Increased vascularity and spontaneous metastasis of breast cancer by hedgehog signaling mediated upregulation of cyr61.
Increased vascularity and spontaneous metastasis of breast cancer by hedgehog signaling mediated upregulation of cyr61.
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DOI：
10.1038/onc.2011.496
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发表时间：
2012-07-12
期刊：
影响因子：
8
通讯作者：
Shevde, L. A.
中科院分区：
文献类型：
--
作者：
Harris, L. G.;Pannell, L. K.;Singh, S.;Samant, R. S.;Shevde, L. A.
Hedgehog(HH)途径因其在个体发育中参与血管生成和血管生成而广为人知。配体Sonic hedgehog(SHH)在发育过程中对血管形成起着重要作用。然而，SHH在肿瘤细胞上表达上调，并可能影响肿瘤微环境。我们分别研究了自分泌和旁分泌HH信号对肿瘤细胞和内皮细胞的影响。在SHH的组成性表达后，乳腺癌细胞表现出侵袭性和快速的异种移植生长，其特征是高度血管生成的肿瘤自发转移。在这些细胞中，SHH引起HH转录因子GLI1的激活，导致强大的促血管生成分泌分子CYR61(富含半胱氨酸的血管生成诱导剂61)的表达上调。从这些表达SHH的HH激活细胞中沉默CYR61可以钝化肿瘤细胞的恶性行为，并导致肿瘤血管减少和有限的血液转移。因此，CYR61是HH影响的促血管生成肿瘤微环境的关键下游贡献者。我们还观察到晚期乳腺癌患者肿瘤中伴随的SHH和CYR61转录上调，进一步证实了我们的研究结果的临床相关性。综上所述，我们定义了一种新型的、不依赖于血管内皮生长因子的、临床相关的促血管生成因子--CYR61，它是HH-GLI信号的转录靶点。
The Hedgehog (Hh) pathway is well known for its involvement in angiogenesis and vasculogenesis during ontogeny. The ligand, Sonic hedgehog (SHH), plays an important role in vascular formation during development. However, SHH expression is upregulated on tumor cells and can impact the tumor microenvironment. We have investigated the effects of autocrine as well as paracrine Hh signaling on tumor cells as well as on endothelial cells, respectively. Upon constitutive expression of SHH, breast cancer cells showed aggressive behavior and rapid xenograft growth characterized by highly angiogenic tumors that were spontaneously metastatic. In these cells, SHH caused activation of the Hh transcription factor, GLI1, leading to upregulated expression of the potent pro-angiogenic secreted molecule, CYR61 (cysteine rich angiogenic inducer 61). Silencing of CYR61 from these SHH-expressing Hh activated cells blunted the malignant behavior of the tumor cells and resulted in reduced tumor vasculature and limited hematogenous metastases. Thus, CYR61 is a critical downstream contributor to the Hh influenced pro-angiogenic tumor microenvironment. We also observed concomitant upregulation of SHH and CYR61 transcripts in tumors from patients with advanced breast cancer, further ratifying the clinical relevance of our findings. In summary, we have defined a novel, VEGF-independent, clinically relevant, pro-angiogenic factor, CYR61, that is a transcriptional target of Hh-GLI signaling.
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影响因子：
4.8
作者：
Das, Shamik;Harris, Lillianne G.;Shevde, Lalita A.
通讯作者：
Shevde, Lalita A.
影响因子：
2.7
作者：
Kleer, Celina G.;Zhang, Yanhong;Merajver, Sofia D.
通讯作者：
Merajver, Sofia D.
影响因子：
4.8
作者：
Chen, CC;Mo, FE;Lau, LF
通讯作者：
Lau, LF
影响因子：
4.8
作者：
Leu, SJ;Lam, SCT;Lau, LF
通讯作者：
Lau, LF
DOI：
10.1073/pnas.95.11.6355
发表时间：
1998-05-26
影响因子：
11.1
作者：
Babic, AM;Kireeva, ML;Lau, LF
通讯作者：
Lau, LF