Dynamic quantitative intravital imaging of glioblastoma progression reveals a lack of correlation between tumor growth and blood vessel density.
Dynamic quantitative intravital imaging of glioblastoma progression reveals a lack of correlation between tumor growth and blood vessel density.
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DOI：
10.1371/journal.pone.0072655
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Debarbieux F
中科院分区：
文献类型：
--
作者：
Ricard C;Stanchi F;Rodriguez T;Amoureux MC;Rougon G;Debarbieux F
对肿瘤中发生的细胞过程进行时空和纵向监测对肿瘤学研究至关重要。多形性胶质母细胞瘤（GBM）是一种不可治疗的高度血管化脑肿瘤，其进展被认为严重依赖于血管提供的氧气和代谢物。我们优化了小鼠原位GBM移植的方案，这些方案能够概括通常控制肿瘤进展的生物物理限制，并且适合活体多光子显微镜。我们在GBM发展过程中反复成像肿瘤细胞和血管。为了覆盖整个肿瘤，我们建立了宽视场动态影像数据的定量相关分析方法。我们研究了对照肿瘤的血管密度、肿瘤细胞密度和增殖之间是否存在相关性。U87肿瘤细胞生长时伴有广泛的血管重构和新生血管的形成，但无论在肿瘤区域或时间点，局部细胞密度与局部血管密度的程度没有很强的相关性。此外，该技术还被证明可用于针对VEGF的贝伐单抗抗血管生成治疗或CXCR4受体拮抗剂AMD3100的小鼠对比分析。贝伐单抗治疗可大幅降低肿瘤血管密度，但仅能短暂降低U87肿瘤生长速率。再一次，局部血管密度和局部细胞密度之间没有相关性。此外，Bev仅在肿瘤植入前应用，其抑制肿瘤生长的程度与移植后治疗相同。AMD3100在没有显著降低血管密度的情况下实现了对肿瘤生长的有效抑制。这些结果表明，在该模型中，在没有血管密度增加的情况下，肿瘤可以在大脑中持续生长，并表明GBM的生长是由基质特性控制的。
The spatiotemporal and longitudinal monitoring of cellular processes occurring in tumors is critical for oncological research. We focused on glioblastoma multiforme (GBM), an untreatable highly vascularized brain tumor whose progression is thought to critically depend on the oxygen and metabolites supplied by blood vessels. We optimized protocols for orthotopic GBM grafting in mice that were able to recapitulate the biophysical constraints normally governing tumor progression and were suitable for intravital multiphoton microscopy. We repeatedly imaged tumor cells and blood vessels during GBM development. We established methods for quantitative correlative analyses of dynamic imaging data over wide fields in order to cover the entire tumor. We searched whether correlations existed between blood vessel density, tumor cell density and proliferation in control tumors. Extensive vascular remodeling and the formation of new vessels accompanied U87 tumor cell growth, but no strong correlation was found between local cell density and the extent of local blood vessel density irrespective of the tumor area or time points. The technique moreover proves useful for comparative analysis of mice subjected either to Bevacizumab anti-angiogenic treatment that targets VEGF or to AMD3100, an antagonist of CXCR4 receptor. Bevacizumab treatment massively reduced tumoral vessel densities but only transiently reduced U87 tumor growth rate. Again, there was no correlation between local blood vessel density and local cell density. Moreover, Bev applied only prior to tumor implantation inhibited tumor growth to the same extent as post-grafting treatment. AMD3100 achieved a potent inhibition of tumor growth without significant reduction in blood vessel density. These results indicate that in the brain, in this model, tumor growth can be sustained without an increase in blood vessel density and suggest that GBM growth is rather governed by stromal properties.
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DOI：
10.4137/cmo.s7232
发表时间：
2011
期刊：
Clinical Medicine Insights. Oncology
影响因子：
--
作者：
Chamberlain MC
通讯作者：
Chamberlain MC
DOI：
10.1038/nrc2442
发表时间：
2008-08
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
影响因子：
8.8
作者：
Alfaro, C.;Suarez, N.;Gonzalez, A.;Solano, S.;Erro, L.;Dubrot, J.;Palazon, A.;Hervas-Stubbs, S.;Gurpide, A.;Lopez-Picazo, J. M.;Grande-Pulido, E.;Melero, I.;Perez-Gracia, J. L.
通讯作者：
Perez-Gracia, J. L.
影响因子：
7.3
作者：
Linde, Nina;Lederle, Wiltrud;Mueller, Margareta M.
通讯作者：
Mueller, Margareta M.
影响因子：
4.7
作者：
HOCHWALD, GM;MAGEE, J;FERGUSON, V
通讯作者：
FERGUSON, V