Hypoxic Tumor Microenvironments Reduce Collagen I Fiber Density
Hypoxic Tumor Microenvironments Reduce Collagen I Fiber Density
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DOI：
10.1593/neo.10344
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发表时间：
2010-08-01
期刊：
影响因子：
4.8
通讯作者：
Glunde, Kristine
中科院分区：
文献类型：
--
作者：
Kakkad, Samata M.;Solaiyappan, Meiyappan;Glunde, Kristine
虽然缺氧影响几个表型特征的机制，如血管生成，选择抗凋亡，抗放疗和化疗，增加侵袭和转移的特点，肿瘤缺氧和细胞外基质（ECM）的成分之间的关系是相对未开发的。实体瘤的胶原I（Col 1）纤维基质是ECM的主要结构部分。Col 1纤维密度可增加肿瘤的发生、进展和转移，癌细胞沿沿着放射状排列的Col 1纤维侵袭。在这里，我们研究了缺氧对Col 1纤维密度的影响，在固体乳腺癌和前列腺肿瘤模型。二次谐波发生（SHG）显微镜用于检测低氧和常氧肿瘤区域之间Col 1纤维密度和体积的差异。通过荧光显微镜检测缺氧区域，使用来源于在缺氧反应元件的转录控制下稳定表达增强型绿色荧光蛋白（EGFP）的人乳腺癌和前列腺癌细胞系的肿瘤。使用内部纤维分析软件从SHG显微镜图像定量分析Coll纤维密度和体积。含氧量正常的肿瘤区域表现出Col 1纤维的密集网格。相反，在缺氧的EGFP表达肿瘤区域检测到较少的和结构改变的Col 1纤维。微阵列基因表达分析表明，与常氧癌细胞相比，缺氧癌细胞赖氨酰氧化酶表达增加，一些基质金属蛋白酶表达减少。这些结果表明，缺氧介导的Col 1纤维重组肿瘤，这可能会影响大分子药物的交付以及细胞的传播。Neoplasia（2010）12，608-617
Although the mechanisms through which hypoxia influences several phenotypic characteristics such as angiogenesis, selection for resistance to apoptosis, resistance to radiation and chemotherapy, and increased invasion and metastasis are well characterized, the relationship between tumor hypoxia and components of the extracellular matrix (ECM) is relatively unexplored. The collagen I (Col1) fiber matrix of solid tumors is the major structural part of the ECM. Col1 fiber density can increase tumor initiation, progression, and metastasis, with cancer cell invasion occurring along radially aligned Col1 fibers. Here we have investigated the influence of hypoxia on Col1 fiber density in solid breast and prostate tumor models. Second harmonic generation (SHG) microscopy was used to detect differences in Col1 fiber density and volume between hypoxic and normoxic tumor regions. Hypoxic regions were detected by fluorescence microscopy, using tumors derived from human breast and prostate cancer cell lines stably expressing enhanced green fluorescent protein (EGFP) under transcriptional control of the hypoxia response element. In-house fiber analysis software was used to quantitatively analyze Col1 fiber density and volume from the SHG microscopy images. Normoxic tumor regions exhibited a dense mesh of Col1 fibers. In contrast, fewer and structurally altered Col1 fibers were detected in hypoxic EGFP-expressing tumor regions. Microarray gene expression analyses identified increased expression of lysyl oxidase and reduced expression of some matrix metalloproteases in hypoxic compared with normoxic cancer cells. These results suggest that hypoxia mediates Col1 fiber restructuring in tumors, which may impact delivery of macromolecular agents as well as dissemination of cells. Neoplasia (2010) 12, 608-617