Hif1a Deletion Reveals Pro-Neoplastic Function of B Cells in Pancreatic Neoplasia.
Hif1a Deletion Reveals Pro-Neoplastic Function of B Cells in Pancreatic Neoplasia.
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DOI：
10.1158/2159-8290.cd-15-0822
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发表时间：
2016-03
期刊：
影响因子：
28.2
通讯作者：
Simon MC
中科院分区：
文献类型：
--
作者：
Lee KE;Spata M;Bayne LJ;Buza EL;Durham AC;Allman D;Vonderheide RH;Simon MC
胰腺导管腺癌（PDAC）是全球癌症相关死亡的主要原因，5年生存率极低。PDAC肿瘤的特征在于广泛的促结缔组织增生基质反应和血管生成不足，这表明肿瘤缺氧可以调节PDAC的起始和/或进展。使用定义明确的、本地KrasG 12 D驱动的小鼠模型以及人类肿瘤，我们证明了缺氧和缺氧诱导因子1α（HIF 1 α）的稳定性，缺氧适应的主要介质，在PDAC的侵袭前阶段早期出现。令人惊讶的是，胰腺特异性Hif 1 α缺失显著加速了KrasG 12 D驱动的胰腺肿瘤形成，并伴有胰腺内B淋巴细胞的显著增加，其特征是罕见的“B1 B”B细胞亚型的显著流入。最后，用去除B细胞的α CD 20单克隆抗体治疗HIF 1 α缺陷小鼠可抑制胰腺上皮内瘤变（PanIN）的进展。我们的数据揭示了B细胞在促进胰腺肿瘤发生中未被认识的作用，并暗示HIF 1 α是PDAC发展的关键调节因子。
Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related deaths worldwide, with an exceedingly low 5-year survival rate. PDAC tumors are characterized by an extensive desmoplastic stromal response and hypovascularity, suggesting that tumor hypoxia could regulate PDAC initiation and/or progression. Using a well-defined, autochthonous KrasG12D-driven murine model, as well as human tumors, we demonstrate that hypoxia and stabilization of hypoxia-inducible factor 1α (HIF1α), a principal mediator of hypoxic adaptation, emerge early during preinvasive stages of PDAC. Surprisingly, pancreas-specific Hif1α deletion drastically accelerated KrasG12D-driven pancreatic neoplasia, and was accompanied by significant increases in intrapancreatic B lymphocytes, featuring prominent influx of a rare “B1b” B cell subtype. Finally, treatment of HIF1α-deficient mice with B cell-depleting αCD20 monoclonal antibodies inhibited progression of pancreatic intraepithelial neoplasia (PanIN). Our data reveal a previously unrecognized role for B cells in promoting pancreatic tumorigenesis, and implicate HIF1α as a critical regulator of PDAC development.