Connective tissue growth factor-specific antibody attenuates tumor growth, metastasis, and angiogenesis in an orthotopic mouse model of pancreatic cancer
Connective tissue growth factor-specific antibody attenuates tumor growth, metastasis, and angiogenesis in an orthotopic mouse model of pancreatic cancer
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DOI：
10.1158/1535-7163.mct-05-0516
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发表时间：
2006-05-01
影响因子：
5.7
通讯作者：
Korc, Murray
中科院分区：
文献类型：
--
作者：
Aikawa, Takuma;Gunn, Jason;Korc, Murray
结缔组织生长因子（CTGF）通过调节细胞迁移和细胞生长在纤维化中起重要作用，但也可以改变肿瘤的生长和转移。由于CTGF在胰腺导管腺癌中过表达，我们研究了CTGF对PANC-1胰腺癌细胞增殖和侵袭力的体外影响，并在原位裸鼠模型中使用完全人CTGF特异性单克隆抗体（FG-3019）检查了其对这些细胞生长和转移的体内抑制的后果。尽管PANC-1细胞表达相对高水平的内源性CTGF mRNA，但在条件培养基中加入CTGF增加了PANC-1细胞的增殖和侵袭力。此外，转化生长因子-β 1引起这些细胞中CTGF表达的进一步增加。在体内，每周两次腹腔注射FG-3019可降低肿瘤生长和转移，并减弱肿瘤血管生成和癌细胞增殖。FG-3019没有增强细胞凋亡，也没有减弱吉西他滨对肿瘤生长和转移的抑制作用。这些发现表明，CTGF可能有助于异常的自分泌和旁分泌途径，促进胰腺癌细胞的生长，侵袭，转移和血管生成。因此，用FG-3019阻断CTGF作用可能代表胰腺导管腺癌的新治疗方法。
Connective tissue growth factor (CTGF) plays an important role in fibrosis by modulating cell migration and cell growth but may also modify tumor growth and metastasis. Because CTGF is overexpressed in pancreatic ductal adenocarcinoma, we investigated the in vitro effects of CTGF on the proliferation and invasiveness of PANC-1 pancreatic cancer cells and examined the consequences of its in vivo inhibition on the growth and metastasis of these cells using a fully human CTGF-specific monoclonal antibody (FG-3019) in an orthotopic nude mouse model. Although PANC-1 cells expressed relatively high levels of endogenous CTGF mRNA, the addition of CTGF to conditioned medium increased the proliferation and invasiveness of PANC-1 cells. Moreover, transforming growth factor-beta 1 caused a further increase in CTGF expression in these cells. In vivo, the twice weekly i.p. administration of FG-3019 decreased tumor growth and metastasis and attenuated tumor angiogenesis and cancer cell proliferation. FG-3019 did not enhance apoptosis and did not attenuate the inhibitory effects of gemcitabine on tumor growth and metastasis. These findings suggest that CTGF may contribute to aberrant autocrine and paracrine pathways that promote pancreatic cancer cell growth, invasion, metastasis, and angiogenesis. Therefore, blocking CTGF actions with FG-3019 may represent a novel therapeutic approach in pancreatic ductal adenocarcinoma.