Bailey J M, Mohr A M, Hollingsworth M A
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198-5950, USA.
Oncogene. 2009 Oct 8;28(40):3513-25. doi: 10.1038/onc.2009.220. Epub 2009 Jul 27.
Sonic hedgehog (SHH) expression is tightly regulated throughout development. In the adult, aberrant expression of SHH is associated with the onset and progression of pancreatic cancer, as evidenced by increased levels of expression in premalignant and malignant lesions of the pancreas. We investigated the hypothesis that SHH, secreted from pancreatic tumors, functions in a paracrine manner to influence the biological condition of mesenchymal and endothelial cells. Orthotopic implantation of a pancreatic tumor cell line expressing SHH (Capan-2) and a transformed primary cell line that overexpresses SHH (T-HPNE.SHH) were used to show that overexpression of SHH increased primary tumor size and metastasis. Treatment with a neutralizing antibody, 5E1, decreased primary tumor volume and inhibited metastasis. Lyve-1+ vessels and stromal fibroblasts in tumors expressed primary cilium and showed localization of the receptor Smoothened to the primary cilium, providing evidence of active SHH signaling through this pathway. Although primary cilia are present on normal ductal cells of the pancreas, we did not observe primary cilium on the ductal tumor cells, suggesting decreased autocrine signaling through pathways mediated by the primary cilium in pancreatic cancer. These data support the hypothesis that SHH, secreted from pancreatic epithelia, is critical in establishing and regulating the tumor microenvironment and thereby contributes to progression of pancreatic cancer.
音猬因子（SHH）的表达在整个发育过程中受到严格调控。在成体中，SHH的异常表达与胰腺癌的发生和进展相关，胰腺的癌前病变和恶性病变中表达水平升高即证明了这一点。我们研究了这样一个假说，即胰腺肿瘤分泌的SHH以旁分泌方式发挥作用，影响间充质细胞和内皮细胞的生物学状态。通过原位植入表达SHH的胰腺肿瘤细胞系（Capan-2）和过表达SHH的转化原代细胞系（T-HPNE.SHH），结果表明SHH的过表达增加了原发肿瘤的大小和转移。用中和抗体5E1处理可减小原发肿瘤体积并抑制转移。肿瘤中的Lyve-1+血管和基质成纤维细胞表达初级纤毛，且受体Smoothened定位于初级纤毛，这为通过该途径的活跃SHH信号传导提供了证据。虽然胰腺的正常导管细胞上存在初级纤毛，但我们在导管肿瘤细胞上未观察到初级纤毛，这表明胰腺癌中通过初级纤毛介导的途径的自分泌信号传导减少。这些数据支持了这样的假说，即胰腺上皮分泌的SHH在建立和调节肿瘤微环境中起关键作用，从而促进胰腺癌的进展。
