The pro-inflammatory peptide LL-37 promotes ovarian tumor progression through recruitment of multipotent mesenchymal stromal cells
The pro-inflammatory peptide LL-37 promotes ovarian tumor progression through recruitment of multipotent mesenchymal stromal cells
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DOI：
10.1073/pnas.0900244106
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发表时间：
2009-03-10
影响因子：
11.1
通讯作者：
Scandurro, Aline B.
中科院分区：
文献类型：
--
作者：
Coffelt, Seth B.;Marini, Frank C.;Scandurro, Aline B.
骨髓源性间充质干细胞或多能间充质基质细胞（MSC）已被证明可以移植到几种肿瘤类型的基质中，在那里它们有助于肿瘤进展和转移。然而，介导MSC迁移到肿瘤的趋化信号仍然知之甚少。以前的研究表明，LL-37（亮氨酸，亮氨酸-37），人类阳离子抗菌蛋白18的C-末端肽，刺激各种细胞类型的迁移，并在卵巢癌，乳腺癌和肺癌中过表达。虽然有证据支持LL-37的促肿瘤作用，但该肽在肿瘤中的功能仍不清楚。在这里，我们证明了LL-37在体内的中和作用显著减少了MSC向卵巢肿瘤异种移植物中的植入，从而抑制了肿瘤生长并破坏了纤维血管网络。在体外进行的迁移和侵袭实验表明，LL-37介导的MSC向肿瘤的迁移可能通过甲酰肽受体样-1发生。为了评估MSC对富含LL-37的肿瘤微环境的反应，评估了来自LL-37处理的MSC的条件培养基，发现与对照相比，其含有增加水平的几种细胞因子和促血管生成因子，包括IL-1受体拮抗剂、IL-6、IL-10、CCL 5、VEGF和基质金属蛋白酶-2。类似地，基质胶与LL-37、MSC或两者的组合混合在裸鼠中导致显著数量的血管通道。这些数据表明，LL- 37通过募集祖细胞群作为表达促血管生成因子的肿瘤基质细胞来促进卵巢肿瘤进展。
Bone marrow-derived mesenchymal stem cells or multipotent mesenchymal stromal cells (MSCs) have been shown to engraft into the stroma of several tumor types, where they contribute to tumor progression and metastasis. However, the chemotactic signals mediating MSC migration to tumors remain poorly understood. Previous studies have shown that LL-37 (leucine, leucine-37), the C-terminal peptide of human cationic antimicrobial protein 18, stimulates the migration of various cell types and is overexpressed in ovarian, breast, and lung cancers. Although there is evidence to support a pro-tumorigenic role for LL-37, the function of the peptide in tumors remains unclear. Here, we demonstrate that neutralization of LL-37 in vivo significantly reduces the engraftment of MSCs into ovarian tumor xenografts, resulting in inhibition of tumor growth as well as disruption of the fibrovascular network. Migration and invasion experiments conducted in vitro indicated that the LL-37-mediated migration of MSCs to tumors likely occurs through formyl peptide receptor like-1. To assess the response of MSCs to the LL-37- rich tumor microenvironment, conditioned medium from LL-37- treated MSCs was assessed and found to contain increased levels of several cytokines and proangiogenic factors compared with controls, including IL-1 receptor antagonist, IL-6, IL-10, CCL5, VEGF, and matrix metalloproteinase-2. Similarly, Matrigel mixed with LL-37, MSCs, or the combination of the two resulted in a significant number of vascular channels in nude mice. These data indicate that LL- 37 facilitates ovarian tumor progression through recruitment of progenitor cell populations to serve as pro-angiogenic factor-expressing tumor stromal cells.