Lack of host SPARC enhances vascular function and tumor spread in an orthotopic murine model of pancreatic carcinoma
Lack of host SPARC enhances vascular function and tumor spread in an orthotopic murine model of pancreatic carcinoma
复制标题
DOI：
10.1242/dmm.003228
复制
发表时间：
2010-01-01
影响因子：
4.3
通讯作者：
Brekken, Rolf A.
中科院分区：
文献类型：
--
作者：
Arnold, Shanna A.;Rivera, Lee B.;Brekken, Rolf A.
利用皮下肿瘤模型，我们先前验证了α-半胱氨酸（分泌的酸性蛋白质，富含半胱氨酸）作为基质反应的关键组成部分，它调节肿瘤大小，血管生成和细胞外基质沉积。在本研究中，我们证明了原位生长在Sparc-null（Sparc（-/-））小鼠中的胰腺肿瘤比生长在野生型（Sparc（+/+））同窝小鼠中的肿瘤更具转移性。在Sparc（-/-）小鼠中生长的肿瘤显示纤维状胶原I和III、基底膜胶原IV和胶原相关蛋白聚糖核心蛋白聚糖的沉积减少。此外，在没有宿主细胞的情况下生长的肿瘤中微血管密度和周细胞募集减少。然而，来自Sparc（-/-）小鼠的肿瘤显示出增加的渗透性和灌注，以及随后的缺氧减少。最后，我们发现在没有宿主巨噬细胞的情况下生长的肿瘤表现出交替激活的巨噬细胞的增加。这些结果表明，在没有宿主细胞的情况下增加的肿瘤负荷是胶原沉积减少、血管基底膜破坏、血管功能增强和免疫耐受、促转移微环境的结果。
Utilizing subcutaneous tumor models, we previously validated SPARC (secreted protein acidic and rich in cysteine) as a key component of the stromal response, where it regulated tumor size, angiogenesis and extracellular matrix deposition. In the present study, we demonstrate that pancreatic tumors grown orthotopically in Sparc-null (Sparc(-/-)) mice are more metastatic than tumors grown in wild-type (Sparc(+/+)) littermates. Tumors grown in Sparc(-/-) mice display reduced deposition of fibrillar collagens I and III, basement membrane collagen IV and the collagen-associated proteoglycan decorin. In addition, microvessel density and pericyte recruitment are reduced in tumors grown in the absence of host SPARC However, tumors from Sparc(-/-) mice display increased permeability and perfusion, and a subsequent decrease in hypoxia. Finally, we found that tumors grown in the absence of host SPARC exhibit an increase in alternatively activated macrophages. These results suggest that increased tumor burden in the absence of host SPARC is a consequence of reduced collagen deposition, a disrupted vascular basement membrane, enhanced vascular function and an immune-tolerant, pro-metastatic microenvironment.