Inhibition of Breast Tumor Cell Growth by Ectopic Expression of p16/INK4A Via Combined Effects of Cell Cycle Arrest, Senescence and Apoptotic Induction, and Angiogenesis Inhibition.
Inhibition of Breast Tumor Cell Growth by Ectopic Expression of p16/INK4A Via Combined Effects of Cell Cycle Arrest, Senescence and Apoptotic Induction, and Angiogenesis Inhibition.
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DOI：
10.7150/jca.4046
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发表时间：
2012
影响因子：
3.9
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Lu Y;Zhang X;Zhang J
p16 介导的癌细胞增殖抑制和肿瘤抑制此前已被研究过；普遍的共识是，p16 的细胞周期阻滞功能在这些作用中发挥着主要作用，同时 p16 还具有一些额外的细胞凋亡诱导作用。然而，p16 可能有助于 p16 介导的抗肿瘤能力的其他作用尚未得到充分研究。包括我们在内的新数据表明，p16 通过诱导肿瘤细胞衰老来发挥其抗癌能力。此外，我们发现p16通过抑制VEGF信号通路和血管生成来抑制乳腺癌细胞生长。在本研究中，我们使用腺病毒介导的p16表达（AdRSVp16）和乳腺癌细胞系MDA-MB-231作为模型，同时分析所有这些p16的抗肿瘤功能。我们证明，腺病毒介导的 p16 表达通过同时抑制乳腺癌细胞的体外生长和体内血管生成、阻止细胞分裂以及诱导衰老和凋亡，表现出多种抗肿瘤功能。体内研究表明，在总体抑制肿瘤生长方面，p16的抗血管生成作用可能比其抗细胞增殖作用更重要。这些结果首次表明，AdRSVp16 介导的肿瘤抑制是 p16 多种抗肿瘤功能综合作用的结果，包括 p16 众所周知的抗增殖/细胞分裂功能、细胞凋亡和衰老诱导功能，以及鲜为人知/研究不足的抗血管生成功能。这些综合结果有力地表明p16基因治疗具有具有不同抗肿瘤功能的多模块平台；因此，由于 p16 具有多种抗肿瘤功能，这项研究证明并促进了病毒介导的 p16 基因疗法作为癌症患者的一种有前途且强大的治疗方法。
p16-mediated inhibition of cancer cell proliferation and tumor suppression have been studied before,; the common consensus is that p16's cell-cycle arrest function plays a primary role in these actions, with some additional apoptotic induction by p16. However, other effects of p16 that may potentially contribute to p16-mediated anti-tumor ability have not been well studied. The emerging data including ours indicated that p16 contributes its anti-cancer ability by inducing tumor cells to senescence. Moreover, we showed that p16 inhibits breast cancer cell growth by inhibiting the VEGF signaling pathway and angiogenesis. In this study, we used adenoviral-mediated p16 expression (AdRSVp16) and breast cancer cell line MDA-MB-231 as the model to simultaneously analyze all these p16's anti-tumor functions. We demonstrated that adenoviral-mediated p16 expression exhibited multiple anti-tumor functions by simultaneously suppressing in vitro growth and in vivo angiogenesis of breast cancer cells, blocking cell division, as well as inducing senescence and apoptosis. The in vivo study implies that p16's effect on anti-angiogenesis may play a more significant role than its anti-cell proliferation in the overall suppression of tumor growth. These results suggest, for the first time, that AdRSVp16-mediated tumor suppression results from a combination of p16's multiple anti-tumor functions including p16's well-known anti-proliferation/cell division function, apoptotic and senescence induction function, and its lesser-known/under-investigated anti-angiogenesis function. These combined results strongly indicate that p16 gene therapy has a multi-module platform with different anti-tumor functions; therefore, this study justifies and promotes the viral-mediated p16 gene therapy as a promising and powerful treatment approach for cancer patients due to p16's multiple anti-tumor functions.
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影响因子：
56.9
作者：
JENSEN, HM;CHEN, I;LEWIS, AE
通讯作者：
LEWIS, AE
影响因子：
6.4
作者：
Lu, Y;Carraher, J;Steiner, MS
通讯作者：
Steiner, MS
影响因子：
56.9
作者：
BREM, SS;GULLINO, PM;MEDINA, D
通讯作者：
MEDINA, D
DOI：
10.1093/jnci/89.2.139
发表时间：
1997-01-15
期刊：
JOURNAL OF THE NATIONAL CANCER INSTITUTE
影响因子：
--
作者：
Gasparini, G;Toi, M;Tominaga, T
通讯作者：
Tominaga, T
DOI：
10.1111/j.1349-7006.1997.tb00371.x
发表时间：
1997-03-01
期刊：
JAPANESE JOURNAL OF CANCER RESEARCH
影响因子：
--
作者：
Itoh, N;Kakehi, Y;Yoshida, O
通讯作者：
Yoshida, O