Department of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA.
Clin Exp Metastasis. 2013 Jun;30(5):615-30. doi: 10.1007/s10585-013-9565-x. Epub 2013 Jan 18.
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 (ECM) microarchitecture revealed that malignant cell invasion was accompanied by extensive ECM 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.
实体瘤由具有独特生长、分化和侵袭能力的遗传和表型多样化的癌细胞亚群组成。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，该模型再现了人类癌组织的细胞多样性和完全的三维细胞-细胞和细胞-基质相互作用。我们发现，“侵袭能力”强的恶性细胞诱导原本“侵袭能力”弱的上皮细胞集体侵袭，并且在侵袭过程中这两种细胞类型始终表现出明显的主导和跟随作用。对细胞外基质（ECM）微结构的分析表明，恶性细胞的侵袭伴随着广泛的 ECM 重塑，包括基质排列和蛋白水解轨道的形成。抑制细胞收缩和蛋白水解介导的基质重排可防止主导-跟随行为和恶性细胞诱导的上皮细胞侵袭。这些结果表明，肿瘤内的异质亚群在肿瘤进展过程中可能具有特殊作用，并表明肿瘤内不同癌细胞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。
