Collagen density promotes mammary tumor initiation and progression.
Collagen density promotes mammary tumor initiation and progression.
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DOI：
10.1186/1741-7015-6-11
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发表时间：
2008-04-28
期刊：
影响因子：
9.3
通讯作者：
Keely PJ
中科院分区：
文献类型：
--
作者：
Provenzano PP;Inman DR;Eliceiri KW;Knittel JG;Yan L;Rueden CT;White JG;Keely PJ
乳腺致密组织是发生乳腺癌的最大危险因素之一。尽管有很强的临床相关性，但乳腺密度与肿瘤发生没有因果关系，主要是因为没有研究乳腺组织密度的动物模型。重要的是，高乳腺密度区域与基质胶原蛋白增加有关。因此，细胞外基质对乳腺癌发展的影响和潜在的分子机制尚不清楚。为了研究胶原密度对乳腺肿瘤形成和进展的影响，我们利用了小鼠乳腺组织中基质胶原增加的双转基因肿瘤模型。用多光子激光扫描显微镜对活肿瘤组织中的肿瘤和肿瘤-基质界面进行成像，以产生内源性荧光团的多光子激发和光谱分辨荧光寿命。二次谐波产生用于成像基质胶原。在此，我们证明小鼠乳腺组织中基质胶原蛋白的增加显著增加肿瘤形成约三倍（p < 0.00001），并导致显著更具侵袭性的表型，肺转移约三倍（p < 0.05）。此外，在重建的三维胶原凝胶内培养肿瘤外植体后，胶原致密乳腺组织内出现的肿瘤细胞的侵袭性表型增加仍然存在。为了更好地理解这种行为，我们使用非线性光学成像方法对活体肿瘤进行成像，以证明局部侵袭是由基质胶原重组促进的，并且这种行为在胶原致密组织中显著增加。此外，使用多光子荧光和光谱寿命成像，我们确定了黄素腺嘌呤二核苷酸的代谢特征，增加荧光强度和寿命，在入侵转移细胞。这项研究提供了第一个数据因果关系增加间质胶原蛋白乳腺肿瘤的形成和转移，并表明，根本的差异出现并持续在上皮肿瘤细胞的胶原密集的微环境中进行。此外，在这项工作中确定的成像技术和签名可以提供有用的诊断工具，以快速评估新鲜组织活检。
Mammographically dense breast tissue is one of the greatest risk factors for developing breast carcinoma. Despite the strong clinical correlation, breast density has not been causally linked to tumorigenesis, largely because no animal model has existed for studying breast tissue density. Importantly, regions of high breast density are associated with increased stromal collagen. Thus, the influence of the extracellular matrix on breast carcinoma development and the underlying molecular mechanisms are not understood. To study the effects of collagen density on mammary tumor formation and progression, we utilized a bi-transgenic tumor model with increased stromal collagen in mouse mammary tissue. Imaging of the tumors and tumor-stromal interface in live tumor tissue was performed with multiphoton laser-scanning microscopy to generate multiphoton excitation and spectrally resolved fluorescent lifetimes of endogenous fluorophores. Second harmonic generation was utilized to image stromal collagen. Herein we demonstrate that increased stromal collagen in mouse mammary tissue significantly increases tumor formation approximately three-fold (p < 0.00001) and results in a significantly more invasive phenotype with approximately three times more lung metastasis (p < 0.05). Furthermore, the increased invasive phenotype of tumor cells that arose within collagen-dense mammary tissues remains after tumor explants are cultured within reconstituted three-dimensional collagen gels. To better understand this behavior we imaged live tumors using nonlinear optical imaging approaches to demonstrate that local invasion is facilitated by stromal collagen re-organization and that this behavior is significantly increased in collagen-dense tissues. In addition, using multiphoton fluorescence and spectral lifetime imaging we identify a metabolic signature for flavin adenine dinucleotide, with increased fluorescent intensity and lifetime, in invading metastatic cells. This study provides the first data causally linking increased stromal collagen to mammary tumor formation and metastasis, and demonstrates that fundamental differences arise and persist in epithelial tumor cells that progressed within collagen-dense microenvironments. Furthermore, the imaging techniques and signature identified in this work may provide useful diagnostic tools to rapidly assess fresh tissue biopsies.
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致密的乳房基质组织显示出乳房上皮浓度的大大增加，但其增殖活性没有增加。
影响因子：
7.4
作者：
Hawes, D;Downey, S;Pearce, CL;Bartow, S;Wan, P;Pike, MC;Wu, AH
通讯作者：
Wu, AH
影响因子：
11.2
作者：
Bavik, C;Coleman, I;Nelson, PS
通讯作者：
Nelson, PS
DOI：
10.1083/jcb.200504124
发表时间：
2005-11-07
期刊：
The Journal of cell biology
影响因子：
--
作者：
Benlimame N;He Q;Jie S;Xiao D;Xu YJ;Loignon M;Schlaepfer DD;Alaoui-Jamali MA
通讯作者：
Alaoui-Jamali MA
影响因子：
4.7
作者：
Boyd, N F;Martin, L J;Yaffe, M J
通讯作者：
Yaffe, M J
影响因子：
3.8
作者：
Aiello, EJ;Buist, DSM;Porter, PL
通讯作者：
Porter, PL