Manni Andrea, Washington Sharlene, Griffith James W, Verderame Michael F, Mauger David, Demers Laurence M, Samant Rajeev S, Welch Danny R
Department of Medicine, Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, Hershey 17033, USA.
Clin Exp Metastasis. 2002;19(2):95-105. doi: 10.1023/a:1014536909007.
Increased cellular activity of ornithine decarboxylase (ODC), the first and rate-limiting enzyme in polyamine (PA) synthesis, is an independent adverse prognostic factor for overall survival in human breast cancer, thus suggesting an important role for PA in tumor progression. The experiments presented here were designed to investigate the role of PA in invasion and metastasis, using the highly aggressive MDA-MB-435 and MDA-MB-231 human breast cancer cell lines. Administration of alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ODC, significantly reduced, in a dose-dependent manner, the invasiveness in matrigel of both MDA-MB-435 and MDA-MB-231 cells by approximately 70%. DFMO treatment also inhibited (P < 0.0001) 'stellate' colony formation (an indicator of aggressive phenotype) by MDA-MB-435 cells plated in the matrigel outgrowth assay. Administration of DFMO (2% in drinking water) reduced the growth rate of both cell lines implanted orthotopically in nude mice. To evaluate metastasis while minimizing effects on proliferation, DFMO-treated mice were sacrificed later to allow their tumors to reach the same size of the tumors in the control mice. The most striking finding was that DFMO, while ineffective in reducing local invasion, nearly totally abolished (P = 0.0152) pulmonary metastasis in mice bearing MDA-MB-435 xenografts. These results support a role of PA in promoting breast cancer aggressiveness, particularly with regard to the development of distant metastasis. Furthermore, the data suggest that PA involvement is distal to local invasion in the metastatic cascade.
鸟氨酸脱羧酶（ODC）是多胺（PA）合成过程中的首个限速酶，其细胞活性增加是人类乳腺癌患者总生存期的一个独立不良预后因素，这表明PA在肿瘤进展中发挥重要作用。本文所呈现的实验旨在利用侵袭性很强的MDA-MB-435和MDA-MB-231人乳腺癌细胞系，研究PA在侵袭和转移中的作用。给予ODC的不可逆抑制剂α-二氟甲基鸟氨酸（DFMO），能以剂量依赖的方式显著降低MDA-MB-435和MDA-MB-231细胞在基质胶中的侵袭能力，降低幅度约为70%。DFMO处理还抑制了（P < 0.0001）MDA-MB-435细胞在基质胶生长试验中形成“星状”集落（侵袭性表型的一个指标）。给予DFMO（饮用水中含2%）降低了原位植入裸鼠体内的这两种细胞系的生长速率。为了在尽量减少对增殖影响的同时评估转移情况，对DFMO处理的小鼠稍后实施安乐死，以使它们的肿瘤大小与对照小鼠的肿瘤相同。最显著的发现是，DFMO虽然在减少局部侵袭方面无效，但几乎完全消除了（P = 0.0152）携带MDA-MB-435异种移植物的小鼠的肺转移。这些结果支持PA在促进乳腺癌侵袭性方面的作用，特别是在远处转移的发生方面。此外，数据表明PA参与转移级联反应发生在局部侵袭之后。
