Han Song, Gonzalo David H, Feely Michael, Rinaldi Carlos, Belsare Sayali, Zhai Haiyan, Kalra Krishan, Gerber Michael H, Forsmark Christopher E, Hughes Steven J
Department of Surgery, University of Florida College of Medicine, Gainesville, FL, USA.
Department of Pathology, University of Florida College of Medicine, Gainesville, FL, USA.
Oncotarget. 2017 Dec 20;9(5):5764-5777. doi: 10.18632/oncotarget.23532. eCollection 2018 Jan 19.
The biology of tumor-associated stroma (TAS) in pancreatic ductal adenocarcinoma (PDAC) is not well understood. The paradoxical observation that stroma-depletion strategies lead to progression of PDAC reinforced the need to critically evaluate the functional contribution of TAS in the initiation and progression of PDAC. PDAC and TAS cells are unique in their expression of specific miRNAs, and this specific miRNA expression pattern alters host to tumor microenvironment interactions. Using primary human pancreatic TAS cells and primary xenograft PDAC cells co-culture, we provide evidence of miRNA trafficking and exchanging between TAS and PDAC cells, in a two-way, cell-contact independent fashion, via extracellular vesicles (EVs) transportation. Selective packaging of miRNAs into EVs led to enrichment of stromal specific miR-145 in EVs secreted by TAS cells. Exosomes, but not microvesicles, derived from human TAS cells demonstrated a tumor suppressive role by inducing PDAC cell apoptosis. This effect was mitigated by anti-miR-145 sequences. Our data suggest that TAS-derived miRNAs are delivered to adjacent PDAC cells via exosomes and suppress tumor cell growth. These data highlight that TAS cells secrete exosomes carrying tumor suppressive genetic materials, a possible anti-tumor capacity. Future work of the development of patient-derived exosomes could have therapeutic implications for unresectable PDAC.
胰腺导管腺癌（PDAC）中肿瘤相关基质（TAS）的生物学特性尚未得到充分了解。基质清除策略会导致PDAC进展这一矛盾的观察结果，强化了严格评估TAS在PDAC起始和进展中的功能作用的必要性。PDAC细胞和TAS细胞在特定miRNA的表达上具有独特性，这种特定的miRNA表达模式改变了宿主与肿瘤微环境之间的相互作用。通过使用原代人胰腺TAS细胞和原代异种移植PDAC细胞共培养，我们提供了证据表明miRNA通过细胞外囊泡（EV）运输，以双向、不依赖细胞接触的方式在TAS细胞和PDAC细胞之间进行运输和交换。miRNA选择性包装到EV中导致TAS细胞分泌的EV中富含基质特异性miR-145。源自人TAS细胞的外泌体而非微囊泡，通过诱导PDAC细胞凋亡发挥肿瘤抑制作用。抗miR-145序列可减轻这种作用。我们的数据表明，TAS来源的miRNA通过外泌体传递给相邻的PDAC细胞并抑制肿瘤细胞生长。这些数据突出表明，TAS细胞分泌携带肿瘤抑制遗传物质的外泌体，具有潜在的抗肿瘤能力。开发患者来源外泌体的未来工作可能对不可切除的PDAC具有治疗意义。
