2012年8月30日 訊 /生物谷BIOON/ --越來越多的證據(jù)表明,，腫瘤微環(huán)境包括腫瘤相關(guān)成纖維細(xì)胞（CAF）可以調(diào)控腫瘤細(xì)胞對(duì)治療的敏感性。一項(xiàng)發(fā)表在Molecular Cancer Research雜志上的研究探究了腫瘤相關(guān)成纖維細(xì)胞在頭頸部鱗狀細(xì)胞癌細(xì)胞株對(duì)拮抗表皮生長因子受體（EGFR）的抗體西妥昔單抗的治療敏感性可能造成的影響,。
西妥昔單抗的治療能引起頭頸部鱗狀細(xì)胞癌細(xì)胞株增殖率的降低,，而頭頸部鱗狀細(xì)胞癌細(xì)胞株派生出來的腫瘤相關(guān)成纖維細(xì)胞的生長卻不受西妥昔單抗的影響,。當(dāng)利用Transwell小室系統(tǒng)共培養(yǎng)腫瘤細(xì)胞與腫瘤相關(guān)成纖維細(xì)胞后，西妥昔單抗誘導(dǎo)腫瘤細(xì)胞生長的抑制被逆轉(zhuǎn),，這表明腫瘤相關(guān)成纖維細(xì)胞能抵消西妥昔單抗對(duì)頭頸部鱗狀細(xì)胞癌細(xì)胞生長的抑制作用,。
腫瘤相關(guān)成纖維細(xì)胞與頭頸部鱗癌細(xì)胞株共培養(yǎng)后，不管是腫瘤相關(guān)成纖維細(xì)胞還是頭頸部鱗癌細(xì)胞株都高表達(dá)基質(zhì)金屬蛋白酶-1（MMP-1）,。
此外,，腫瘤相關(guān)成纖維細(xì)胞所誘導(dǎo)的耐藥性部分是有基質(zhì)金屬蛋白酶抑制劑存在下的條件下才表現(xiàn)出來的。然而,，用用靶向干擾MMP-1表達(dá)的siRNA處理腫瘤相關(guān)成纖維細(xì)胞后,，西妥昔單抗重新獲得抑制腫瘤細(xì)胞的能力。這些結(jié)果確定了腫瘤相關(guān)成纖維細(xì)胞依賴性的調(diào)控西妥昔單抗的敏感性,，并提示抑制基質(zhì)金屬蛋白酶可以改善表皮生長因子受體靶向藥物的治療效果,。（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
