Metastasis suppressor genes: basic biology and potential clinical use.
Metastasis suppressor genes: basic biology and potential clinical use.
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DOI：
10.3816/cbc.2003.n.012
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发表时间：
2003-04-01
影响因子：
3.1
通讯作者：
Salerno, Massimiliano
中科院分区：
文献类型：
--
作者：
Steeg, Patricia S;Ouatas, Taoufik;Salerno, Massimiliano
转移性疾病仍然是乳腺癌患者发病率和死亡率的重要因素。对转移过程的分子和生物化学理解的提高有望推动新治疗方法的发展。尽管肿瘤细胞表达癌基因和促进转移的事件，但肿瘤转移的抑制已经成为一个多样化和富有成效的研究领域。尽管许多基因事件促进转移，但在小鼠模型系统中的转移性肿瘤细胞和侵袭性人类肿瘤中，几种基因显示相对降低的表达水平。转移抑制基因在转移性肿瘤细胞系中的再表达导致体内转移行为的显著减少，而对致瘤性没有影响。已知的转移抑制基因产物nm 23、KAI 1、丝裂原活化蛋白激酶激酶4、乳腺癌转移抑制因子-1、KiSS 1、RHOGDI 2、CRSP 3和维生素D3上调蛋白/硫氧还蛋白相互作用蛋白表现出意想不到的生化功能，这些功能为转移中重要的信号传导事件提供了新的线索。大多数转移抑制因子在远处微转移肿瘤细胞生长的重要阶段发挥作用。我们假设，在乳腺癌患者的辅助高危人群中，微转移肿瘤细胞中转移抑制基因表达的升高将阻止转移定植并具有临床益处。DNA甲基化抑制剂在增加转移抑制基因表达方面显示出有限的前景，并且核激素受体家族的配体目前正在体外和体内研究中。增加转移抑制基因表达的药物的临床试验预计需要量身定制的试验设计。
Metastatic disease remains a significant contributor to morbidity and mortality in patients with breast cancer. An improved molecular and biochemical understanding of the metastatic process is expected to fuel the development of new therapeutic approaches. The suppression of tumor metastasis, despite tumor cell expression of oncogenes and metastasis-promoting events, has become a diverse and fruitful field of investigation. Although many genetic events promote metastasis, several genes show relatively reduced expression levels in metastatic tumor cells in mouse model systems and in aggressive human tumors. Re-expression of a metastasis-suppressor gene in a metastatic tumor cell line results in a significant reduction in metastatic behavior in vivo with no effect on tumorigenicity. The known metastasis-suppressor gene products nm23, KAI1, mitogen-activated protein kinase kinase 4, breast cancer metastasis suppressor-1, KiSS1, RHOGDI2, CRSP3, and vitamin D3-upregulated protein/thioredoxin interacting protein exhibit unexpected biochemical functions that have shed new light on signaling events that are important in metastasis. Most metastasis suppressors function at the translationally important stage of outgrowth of micrometastatic tumor cells at a distant site. We hypothesize that elevation of metastasis suppressor gene expression in micrometastatic tumor cells in the adjuvant high-risk population of patients with breast cancer will halt metastatic colonization and have a clinical benefit. DNA methylation inhibitors have shown limited promise in increasing metastasis-suppressor gene expression, and ligands of the nuclear hormone receptor family are currently under investigation in vitro and in vivo. Clinical testing of agents that increase metastasis-suppressor gene expression is expected to require tailored trial designs.