2012年8月30日 讯 /生物谷BIOON/ --越来越多的证据表明，肿瘤微环境包括肿瘤相关成纤维细胞（CAF）可以调控肿瘤细胞对治疗的敏感性。一项发表在Molecular Cancer Research杂志上的研究探究了肿瘤相关成纤维细胞在头颈部鳞状细胞癌细胞株对拮抗表皮生长因子受体（EGFR）的抗体西妥昔单抗的治疗敏感性可能造成的影响。
西妥昔单抗的治疗能引起头颈部鳞状细胞癌细胞株增殖率的降低，而头颈部鳞状细胞癌细胞株派生出来的肿瘤相关成纤维细胞的生长却不受西妥昔单抗的影响。当利用Transwell小室系统共培养肿瘤细胞与肿瘤相关成纤维细胞后，西妥昔单抗诱导肿瘤细胞生长的抑制被逆转，这表明肿瘤相关成纤维细胞能抵消西妥昔单抗对头颈部鳞状细胞癌细胞生长的抑制作用。
肿瘤相关成纤维细胞与头颈部鳞癌细胞株共培养后，不管是肿瘤相关成纤维细胞还是头颈部鳞癌细胞株都高表达基质金属蛋白酶-1（MMP-1）。
此外，肿瘤相关成纤维细胞所诱导的耐药性部分是有基质金属蛋白酶抑制剂存在下的条件下才表现出来的。然而，用用靶向干扰MMP-1表达的siRNA处理肿瘤相关成纤维细胞后，西妥昔单抗重新获得抑制肿瘤细胞的能力。这些结果确定了肿瘤相关成纤维细胞依赖性的调控西妥昔单抗的敏感性，并提示抑制基质金属蛋白酶可以改善表皮生长因子受体靶向药物的治疗效果。（生物谷：Bioon.com）
doi:10.1158/1541-7786.MCR-12-0030
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Cancer-Associated Fibroblasts Induce Matrix Metalloproteinase–Mediated Cetuximab Resistance in Head and Neck Squamous Cell Carcinoma Cells
Ann-Charlotte Johansson, Anna Ansell, Fredrik Jerhammar, Maja Bradic Lindh, et al.
A growing body of evidence suggests that components of the tumor microenvironment, including cancer-associated fibroblasts (CAF), may modulate the treatment sensitivity of tumor cells. Here, we investigated the possible influence of CAFs on the sensitivity of head and neck squamous cell carcinoma (HNSCC) cell lines to cetuximab, an antagonistic epidermal growth factor receptor (EGFR) antibody. Cetuximab treatment caused a reduction in the proliferation rate of HNSCC cell lines, whereas the growth of HNSCC-derived CAF cultures was unaffected. When tumor cells were cocultured with CAFs in a transwell system, the cetuximab-induced growth inhibition was reduced, and a complete protection from growth inhibition was observed in one of the tumor cell lines investigated. Media that had been conditioned by CAFs offered protection from cetuximab treatment in a concentration-dependent manner, suggesting that the resistance to treatment was mediated by CAF-derived soluble factors. The coculture of HNSCC cell lines with CAFs resulted in an elevated expression of matrix metalloproteinase-1 (MMP-1) in both the tumor cells and CAFs. Moreover, the CAF-induced resistance was partly abolished by the presence of an MMP inhibitor. However, CAFs treated with siRNA targeting MMP-1 still protected tumor cells from cetuximab treatment, suggesting that several MMPs may cooperate to facilitate resistance or that the protective effect is mediated by another member of the MMP family. These results identify a novel CAF-dependent modulation of cetuximab sensitivity and suggest that inhibiting MMPs may improve the effects of EGFR-targeted therapy
