Blockade of hedgehog signaling inhibits pancreatic cancer invasion and metastases: A new paradigm for combination therapy in solid cancers
Blockade of hedgehog signaling inhibits pancreatic cancer invasion and metastases: A new paradigm for combination therapy in solid cancers
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DOI：
10.1158/0008-5472.can-06-3281
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发表时间：
2007-03-01
期刊：
影响因子：
11.2
通讯作者：
Maitra, Anirban
中科院分区：
文献类型：
--
作者：
Feldmann, Georg;Dhara, Surajit;Maitra, Anirban
在胰腺癌的背景下，转移仍然是可切除性的最关键决定因素，因此生存。本研究的目的是确定Hedgehog（Hh）信号传导是否在胰腺癌侵袭和转移中起作用，因为这可能具有深远的临床意义。在胰腺癌细胞系中，用环巴胺抑制Hh导致snail的下调和E-钙粘蛋白的上调，这与上皮向间质转化的抑制一致，并且通过体外侵袭能力的显著降低来反映（P < 0.0001）。相反，Gli 1在永生化的人胰腺导管上皮细胞中的过表达导致显著的侵袭性表型（P < 0.0001）和几乎完全下调的E-钙粘蛋白。在原位异种移植模型中，环巴胺深刻地抑制转移扩散，只有一个环巴胺治疗的7只小鼠肺微转移与7只小鼠与多个宏观转移在对照动物。吉西他滨和环巴胺的组合完全消除了转移，同时也显著减小了“原发性”肿瘤的大小。与匹配的原发性肿瘤相比，转移性人胰腺癌组织样本中Gli 1水平上调。醛脱氢酶（ALDH）过表达是造血祖细胞和白血病干细胞的特征;环巴胺优先减少“ALDH高”细胞，减少幅度接近3倍（P = 0.048）。我们确认药理学Hh通路抑制作为胰腺癌的有效治疗策略，并首次显示其对转移扩散的特定疗效。通过靶向可能参与转移部位肿瘤起始的特定细胞亚群，Hh抑制剂可能为治疗播散性恶性肿瘤提供新的范例，特别是当与减少“体积”肿瘤大小的常规抗代谢物联合使用时。
In the context of pancreatic cancer, metastasis remains the most critical determinant of resectability, and hence survival. The objective of this study was to determine whether Hedgehog (Hh) signaling plays a role in pancreatic cancer invasion and metastasis because this is likely to have profound clinical implications. In pancreatic cancer cell lines, Hh inhibition with cyclopamine resulted in down-regulation of snail and up-regulation of E-cadherin, consistent with inhibition of epithelial-to-mesenchymal transition, and was mirrored by a striking reduction of in vitro invasive capacity (P < 0.0001). Conversely, Gli1 overexpression in immortalized human pancreatic ductal epithelial cells led to a markedly invasive phenotype (P < 0.0001) and near total down-regulation of E-cadherin. In an orthotopic xenograft model, cyclopamine profoundly inhibited metastatic spread; only one of seven cyclopamine-treated mice developed pulmonary micrometastases versus seven of seven mice with multiple macrometastases in control animals. Combination of gemcitabine and cyclopamine completely abrogated metastases while also significantly reducing the size of "primary" tumors. Gli1 levels were up-regulated in tissue samples of metastatic human pancreatic cancer samples compared with matched primary tumors. Aldehyde dehydrogenase (ALDH) overexpression is characteristic for both hematopoietic progenitors and leukemic stem cells; cyclopamine preferentially reduced "ALDH-high" cells by similar to 3-fold (P = 0.048). We confirm pharmacologic Hh pathway inhibition as a valid therapeutic strategy for pancreatic cancer and show for the first time its particular efficacy against metastatic spread. By targeting specific cellular subpopulations likely involved in tumor initiation at metastatic sites, Hh inhibitors may provide a new paradigm for therapy of disseminated malignancies, particularly when used in combination with conventional antimetabolites that reduce "bulk" tumor size.