Intrinsic genetic characteristics determine tumor-modifying capacity of fibroblasts: matrix metalloproteinase-3 5A/5A genotype enhances breast cancer cell invasion.
Intrinsic genetic characteristics determine tumor-modifying capacity of fibroblasts: matrix metalloproteinase-3 5A/5A genotype enhances breast cancer cell invasion.
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内在遗传特征决定了成纤维细胞的肿瘤修饰能力：基质金属蛋白酶-3 5A/5A基因型可增强乳腺癌细胞的侵袭。
DOI：
10.1186/bcr1775
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发表时间：
2007
期刊：
影响因子：
--
通讯作者：
Jones JL
中科院分区：
文献类型：
--
作者：
Holliday DL;Hughes S;Shaw JA;Walker RA;Jones JL
间质成纤维细胞可以通过释放基质金属蛋白酶（MMPs）促进肿瘤侵袭。人群研究表明，MMP基因的单核苷酸多态性（SNP）影响表达水平，并可能与乳腺癌风险和疾病进展有关。本研究直接检测MMP SNP基因型对宿主成纤维细胞促进肿瘤细胞侵袭能力的影响。从患有（n = 13）或没有（n = 19）乳腺癌的患者分离原代乳腺成纤维细胞，并且在体外侵袭测定中测量它们促进乳腺癌细胞侵袭的能力。采用独立样本t检验和方差分析，分析成纤维细胞侵袭促进能力（IPC）与供体类型（肿瘤或非肿瘤患者）、MMP-1、MMP-3和MMP-9 SNP基因型和MMP活性的关系。所有统计检验均为双侧检验。肿瘤来源的成纤维细胞比正常成纤维细胞促进更高水平的侵袭（p = 0.041）。当IPC与基因型相关时，与5A/6A和6A/6A基因型相比，具有高表达MMP-3 5A/5A基因型的肿瘤成纤维细胞产生更高水平的IPC（分别为p = 0.05和0.07），这与MMP-3释放增强相关。MMP-3的功能的重要性，证明了增强的侵袭重组MMP-3的存在下，而减少发生在一个特定的MMP-3抑制剂的存在下。成纤维细胞IPC与高表达MMP-1基因型呈负相关（p = 0.031），但与MMP-9 SNP状态无相关性。相比之下，正常成纤维细胞未显示与MMP基因型相关的IPC变化，MMP-3 5A/5A成纤维细胞表现出比其肿瘤衍生的对应物显著更低的IPC水平（p = 0.04）。这项研究表明，肿瘤来源的成纤维细胞表现出比正常成纤维细胞更高水平的IPC，并且MMP-3 5A/5A基因型通过增强MMP-3释放而对此做出贡献。尽管有高表达基因型，正常成纤维细胞不表现出较高的IPC或增强的MMP释放。这表明在肿瘤来源的成纤维细胞中发生更复杂的变化，使得MMP SNP基因型能够完全表达，并且这些可能在本质上是表观遗传的。结果确实表明，在乳腺癌患者中，高表达MMP-3基因型可能更有效地促进肿瘤进展。
Stromal fibroblasts can contribute to tumor invasion through the release of matrix metalloproteinases (MMPs). Population studies have suggested that single nucleotide polymorphisms (SNPs) in MMP genes influence levels of expression and may be associated with breast cancer risk and with disease progression. This study directly examined the impact of MMP SNP genotype on the ability of host fibroblasts to promote tumor cell invasion. Primary breast fibroblasts were isolated from patients with (n = 13) or without (n = 19) breast cancer, and their ability to promote breast cancer cell invasion was measured in in vitro invasion assays. Fibroblast invasion-promoting capacity (IPC) was analyzed in relation to donor type (tumor or non-tumor patient), MMP-1, MMP-3, and MMP-9 SNP genotype and MMP activity using independent samples t test and analysis of variance. All statistical tests were two-sided. Tumor-derived fibroblasts promoted higher levels of invasion than normal fibroblasts (p = 0.041). When IPC was related to genotype, higher levels of IPC were generated by tumor fibroblasts with the high-expressing MMP-3 5A/5A genotype compared with the 5A/6A and 6A/6A genotypes (p = 0.05 and 0.07, respectively), and this was associated with enhanced MMP-3 release. The functional importance of MMP-3 was demonstrated by enhanced invasion in the presence of recombinant MMP-3, whereas reduction occurred in the presence of a specific MMP-3 inhibitor. An inverse relationship was demonstrated between fibroblast IPC and the high-expressing MMP-1 genotype (p = 0.031), but no relationship was seen with MMP-9 SNP status. In contrast, normal fibroblasts showed no variation in IPC in relation to MMP genotype, with MMP-3 5A/5A fibroblasts exhibiting significantly lower levels of IPC than their tumor-derived counterparts (p = 0.04). This study has shown that tumor-derived fibroblasts exhibit higher levels of IPC than normal fibroblasts and that the MMP-3 5A/5A genotype contributes to this through enhanced MMP-3 release. Despite a high-expressing genotype, normal fibroblasts do not exhibit higher IPC or enhanced MMP release. This suggests that more complex changes occur in tumor-derived fibroblasts, enabling full expression of the MMP SNP genotype and these possibly are epigenetic in nature. The results do suggest that, in women with breast cancer, a high-expressing MMP-3 genotype may promote tumor progression more effectively.
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影响因子：
56.9
作者：
Howe, JR;Roth, S;Aaltonen, LA
通讯作者：
Aaltonen, LA
影响因子：
7.3
作者：
Jones, JL;Shaw, JA;Walker, RA
通讯作者：
Walker, RA
DOI：
10.1073/pnas.0401064101
发表时间：
2004-04-06
影响因子：
11.1
作者：
Kuperwasser, C;Chavarria, T;Weinberg, RA
通讯作者：
Weinberg, RA
影响因子：
7.8
作者：
Lochter, A;Galosy, S;Muschler, J;Freedman, N;Werb, Z;Bissell, MJ
通讯作者：
Bissell, MJ
影响因子：
11.5
作者：
Krippl, P;Langsenlehner, U;Samonigg, H
通讯作者：
Samonigg, H