瘤生长加速和通过灌注减少而损害化疗药物的递送/功效相关的结缔组织增生。血管紧张素II 1型受体（AT 1）的遗传和药理学抑制可逆转肥胖增强的结缔组织增生和肿瘤生长，并改善对化疗的反应。肥胖症中胰腺星状细胞（PSC）的增强活化由脂肪细胞分泌的IL-1β募集的肿瘤相关中性粒细胞（TAN）诱导。PSC进一步分泌IL-1β，并且PSC的失活减少IL-1β表达和TAN募集。此外，TAN的消耗、IL-1β抑制或PSC的失活可防止肥胖加速的肿瘤生长。在胰腺癌患者中，我们证实肥胖与结缔组织增生增加和化疗反应降低有关。我们的结论是，脂肪细胞，TAN和PSC之间的串扰加重结缔组织增生，促进肥胖症的肿瘤进展。
It remains unclear how obesity worsens treatment outcomes in patients with pancreatic ductal adenocarcinoma (PDAC). In normal pancreas, obesity promotes inflammation and fibrosis. We found in mouse models of PDAC that obesity also promotes desmoplasia associated with accelerated tumor growth and impaired delivery/efficacy of chemotherapeutics through reduced perfusion. Genetic and pharmacological inhibition of angiotensin-II type-1 receptor (AT1) reverses obesity-augmented desmoplasia and tumor growth and improves response to chemotherapy. Augmented activation of pancreatic stellate cells (PSCs) in obesity is induced by tumor-associated neutrophils (TANs) recruited by adipocyte-secreted IL-1β. PSCs further secrete IL-1β, and inactivation of PSCs reduces IL-1β expression and TAN recruitment. Furthermore, depletion of TANs, IL-1β inhibition, or inactivation of PSCs prevents obesity-accelerated tumor growth. In pancreatic cancer patients, we confirmed that obesity is associated with increased desmoplasia and reduced response to chemotherapy. We conclude that crosstalk between adipocytes, TANs, and PSCs exacerbates desmoplasia and promotes tumor progression in obesity.