Metastasis, the leading cause of mortality in cancer patients, depends upon the ability of cancer cells to invade into the extracellular matrix that surrounds the primary tumor and to escape into the vasculature. To investigate the features of the microenvironment that regulate invasion and escape, we generated solid microtumors of MDA-MB-231 human breast carcinoma cells within gels of type I collagen. The microtumors were formed at defined distances adjacent to an empty cavity, which served as an artificial vessel into which the constituent tumor cells could escape. To define the relative contributions of matrix degradation and cell proliferation on invasion and escape, we used pharmacological approaches to block the activity of matrix metalloproteinases (MMPs) or to arrest the cell cycle. We found that blocking MMP activity prevents both invasion and escape of the breast cancer cells. Surprisingly, blocking proliferation increases the rate of invasion but has no effect on that of escape. We found that arresting the cell cycle increases the expression of MMPs, consistent with the increased rate of invasion. To gain additional insight into the role of cell proliferation in the invasion process, we generated microtumors from cells that express the fluorescent ubiquitination-based cell cycle indicator. We found that the cells that initiate invasions are preferentially quiescent, whereas cell proliferation is associated with the extension of invasions. These data suggest that matrix degradation and cell proliferation are coupled during the invasion and escape of human breast cancer cells and highlight the critical role of matrix proteolysis in governing tumor phenotype.

中文翻译：

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基质降解和细胞增殖相结合，促进工程化人类乳腺微肿瘤的侵袭和逃逸


转移是癌症患者死亡的主要原因，它取决于癌细胞侵入原发肿瘤周围的细胞外基质并逃入脉管系统的能力。为了研究调节侵袭和逃逸的微环境的特征，我们在 I 型胶原凝胶内产生了 MDA-MB-231 人乳腺癌细胞的实体微肿瘤。微肿瘤在邻近空腔的规定距离处形成，该空腔充当人造血管，组成的肿瘤细胞可以逃逸到其中。为了确定基质降解和细胞增殖对入侵和逃逸的相对贡献，我们使用药理学方法来阻断基质金属蛋白酶（MMP）的活性或阻止细胞周期。我们发现阻断 MMP 活性可以防止乳腺癌细胞的侵袭和逃逸。令人惊讶的是，阻断增殖会增加入侵率，但对逃逸率没有影响。我们发现，细胞周期停滞会增加 MMP 的表达，这与侵袭率的增加一致。为了进一步了解细胞增殖在侵袭过程中的作用，我们从表达基于荧光泛素化的细胞周期指标的细胞中产生了微肿瘤。我们发现发起入侵的细胞优先处于静止状态，而细胞增殖则与入侵的扩展相关。这些数据表明，在人乳腺癌细胞的侵袭和逃逸过程中，基质降解和细胞增殖是耦合的，并强调了基质蛋白水解在控制肿瘤表型中的关键作用。