CTGF is a therapeutic target for metastatic melanoma.
CTGF is a therapeutic target for metastatic melanoma.
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转移性黑色素瘤仍然是一种毁灭性的疾病，5年存活率不到5%。尽管最近针对黑色素瘤的靶向治疗取得了进展，但只有一小部分黑色素瘤患者经历了持久的缓解。因此，寻找治疗晚期黑色素瘤的新疗法至关重要。在此，我们将结缔组织生长因子(CTGF)定义为转移性黑色素瘤的治疗靶点。在临床上，CTGF的表达与肿瘤的进展相关，并通过HIF-1和HIF-2依赖的机制在低氧条件下强烈诱导。在人类黑色素瘤细胞中，CTGF的基因抑制足以显著减少原位肿瘤的生长，以及严重联合免疫缺陷(SCID)小鼠肺部转移性肿瘤的生长。从机制上讲，抑制CTGF可减少侵袭和迁移，这与基质金属蛋白酶-9的表达减少有关。最重要的是，抗CTGF抗体FG-3019对已建立的转移性黑色素瘤的进展有深刻的抑制作用。这些结果首次提供了抗CTGF治疗晚期黑色素瘤的临床前验证，并强调了肿瘤缺氧在黑色素瘤进展中的重要性。
Metastatic melanoma remains a devastating disease with a 5-year survival rate of less than five percent. Despite recent advances in targeted therapies for melanoma, only a small percentage of melanoma patients experience durable remissions. Therefore, it is critical to identify new therapies for the treatment of advanced melanoma. Here, we define connective tissue growth factor (CTGF) as a therapeutic target for metastatic melanoma. Clinically, CTGF expression correlates with tumor progression and is strongly induced by hypoxia through HIF-1 and HIF-2-dependent mechanisms. Genetic inhibition of CTGF in human melanoma cells is sufficient to significantly reduce orthotopic tumor growth, as well as metastatic tumor growth in the lung of severe combined immunodeficient (SCID) mice. Mechanistically, inhibition of CTGF decreased invasion and migration associated with reduced matrix metalloproteinase-9 expression. Most importantly, the anti-CTGF antibody, FG-3019, had a profound inhibitory effect on the progression of established metastatic melanoma. These results offer the first preclinical validation of anti-CTGF therapy for the treatment of advanced melanoma and underscore the importance of tumor hypoxia in melanoma progression.
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DOI：
10.1074/jbc.m901790200
发表时间：
2009-06-19
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Mole DR;Blancher C;Copley RR;Pollard PJ;Gleadle JM;Ragoussis J;Ratcliffe PJ
通讯作者：
Ratcliffe PJ
DOI：
10.1196/annals.1339.049
发表时间：
2005-01-01
期刊：
TUMOR PROGRESSION AND THERAPEUTIC RESISTANCE
影响因子：
--
作者：
Bindra, RS;Schaffer, PJ;Glazer, PM
通讯作者：
Glazer, PM
影响因子：
2.2
作者：
Lartigau, E;Randrianarivelo, H;Guichard, M
通讯作者：
Guichard, M
影响因子：
15.9
作者：
Bedogni, Barbara;Warneke, James A.;Powell, Marianne Broome
通讯作者：
Powell, Marianne Broome
影响因子：
14.9
作者：
Hubble J;Demeter J;Jin H;Mao M;Nitzberg M;Reddy TB;Wymore F;Zachariah ZK;Sherlock G;Ball CA
通讯作者：
Ball CA