Université Paris 13, CNRS FRE CSPBAT, Laboratoire de Chimie Structurale Biomoléculaire, UFR SMBH, Bobigny, France.
PLoS One. 2011;6(8):e23334. doi: 10.1371/journal.pone.0023334. Epub 2011 Aug 15.
The poor efficacy of various anti-cancer treatments against metastatic cells has focused attention on the role of tumor microenvironment in cancer progression. To understand the contribution of the extracellular matrix (ECM) environment to this phenomenon, we isolated ECM surrogate invading cell populations from MDA-MB-231 breast cancer cells and studied their genotype and malignant phenotype.
We isolated invasive subpopulations (INV) from non invasive populations (REF) using a 2D-Matrigel assay, a surrogate of basal membrane passage. INV and REF populations were investigated by microarray assay and for their capacities to adhere, invade and transmigrate in vitro, and to form metastases in nude mice.
REF and INV subpopulations were stable in culture and present different transcriptome profiles. INV cells were characterized by reduced expression of cell adhesion and cell-cell junction genes (44% of down regulated genes) and by a gain in expression of anti-apoptotic and pro-angiogenic gene sets. In line with this observation, in vitro INV cells showed reduced adhesion and increased motility through endothelial monolayers and fibronectin. When injected into the circulation, INV cells induced metastases formation, and reduced injected mice survival by up to 80% as compared to REF cells. In nude mice, INV xenografts grew rapidly inducing vessel formation and displaying resistance to apoptosis.
Our findings reveal that the in vitro ECM microenvironment per se was sufficient to select for tumor cells with a stable metastatic phenotype in vivo characterized by loss of adhesion molecules expression and induction of pro-angiogenic and survival factors.
各种抗癌疗法对转移性细胞的疗效不佳，这使得人们开始关注肿瘤微环境在癌症进展中的作用。为了了解细胞外基质（ECM）环境对此现象的贡献，我们从 MDA-MB-231 乳腺癌细胞中分离出 ECM 替代侵袭细胞群，并研究了它们的基因型和恶性表型。
我们使用二维 Matrigel 测定法（基底膜通过的替代物）从非侵袭性群体（REF）中分离出侵袭性亚群（INV）。通过微阵列分析和体外黏附、侵袭和迁移能力以及在裸鼠中形成转移的能力来研究 INV 和 REF 群体。
REF 和 INV 亚群在培养中稳定，表现出不同的转录组谱。INV 细胞的特征是细胞黏附和细胞-细胞连接基因表达下调（下调基因的 44%），同时抗凋亡和促血管生成基因集的表达增加。与此观察结果一致，INV 细胞在体外表现出减少的黏附性和增加的穿过内皮单层和纤维连接蛋白的迁移性。当注入循环系统时，INV 细胞诱导转移形成，并使注射小鼠的存活率降低高达 80%，与 REF 细胞相比。在裸鼠中，INV 异种移植物生长迅速，诱导血管形成，并表现出对凋亡的抗性。
我们的研究结果表明，体外 ECM 微环境本身足以选择具有稳定的体内转移表型的肿瘤细胞，其特征是黏附分子表达的丧失和促血管生成和生存因子的诱导。
