Hedgehog promotes neovascularization in pancreatic cancers by regulating Ang-1 and IGF-1 expression in bone-marrow derived pro-angiogenic cells.
Hedgehog promotes neovascularization in pancreatic cancers by regulating Ang-1 and IGF-1 expression in bone-marrow derived pro-angiogenic cells.
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DOI：
10.1371/journal.pone.0008824
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发表时间：
2010-01-21
期刊：
影响因子：
3.7
通讯作者：
Kohgo Y
中科院分区：
文献类型：
--
作者：
Nakamura K;Sasajima J;Mizukami Y;Sugiyama Y;Yamazaki M;Fujii R;Kawamoto T;Koizumi K;Sato K;Fujiya M;Sasaki K;Tanno S;Okumura T;Shimizu N;Kawabe J;Karasaki H;Kono T;Ii M;Bardeesy N;Chung DC;Kohgo Y
刺猬蛋白 (Hh) 通路与包括胰腺导管腺癌 (PDAC) 在内的癌症的发病机制有关。最近的研究表明，Hh 在 PDAC 中的致癌功能涉及基质细胞中的信号传导，而不是对肿瘤细胞的细胞自主作用。然而，对 Hh 信号传导有反应的基质细胞类型的起源和性质仍然未知。由于 Hh 信号在胚胎和出生后血管发生过程中发挥着至关重要的作用，我们推测 Hh 配体可能作用于肿瘤血管系统，特别是骨髓 (BM) 来源的细胞。环巴明用于抑制人 PDAC 细胞系及其异种移植物中的 Hh 途径。采用 BM 移植、肿瘤细胞和 BM 衍生的促血管生成细胞 (BMPC) 的共培养系统来评估肿瘤衍生的 Hh 在调节 BM 区室中的作用以及 BM 衍生的细胞对 PDAC 中血管生成的贡献。环巴明的施用减弱了基质中的 Hh 信号传导，而不是癌细胞中的 Hh 信号传导，这反映在全长 Gli2 蛋白和 Gli1 mRNA 的表达特别是在隔室中的减少。环巴明抑制 PDAC 异种移植物的生长，与肿瘤血管系统的消退相关，并减少 BM 衍生细胞向肿瘤的归巢。在肿瘤异种移植物中，环巴明下调了宿主来源的 Ang-1 和 IGF-1 mRNA 水平。体外共培养和基质胶塞测定表明，PDAC 细胞衍生的 Shh 诱导 BMPC 产生 Ang-1 和 IGF-1，从而增强其迁移和毛细血管形态发生活性。我们将 BMPC 确定为 PDAC 中 Hh 配体的替代基质靶标，表明肿瘤脉管系统是 Hh 阻断的一个有吸引力的治疗靶点。我们的数据与新兴概念一致，即骨髓来源的细胞对上皮肿瘤发生做出重要贡献。
The hedgehog (Hh) pathway has been implicated in the pathogenesis of cancer including pancreatic ductal adenocarcinoma (PDAC). Recent studies have suggested that the oncogenic function of Hh in PDAC involves signaling in the stromal cells rather than cell autonomous effects on the tumor cells. However, the origin and nature of the stromal cell type(s) that are responsive to Hh signaling remained unknown. Since Hh signaling plays a crucial role during embryonic and postnatal vasculogenesis, we speculated that Hh ligand may act on tumor vasculature specifically focusing on bone marrow (BM)-derived cells. Cyclopamine was utilized to inhibit the Hh pathway in human PDAC cell lines and their xenografts. BM transplants, co-culture systems of tumor cells and BM-derived pro-angiogenic cells (BMPCs) were employed to assess the role of tumor-derived Hh in regulating the BM compartment and the contribution of BM-derived cells to angiogenesis in PDAC. Cyclopamine administration attenuated Hh signaling in the stroma rather than in the cancer cells as reflected by decreased expression of full length Gli2 protein and Gli1 mRNA specifically in the compartment. Cyclopamine inhibited the growth of PDAC xenografts in association with regression of the tumor vasculature and reduced homing of BM-derived cells to the tumor. Host-derived Ang-1 and IGF-1 mRNA levels were downregulated by cyclopamine in the tumor xenografts. In vitro co-culture and matrigel plug assays demonstrated that PDAC cell-derived Shh induced Ang-1 and IGF-1 production in BMPCs, resulting in their enhanced migration and capillary morphogenesis activity. We identified the BMPCs as alternative stromal targets of Hh-ligand in PDAC suggesting that the tumor vasculature is an attractive therapeutic target of Hh blockade. Our data is consistent with the emerging concept that BM-derived cells make important contributions to epithelial tumorigenesis.
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