Type III Collagen Directs Stromal Organization and Limits Metastasis in a Murine Model of Breast Cancer
Type III Collagen Directs Stromal Organization and Limits Metastasis in a Murine Model of Breast Cancer
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DOI：
10.1016/j.ajpath.2015.01.029
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发表时间：
2015-05-01
影响因子：
6
通讯作者：
Volk, Susan W.
中科院分区：
文献类型：
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作者：
Brisson, Becky K.;Mauldin, Elizabeth A.;Volk, Susan W.
乳腺癌转移是全世界妇女癌症相关死亡的主要原因。肿瘤微环境中的胶原蛋白在调节肿瘤进展中起着至关重要的作用。我们已经表明，III型胶原蛋白（Col 3），肿瘤基质的组成部分，调节肌成纤维细胞分化和皮肤损伤后的瘢痕形成。在这些伤口愈合研究的过程中，我们注意到与野生型同窝对照相比，Col 3（+/-）小鼠中肿瘤的发生频率更高。因此，我们使用小鼠乳腺癌细胞系4 T1研究了Col 3缺陷对肿瘤行为的影响。值得注意的是，与同窝出生的Col 3（+/+）小鼠相比，原位注射4 T1细胞后，Col 3（+/-）小鼠的肿瘤体积和肺转移负荷增加。通过使用鼠（411）和人（MDA-MB-231）乳腺癌细胞生长在Col 3-穷人和Col 3-丰富的微环境在体外，我们发现，转移过程中的几个主要事件被抑制Col 3，包括粘附，侵袭和迁移。此外，Col 3缺陷增加增殖和减少凋亡的4 T1细胞在体外和在体内原发性肿瘤。在机制上，Col 3通过调节基质组织（包括纤维状胶原和肌成纤维细胞的密度和排列）来抑制致癌微环境。我们认为Col 3通过抑制肿瘤相关间质的促转移特性在肿瘤微环境中发挥重要作用。
Breast cancer metastasis is the leading cause of cancer-related deaths in women worldwide. Collagen in the tumor microenvironment plays a crucial role in regulating tumor progression. We have shown that type III collagen (Col3), a component of tumor stroma, regulates myofibroblast differentiation and scar formation after cutaneous injury. During the course of these wound-healing studies, we noted that tumors developed at a higher frequency in Col3(+/-) mice compared to wild-type littermate controls. We, therefore, examined the effect of Col3 deficiency on tumor behavior, using the murine mammary carcinoma cell Line 4T1. Notably, tumor volume and pulmonary metastatic burden after orthotopic injection of 4T1 cells were increased in Col3(+/-) mice compared to Col3(+/+) Littermates. By using murine (411) and human (MDA-MB-231) breast cancer cells grown in Col3-poor and Col3-enriched microenvironments in vitro, we found that several major events of the metastatic process were suppressed by Col3, including adhesion, invasion, and migration. In addition, Col3 deficiency increased proliferation and decreased apoptosis of 4T1 cells both in vitro and in primary tumors in vivo. Mechanistically, Col3 suppresses the procarcinogenic microenvironment by regulating stromaL organization, including density and alignment of fibrillar collagen and myofibroblasts. We propose that Col3 plays an important role in the tumor microenvironment by suppressing metastasis-promoting characteristics of the tumor-associated stroma.