Platelet-Derived Growth Factor-B Normalizes Micromorphology and Vessel Function in Vascular Endothelial Growth Factor-A-Induced Squamous Cell Carcinomas
Platelet-Derived Growth Factor-B Normalizes Micromorphology and Vessel Function in Vascular Endothelial Growth Factor-A-Induced Squamous Cell Carcinomas
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DOI：
10.2353/ajpath.2010.080998
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发表时间：
2010-02-01
影响因子：
6
通讯作者：
Mueller, Margareta M.
中科院分区：
文献类型：
--
作者：
Lederle, Wiltrud;Linde, Nina;Mueller, Margareta M.
血管内皮生长因子(VEGF)是血管生成的关键调节因子，常可诱导形成通透性增加、血管功能降低的未成熟血管。在这里，我们证明了从头表达小鼠(M)血管内皮生长因子-164诱导HaCaT角质形成细胞的恶性和侵袭性肿瘤生长。然而，mVEGF-164诱导的肿瘤是溃烂的，上皮细胞紊乱，被有限的基底膜和内皮细胞覆盖的陷窝打断。血管成熟度严重受损。联合表达人血小板衍生生长因子(HPDGF)-B和mVEGF-164可显著改善肿瘤和血管的微形态。尽管肿瘤的大小和恶性程度与单独表达mVEGF-164或联合表达人PDGF-B和mVEGF-164相似，但联合表达hPDGF-B和mVEGF-164可使肿瘤组织更坚实、更致密，具有成熟的功能肿瘤血管和更高的微血管密度，正如组织学和动态增强磁共振成像所证明的那样。用甲磺酸伊马替尼阻断PDGF-B信号转导可逆转hPDGF-B和mVEGF-164表达的肿瘤。此外，在体外与成纤维细胞的三维器型共培养中证实，mVEGF-164和mVEGF-164加hPDGF-B转染体体内的肿瘤细胞侵袭与肿瘤来源的基质金属蛋白酶-1和基质基质金属蛋白酶-9和-13的诱导显著相关。这些数据清楚地表明，在建立具有功能血管的实体肿瘤时，需要不同生长因子的协同作用，并强调了多因素治疗的必要性。(Am J Pathol2010,176：981-994；DOI：10.2353/ajpath.2010.080998)
Vascular endothelial growth factor (VEGF), which is a key regulator of angiogenesis, often induces formation of immature vessels with increased permeability and reduced vessel functionality. Here, we demonstrate that de novo expression of murine (m)VEGF-164 induces malignant and invasive tumor growth of HaCaT keratinocytes. However, the mVEGF-164-induced tumors are ulcerated with a disorganized epithelium that is interrupted by lacunae with limited basement membrane and endothelial cell coverage. Vessel maturation is strongly impaired. Tumor and vessel micromorphology are markedly improved by the combined expression of human platelet-derived growth factor (hPDGF)-B and mVEGF-164. Although tumor size and malignancy are comparable with either mVEGF-164 alone or combined human PDGF-B and mVEGF-164 expression, combined hPDGF-B and mVEGF-164 expression leads to a more solid and compact tumor tissue with a mature functional tumor vasculature and a higher microvessel density, as demonstrated histologically and by dynamic contrast-enhanced magnetic resonance imaging. Treatment of the hPDGF-B- and mVEGF-164-expressing tumors with imatinib mesylate to block PDGF-B signaling reverses this effect. In addition, tumor cell invasion of mVEGF-164 transfectants and mVEGF-164 plus hPDGF-B transfectants in vivo is associated with a marked induction of tumor-derived matrix metalloproteinase-1 and stromal matrix metalloproteinase-9 and -13, as was confirmed in three-dimensional organotypic co-cultures with fibroblasts in vitro. These data clearly demonstrate the need for a concerted action of different growth factors in the establishment of solid tumors with functional vasculature and emphasize the need for a multifactorial therapy. (Am J Pathol 2010, 176:981-994; DOI: 10.2353/ajpath.2010.080998)