Significance of tumor-associated stroma in promotion of intratumoral lymphangiogenesis - Pivotal role of a hyaluronan-rich tumor microenvironment
Significance of tumor-associated stroma in promotion of intratumoral lymphangiogenesis - Pivotal role of a hyaluronan-rich tumor microenvironment
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DOI：
10.2353/ajpath.2008.070360
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发表时间：
2008-01-01
影响因子：
6
通讯作者：
Itano, Naoki
中科院分区：
文献类型：
--
作者：
Koyama, Hiroshi;Kobayashi, Nobutaka;Itano, Naoki
基质细胞与细胞外基质成分一起提供了对癌细胞生长和进展至关重要的肿瘤微环境。在我们以前的研究中，使用乳腺癌的条件转基因小鼠模型，透明质酸，一种主要的细胞外成分，通过基质细胞募集加速肿瘤血管生成的过度生产。这一发现使我们研究透明质酸在淋巴管系统中的作用。在这里，我们发现微环境透明质酸促进肿瘤淋巴管生成的同时，基质结构的形成。此外，淋巴管经常渗透和积累到间质区室，并在肿瘤间质界面检测到血管内皮生长因子-C和-D的上调。为了评估基质细胞对体内淋巴管生成的贡献，我们从透明质酸过度产生的乳腺肿瘤中建立了肿瘤相关成纤维细胞，并将其与来自对照肿瘤的癌细胞或MCF-7人乳腺癌细胞一起植入裸鼠体内。癌细胞生长迅速，伴有显著的间质反应和淋巴管生成。然而，没有基质细胞，肿瘤发展缓慢，基质和淋巴管较少。这些发现强调了肿瘤相关基质在促进肿瘤内淋巴管生成中的重要性，并提示富含透明质酸的肿瘤微环境具有关键作用。
Stromal cells, together with extracellular matrix components, provide a tumor microenvironment that is pivotal for cancer cell growth and progression. In our previous study using a conditional transgenic mouse model of breast cancer, the overproduction of hyaluronan, a major extracellular constituent, accelerated tumor angiogenesis through stromal cell recruitment. This finding led us to investigate the role of hyaluronan in the lymphatic vessel system. Here, we have found that microenvironmental hyaluronan promoted tumor lymphangiogenesis concurrently with the formation of stromal structures. Additionally, lymphatic vessels frequently penetrated and accumulated into stromal compartments, and up-regulation of vascular endothelial growth factor-C and -D was detected at tumor-stromal interfaces. To assess the contribution of stromal cells to lymphangiogenesis in vivo, we established tumor-associated fibroblasts from hyaluronan-overproducing mammary tumors and implanted them together with carcinoma cells from control tumors or MCF-7 human breast carcinoma cells in nude mice. Carcinoma cells grew rapidly in association with marked stromal reactions and lymphangiogenesis. Without the stromal cells, however, the tumors developed slowly with less stroma and lymphatic vessels. These findings underline the significance of tumor-associated stroma in the promotion of intratumoral lymphangiogenesis and suggest a pivotal role for the hyaluronan-rich tumor microenvironment.