Leading malignant cells initiate collective epithelial cell invasion in a three-dimensional heterotypic tumor spheroid model.
Leading malignant cells initiate collective epithelial cell invasion in a three-dimensional heterotypic tumor spheroid model.
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DOI：
10.1007/s10585-013-9565-x
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发表时间：
2013-06
影响因子：
4
通讯作者：
Reinhart-King CA
中科院分区：
文献类型：
--
作者：
Carey SP;Starchenko A;McGregor AL;Reinhart-King CA
实体瘤由具有独特的生长、分化和侵袭能力的遗传和表型多样的癌细胞亚群组成。虽然异质性的分子和微环境基础越来越受到重视，但这种肿瘤内异质性的结果，特别是在肿瘤侵袭和转移的背景下，仍然知之甚少。为了研究异型细胞-细胞相互作用并阐明肿瘤内异质性的生物学后果，我们开发了一种组织工程多细胞球体（MCS）共培养模型，该模型概括了人类癌症的细胞多样性和完全三维的细胞-细胞和细胞-基质相互作用。我们发现，“入侵能力”的恶性细胞诱导集体入侵，否则“入侵无能”的上皮细胞，这两种细胞类型始终表现出不同的领导者和追随者的角色在入侵。细胞外基质的微结构分析表明，恶性肿瘤细胞的侵袭伴随着广泛的细胞外基质重塑，包括基质排列和蛋白水解的轨道制作。抑制细胞收缩和蛋白水解介导的基质重组，防止领导者-追随者行为和恶性细胞诱导的上皮细胞侵袭。这些结果表明，肿瘤内的异质亚群可能在肿瘤进展期间具有专门的作用，并表明肿瘤内癌细胞的各种亚群之间的复杂相互作用可能调节肿瘤生物学的关键方面并影响临床结果。
Solid tumors consist of genetically and phenotypically diverse subpopulations of cancer cells with unique capacities for growth, differentiation, and invasion. While the molecular and microenvironmental bases for heterogeneity are increasingly appreciated, the outcomes of such intratumor heterogeneity, particularly in the context of tumor invasion and metastasis, remain poorly understood. To study heterotypic cell-cell interactions and elucidate the biological consequences of intratumor heterogeneity, we developed a tissue-engineered multicellular spheroid (MCS) co-culture model that recapitulates the cellular diversity and fully three-dimensional cell-cell and cell-matrix interactions that characterize human carcinomas. We found that “invasion-competent” malignant cells induced the collective invasion of otherwise “invasion-incompetent” epithelial cells, and that these two cell types consistently exhibited distinct leader and follower roles during invasion. Analysis of extracellular matrix microarchitecture revealed that malignant cell invasion was accompanied by extensive extracellular matrix remodeling including matrix alignment and proteolytic track-making. Inhibition of cell contractility- and proteolysis-mediated matrix reorganization prevented leader-follower behavior and malignant cell-induced epithelial cell invasion. These results indicate that heterogeneous subpopulations within a tumor may possess specialized roles during tumor progression and suggest that complex interactions among the various subpopulations of cancer cells within a tumor may regulate critical aspects of tumor biology and affect clinical outcome.
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影响因子：
4.8
作者：
Debnath, J;Muthuswamy, SK;Brugge, JS
通讯作者：
Brugge, JS
影响因子：
6.2
作者：
Carey, Shawn P.;D'Alfonso, Timothy M.;Shin, Sandra J.;Reinhart-King, Cynthia A.
通讯作者：
Reinhart-King, Cynthia A.
影响因子：
6.4
作者：
Burdett, Emily;Kasper, F. Kurtis;Ludwig, Joseph A.
通讯作者：
Ludwig, Joseph A.
影响因子：
--
作者：
Aubele, M;Mattis, A;Werner, M
通讯作者：
Werner, M
影响因子：
14
作者：
Carey, Shawn P.;Kraning-Rush, Casey M.;Williams, Rebecca M.;Reinhart-King, Cynthia A.
通讯作者：
Reinhart-King, Cynthia A.