Hung Chao-Ming, Hsu Yi-Chiang, Chen Tzu-Yu, Chang Chi-Chang, Lee Mon-Juan
Department of General Surgery, E-Da Hospital, I-Shou, University, Kaohsiung, Taiwan.
Graduate Institute of Medical Sciences, Chang Jung Christian University, Tainan, Taiwan.
Cell Biol Int. 2017 Mar;41(3):345-352. doi: 10.1002/cbin.10726. Epub 2017 Jan 23.
Cyclophosphamide is indicated for the treatment of cancerous diseases such as breast cancer and cervical cancer. Recent studies have shown that cyclophosphamide may induce cancer metastasis, but the cause of this unexpected adverse effect is not fully understood. In this study, we investigate the effect of cyclophosphamide on cancer cell migration and its correlation to chemokine (C-X-C motif) receptor 4 (CXCR4), a biomarker for cancer metastasis. Two human cancer cell lines with significant difference in endogenous CXCR4 expression, the breast cancer cell line, MDA-MB-231, and the melanoma cell line, MDA-MB-435S, were treated with various concentrations of cyclophosphamide, followed by the assessment of CXCR4 expression and cell migration. We found that the migration ability of MDA-MB-231 cells was enhanced with increasing concentrations of cyclophosphamide, which induced the cell-surface expression of CXCR4, but had no effect on the overall amount of CXCR4. In MDA-MB-435S cells, in which CXCR4 was barely detectable, cyclophosphamide was unable to activate cell-surface CXCR4, and did not promote cell migration. Studies on the mRNA expression profile of matrix metalloproteinases (MMPs) in MDA-MB-231 cells further indicate that MMP9 and MMP13 may be involved in the action of cyclophosphamide. The protein expression of both MMP9 and MMP13 was increased in the presence of cyclophosphamide. Results from this study provide the molecular basis for the possible pathway of cyclophosphamide to induce cancer metastasis.
环磷酰胺适用于治疗诸如乳腺癌和宫颈癌等癌症疾病。最近的研究表明，环磷酰胺可能会诱导癌症转移，但其这种意外副作用的原因尚未完全了解。在本研究中，我们调查了环磷酰胺对癌细胞迁移的影响及其与趋化因子（C-X-C基序）受体4（CXCR4）的相关性，CXCR4是一种癌症转移的生物标志物。用不同浓度的环磷酰胺处理内源性CXCR4表达存在显著差异的两个人类癌细胞系，即乳腺癌细胞系MDA-MB-231和黑色素瘤细胞系MDA-MB-435S，随后评估CXCR4表达和细胞迁移情况。我们发现，随着环磷酰胺浓度的增加，MDA-MB-231细胞的迁移能力增强，环磷酰胺诱导了CXCR4的细胞表面表达，但对CXCR4的总量没有影响。在几乎检测不到CXCR4的MDA-MB-435S细胞中，环磷酰胺无法激活细胞表面的CXCR4，也不促进细胞迁移。对MDA-MB-231细胞中基质金属蛋白酶（MMPs）的mRNA表达谱的研究进一步表明，MMP9和MMP13可能参与了环磷酰胺的作用。在存在环磷酰胺的情况下，MMP9和MMP13的蛋白表达均增加。本研究结果为环磷酰胺诱导癌症转移的可能途径提供了分子基础。
