The Donnelly Centre for Cellular and Biomolecular Research, Department of Chemical Engineering and Applied Chemistry, Institute of Biomaterials and Biomedical Engineering, University of Toronto, 160 College Street, Toronto Ontario, M5S 3E1, Canada.
Department of Chemistry, University of Minnesota, Minneapolis MN, 55455, USA.
Biomaterials. 2018 Sep;178:751-766. doi: 10.1016/j.biomaterials.2018.01.032. Epub 2018 Feb 13.
Breast cancer cell invasion is influenced by growth factor concentration gradients in the tumor microenvironment. However, studying the influence of growth factor gradients on breast cancer cell invasion is challenging due to both the complexities of in vivo models and the difficulties in recapitulating the tumor microenvironment with defined gradients using in vitro models. A defined hyaluronic acid (HA)-based hydrogel crosslinked with matrix metalloproteinase (MMP) cleavable peptides and modified with multiphoton labile nitrodibenzofuran (NDBF) was synthesized to photochemically immobilize epidermal growth factor (EGF) gradients. We demonstrate that EGF gradients can differentially influence breast cancer cell invasion and drug response in cell lines with different EGF receptor (EGFR) expression levels. Photopatterned EGF gradients increase the invasion of moderate EGFR expressing MDA-MB-231 cells, reduce invasion of high EGFR expressing MDA-MB-468 cells, and have no effect on invasion of low EGFR-expressing MCF-7 cells. We evaluate MDA-MB-231 and MDA-MB-468 cell response to the clinically tested EGFR inhibitor, cetuximab. Interestingly, the cellular response to cetuximab is completely different on the EGF gradient hydrogels: cetuximab decreases MDA-MB-231 cell invasion but increases MDA-MB-468 cell invasion and cell number, thus demonstrating the importance of including cell-microenvironment interactions when evaluating drug targets.
乳腺癌细胞的侵袭受到肿瘤微环境中生长因子浓度梯度的影响。然而，由于体内模型的复杂性以及在体外模型中用定义的梯度重现肿瘤微环境的困难，研究生长因子梯度对乳腺癌细胞侵袭的影响具有挑战性。合成了一种用基质金属蛋白酶 (MMP) 可切割肽交联的、并修饰有多光子不稳定硝二苯并呋喃 (NDBF) 的、定义明确的透明质酸 (HA) 水凝胶，以光化学固定表皮生长因子 (EGF) 梯度。我们证明 EGF 梯度可以在具有不同表皮生长因子受体 (EGFR) 表达水平的细胞系中差异影响乳腺癌细胞的侵袭和药物反应。光图案化的 EGF 梯度增加了中度 EGFR 表达的 MDA-MB-231 细胞的侵袭，降低了高 EGFR 表达的 MDA-MB-468 细胞的侵袭，对低 EGFR 表达的 MCF-7 细胞的侵袭没有影响。我们评估了 MDA-MB-231 和 MDA-MB-468 细胞对临床测试的 EGFR 抑制剂西妥昔单抗的反应。有趣的是，西妥昔单抗在 EGF 梯度水凝胶上对 MDA-MB-231 细胞的反应完全不同：西妥昔单抗降低 MDA-MB-231 细胞的侵袭，但增加 MDA-MB-468 细胞的侵袭和细胞数量，从而证明在评估药物靶点时考虑细胞-微环境相互作用的重要性。
