Expression of gastrin precursors by CD133-positive colorectal cancer cells is crucial for tumour growth.
Expression of gastrin precursors by CD133-positive colorectal cancer cells is crucial for tumour growth.
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DOI：
10.1016/j.bbamcr.2009.01.004
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发表时间：
2009-03
期刊：
影响因子：
--
通讯作者：
Baldwin GS
中科院分区：
文献类型：
--
作者：
Ferrand A;Sandrin MS;Shulkes A;Baldwin GS
胃泌素激素的前体、前胃泌素和甘氨酸延伸胃泌素 (G-gly) 已在结直肠息肉和肿瘤以及结直肠癌 (CRC) 患者的血液中检测到，而它们在健康受试者中的表达较低。表面糖蛋白 CD133 和 CD44 已被确定为结直肠癌干细胞的可能标记。我们的目的是研究人 CRC 组织和人 CRC 细胞系 DLD-1 中的 CD133 阳性细胞是否表达前胃泌素和 G-gly，并确定这种表达是否具有生物学相关性。在保留干细胞样亚群的 DLD-1 细胞和人类结直肠癌标本中，绝大多数表达 CD133 的细胞也表达胃泌素前体。与CD133low/CD44low/前胃泌素低细胞相比，CD133high/CD44high/前胃泌素高细胞在SCID小鼠中产生更大的肿瘤。 CD133high/CD44high/progastrinhigh 细胞表现出信号分子 JAK2、STAT3、ERK1/2 和 Akt 的增强激活，已知这些信号分子可调节胃泌素前体诱导增殖和/或存活。此外，DLD-1细胞中胃泌素基因的下调可降低癌症干细胞标志物的表达，并消除SCID小鼠的肿瘤发展。我们的结论是，胃泌素前体可能为针对负责肿瘤发生和复发的细胞的治疗提供靶点。
Precursors of the hormone gastrin, progastrin and glycine-extended gastrin (G-gly), have been detected in colorectal polyps and tumours, and in the blood of patients with colorectal cancer (CRC), while their expression is lower in healthy subjects. The surface glycoproteins CD133 and CD44 have been identified as possible markers for CRC stem cells. Our aims were to investigate whether progastrin and G-gly are expressed by CD133-positive cells in human CRC tissues and in the human CRC cell line DLD-1, and to determine whether this expression is biologically relevant. The great majority of the cells expressing CD133 also expressed gastrin precursors in both DLD-1 cells, which retain a stem cell-like subpopulation, and human CRC specimens. The CD133high/CD44high/progastrinhigh cells gave rise to larger tumours in SCID mice compared to CD133low/CD44low/progastrinlow cells. The CD133high/CD44high/progastrinhigh cells displayed enhanced activation of the signalling molecules JAK2, STAT3, ERK1/2 and Akt, known to regulate the induction of proliferation and/or survival by gastrin precursors. Moreover, downregulation of the gastrin gene in DLD-1 cells reduced the expression of cancer stem cell markers and abolished tumour development in SCID mice. We conclude that gastrin precursors may provide a target for therapies directed against the cells responsible for tumour development and recurrence.
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DOI：
10.1073/pnas.0703478104
发表时间：
2007-06-12
影响因子：
11.1
作者：
Dalerba, Piero;Dylla, Scott J.;Clarke, Michael F.
通讯作者：
Clarke, Michael F.
影响因子：
11.2
作者：
Collins, AT;Berry, PA;Maitland, NJ
通讯作者：
Maitland, NJ
影响因子：
11.5
作者：
Duan, Zhenfeng;Foster, Rosemary;Seiden, Michael V.
通讯作者：
Seiden, Michael V.
影响因子：
11.2
作者：
Locke, M;Heywood, M;Mackenzie, IC
通讯作者：
Mackenzie, IC
影响因子：
29.4
作者：
Ma, Stephanie;Chan, Kwok-Wah;Guan, Xin-Yuan
通讯作者：
Guan, Xin-Yuan