SDF-1/CXCR4信號軸已被證實與乳腺癌轉移有著密切聯(lián)系,。相比較于其在某些器官特異性腫瘤細胞歸巢轉移和定居中的作用，其在血管內特別是在缺氧的環(huán)境下是如何發(fā)揮作用的仍然知之甚少。
最初，研究發(fā)現(xiàn)趨化因子SDF-1及其受體CXCR4存在于浸潤性導管癌標本組織的微血管中,。近來，為了闡明腫瘤血管內皮細胞中SDF-1/CXCR4信號軸在腫瘤細胞入血管中的作用,，研究人員選用人臍靜脈內皮細胞和真皮微血管內皮細胞（HUVEC和HDMEC）,，研究了體外培養(yǎng)的HUVEC、HDMEC以及乳腺癌細胞（MDA/MB-231和MCF7）中CXCR4的活化情況,。
缺氧可以導致血管內皮細胞的增殖,、遷移和管形成?？茖W家觀察在缺氧環(huán)境下SDF-1和CXCR4在血管內皮細胞是上調的,。缺氧誘導腫瘤細胞與血管內皮細胞的粘附，刺激腫瘤細胞跨內皮遷移,。缺氧對腫瘤細胞的影響依賴于其缺氧誘導因子（HIF）的活性,。
抗SDF-1的中和抗體作用于血管內皮細胞或慢病毒CXCR4抑制乳腺癌細胞后，腫瘤細胞通過臍靜脈內皮細胞單層的粘附和遷移被顯著抑制,。這些數(shù)據(jù)表明內皮細胞分泌的SDF-1與腫瘤細胞CXCR4相互作用,，以便刺激腫瘤細胞的跨內皮遷移。
研究結果表明SDF-1/CXCR4信號軸對于血管生成和腫瘤細胞入血管遷移時非常重要的,。由于這兩種蛋白質在人乳腺癌標本中用免疫組化技術很容易識別到,，因此當SDF-1和CXCR4共表達時，CXCR4可能是治療腫瘤的一個潛在靶標,。（生物谷：Bioon.com）
doi:10.1158/1541-7786.MCR-11-0498
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New insight into the SDF-1/CXCR4 axis in a breast carcinoma model: Hypoxia-induced endothelial SDF-1 and tumor cell CXCR4 are required for tumor cell intravasation
Fengyan Jin1, Ulf Brockmeier2, Friedrich Otterbach3, and Eric Metzen2,*
The SDF-1/CXCR4 axis has been implicated in breast cancer metastasis. In contrast to its well established role in organ-specific homing and colonization of tumor cells, the involvement in intravasation, especially in a hypoxic environment, is still poorly understood. Initially, we detected both, the chemokine SDF-1 and its receptor CXCR4 in microvessels in invasive ductal cancer samples. To elucidate the role of the SDF-1/CXCR4 axis in vascular endothelium for tumor intravasation, we evaluated the effects of CXCR4 activation in human umbilical vein and dermal microvascular endothelial cells (HUVEC and HDMEC) and in cultured mammary carcinoma cells (MDA MB231 and MCF7). We observed an up-regulation of SDF-1 and CXCR4 in HUVECs in hypoxia which led to proliferation, migration and tube formation. Hypoxia induced adhesion of tumor cells to endothelial cells and stimulated transendothelial migration. The effects of hypoxia were dependent on the activity of the transcription factor hypoxia-inducible factor (HIF). Adhesion to and migration through a HUVEC monolayer were significantly reduced by lentiviral inhibition of CXCR4 in breast carcinoma cells or treatment of endothelial cells with an anti-SDF-1 neutralizing antibody. These data demonstrate that the interaction of SDF-1 secreted by ECs with tumor cell CXCR4 is sufficient to stimulate transendothelial migration of the tumor cells. Our results suggest that the SDF-1/CXCR4 axis is important in angiogenesis and tumor cell intravasation. Because both proteins were readily identifiable in a significant fraction of human breast cancer samples by immunohistochemistry, CXCR4 may constitute a molecular target for therapy when both, SDF-1 and CXCR4 are expressed.
