PDF(Pubmed)
Abstract：
Bladder, colon, gastric, prostate, and uterine cancers originate in organs surrounded by laminin-coated smooth muscle. In human prostate cancer, tumors that are organ confined, without extracapsular extension through muscle, have an overall cancer survival rate of up to 97% compared with 32% for metastatic disease. Our previous work modeling extracapsular extension reported the blocking of tumor invasion by mutation of a laminin-binding integrin called α6β1. Expression of the α6AA mutant resulted in a biophysical switch from cell-ECM (extracellular matrix) to cell-cell adhesion with drug sensitivity properties and an inability to invade muscle. Here we used different admixtures of α6AA and α6WT cells to test the cell heterogeneity requirements for muscle invasion. Time-lapse video microscopy revealed that tumor mixtures self-assembled into invasive networks in vitro, whereas α6AA cells assembled only as cohesive clusters. Invasion of α6AA cells into and through live muscle occurred using a 1:1 mixture of α6AA and α6WT cells. Electric cell-substrate impedance sensing measurements revealed that compared with α6AA cells, invasion-competent α6WT cells were 2.5-fold faster at closing a cell-ECM or cell-cell wound, respectively. Cell-ECM rebuilding kinetics show that an increased response occurred in mixtures since the response was eightfold greater compared with populations containing only one cell type. A synthetic cell adhesion cyclic peptide called MTI-101 completely blocked electric cell-substrate impedance sensing cell-ECM wound recovery that persisted in vitro up to 20 h after the wound. Treatment of tumor-bearing animals with 10 mg/kg MTI-101 weekly resulted in a fourfold decrease of muscle invasion by tumor and a decrease of the depth of invasion into muscle comparable to the α6AA cells. Taken together, these data suggest that mixed biophysical phenotypes of tumor cells within a population can provide functional advantages for tumor invasion into and through muscle that can be potentially inhibited by a synthetic cell adhesion molecule.
摘要：
膀胱,结肠,胃,前列腺,子宫癌起源于被层粘连蛋白覆盖的平滑肌包围的器官。在人类前列腺癌中，器官受限的肿瘤，没有通过肌肉的囊外延伸（ECE），与转移性疾病的32％相比，癌症的总体生存率高达97％。我们先前的工作建模ECE报道了通过称为α6β1的层粘连蛋白结合整合素的突变阻断肿瘤侵袭。α6AA突变体的表达导致从细胞-ECM（细胞外基质）到细胞-细胞粘附的生物物理转换，具有药物敏感性，并且无法侵入肌肉。在这里，我们使用了α6AA和α6WT细胞的不同混合物来测试肌肉侵袭的细胞异质性要求。延时视频显微镜显示，肿瘤混合物在体外自组装成侵入性网络，而α6AA细胞仅组装为粘性簇。使用α6AA和α6WT细胞的1:1混合物发生α6AA细胞侵入和穿过活肌肉。电细胞阻抗传感(ECIS)测量显示，与α6AA细胞相比，有侵袭能力的α6WT细胞闭合细胞-ECM或细胞-细胞伤口的速度快2.5倍，分别。细胞-ECM重建动力学显示在混合物中发生增加的响应,因为与仅含有一种细胞类型的群体相比,响应大8倍。称为MTI-101的合成细胞粘附环肽完全阻断ECIS细胞-ECM伤口恢复,其在伤口后在体外持续长达20小时。每周用10mg/kgMTI-101处理荷瘤动物导致与α6AA细胞相当的肿瘤的肌肉侵袭减少4倍,并且进入肌肉的深度降低。一起来看,这些数据表明,群体内肿瘤细胞的混合生物物理表型可以为肿瘤侵入肌肉和通过肌肉提供功能优势,而这种功能可能被合成细胞粘附分子抑制.许多上皮癌，包括膀胱，结肠,前列腺作为一个有凝聚力的群体穿过器官周围的平滑肌，逃离了原发部位。防止粘性肿瘤簇侵入肌肉并通过肌肉并因此防止转移性疾病将显著提高癌症特异性死亡率。当前的研究表明，肿瘤群体内细胞-上皮（细胞-细胞）和间充质（细胞-ECM）合作的特定生物物理表型混合物可以增加侵袭。不同的生物物理表型具有不同的治疗药物反应。相比之下,用合成整合素配体靶向细胞粘附表明，肿瘤侵入和通过活体小鼠肌肉被阻断，并作为预防转移的合成分子方法的一个例子。
