Cancer Biology Graduate Interdisciplinary Program, University of Arizona, Tucson, Arizona; Medical Scientist Training Program, College of Medicine, University of Arizona, Tucson, Arizona.
University of Arizona Cancer Center, Tucson, Arizona.
Biophys J. 2023 Nov 7;122(21):4194-4206. doi: 10.1016/j.bpj.2023.09.016. Epub 2023 Sep 26.
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 α6 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 α6 and α6 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 α6 cells assembled only as cohesive clusters. Invasion of α6 cells into and through live muscle occurred using a 1:1 mixture of α6 and α6 cells. Electric cell-substrate impedance sensing measurements revealed that compared with α6 cells, invasion-competent α6 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 α6 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.
膀胱、结肠、胃、前列腺和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，局限于器官内的肿瘤，没有通过肌肉的包膜外扩展，其总体癌症存活率高达 97%，而转移性疾病的存活率为 32%。我们之前的研究报告称，通过突变一种称为α6β1 的层粘连蛋白结合整合素来阻断肿瘤侵袭，从而阻断肿瘤侵袭。α6 突变体的表达导致了从细胞-细胞外基质（细胞外基质）到细胞-细胞粘附的生物物理转变，具有药物敏感性和无法侵袭肌肉的特性。在这里，我们使用不同比例的α6 和α6 细胞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我组装成侵袭网络，而α6 细胞仅组装成凝聚簇。使用α6 和α6 细胞 1:1 的混合物，α6 细胞可侵入并穿过活肌肉。电动细胞-基底阻抗传感测量显示，与α6 细胞相比，侵袭能力强的α6 细胞在分别闭合细胞-细胞外基质或细胞-细胞伤口时的速度快 2.5 倍。细胞-细胞外基质重建动力学表明，与仅含有一种细胞类型的群体相比，混合物中的反应增加了 8 倍。一种称为 MTI-101 的合成细胞粘附环肽完全阻断了电动细胞-基底阻抗传感细胞-细胞外基质伤口恢复，该恢复在伤口后 20 小时内仍持续存在。每周给荷瘤动物注射 10mg/kg MTI-101 可使肿瘤对肌肉的侵袭减少四倍，并使肿瘤侵入肌肉的深度减少到与α6 细胞相当的程度。综上所述，这些数据表明，群体中肿瘤细胞的混合生物物理表型可为肿瘤侵袭肌肉提供功能优势，而这一过程可能会被一种合成细胞粘附分子抑制。
