Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis
Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis
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DOI：
10.1101/gad.13.11.1382
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发表时间：
1999-06-01
影响因子：
10.5
通讯作者：
Hanahan, D
中科院分区：
文献类型：
--
作者：
Coussens, LM;Raymond, WW;Hanahan, D
HPV 16早期区基因在转基因宫颈癌多阶段转化中基底角朊细胞的表达我们报道了肥大细胞的浸润和基质金属蛋白酶MMP-9/明胶酶B的激活与癌前病变中的血管生成转换相一致。肥大细胞浸润癌的增生、发育不良和浸润前沿，但不浸润实体瘤的核心，在那里它们与毛细血管和上皮基底膜紧密贴壁，释放肥大细胞特异性丝氨酸蛋白酶MCP-C（糜酶）和MCP-6（类胰蛋白酶）。MCP-6被证明是在反应性基质中增殖的真皮成纤维细胞的有丝分裂原，而MCP-4可以激活明胶酶B并在体外生物测定中诱导增生皮肤成为血管生成的。值得注意的是，癌前血管生成在肥大细胞缺陷型（KITW/KITWWv）HPV 16转基因小鼠中减少。数据表明，在该模型中的肿瘤进展涉及利用对组织异常的炎症反应。因此，在鳞状细胞癌发生过程中，血管生成的调节是双相的：在增生、发育不良和侵袭性癌前沿，炎性肥大细胞被征召来重组基质结构并过度激活血管生成;在癌核心内，肿瘤细胞中血管生成因子的上调显然使它们在维持新血管生成方面自给自足。
Expression of HPV16 early region genes in basal keratinocytes of transgenic mise elicits a multistage pathway to squamous carcinoma. We report that infiltration by mast cells and activation of the matrix metalloproteinase MMP-9/gelatinase B coincides with the angiogenic switch in premalignant lesions. Mast cells infiltrate hyperplasias, dysplasias, and invasive fronts of carcinomas, but not the core of solid turners, where they degranulate in close apposition to capillaries and epithelial basement membranes, releasing mast-cell-specific serine proteases MCP-C (chymase) and MCP-6 (tryptase). MCP-6 is shown to be a mitogen for dermal fibroblasts that proliferate in the reactive stroma, whereas MCP-4 can activate progelatinase B and induce hyperplastic skin to become angiogenic in an in vitro bioassay. Notably, premalignant angiogenesis is abated in a mast-cell-deficient (KITW/KITWWv) HPV16 transgenic mouse. The data indicate that neoplastic progression in this model involves exploitation of an inflammatory response to tissue abnormality. Thus, regulation of angiogenesis during squamous carcinogenesis is biphasic: In hyperplasias, dysplasias, and invading cancer fronts, inflammatory mast cells are conscripted to reorganize stromal architecture and hyperactivate angiogenesis; within the cancer core, upregulation of angiogenesis factors in tumor cells apparently renders them self-sufficient at sustaining neovascularization.