Macrophages regulate the angiogenic switch in a mouse model of breast cancer
Macrophages regulate the angiogenic switch in a mouse model of breast cancer
复制标题
DOI：
10.1158/0008-5472.can-06-1278
复制
发表时间：
2006-12-01
期刊：
影响因子：
11.2
通讯作者：
Pollard, Jeffrey W.
中科院分区：
文献类型：
--
作者：
Lin, Elaine Y.;Li, Jiu-Feng;Pollard, Jeffrey W.
肿瘤血管系统的发育或进入宿主血管系统是恶性肿瘤生存和转移的关键步骤。虽然正在开发试图在肿瘤发展过程中抑制这一步骤的治疗策略，但这一过程的生物学调节在很大程度上仍然未知。使用易患乳腺癌的转基因小鼠PyMT小鼠，我们已经表征了乳腺肿瘤进展为恶性肿瘤期间血管系统的发展。我们发现，发病的血管生成开关，确定为形成一个高密度的血管网络，是密切相关的过渡到恶性肿瘤。更重要的是，在原发性乳腺肿瘤中，血管生成开关和恶性进展都受到浸润的巨噬细胞的调节。抑制巨噬细胞浸润到肿瘤中延迟了血管生成转换和恶性转化，而这些肿瘤中巨噬细胞群体的遗传恢复则挽救了血管表型。此外，过早诱导巨噬细胞浸润到癌前病变促进了独立于肿瘤进展的血管生成开关的早期发作。总而言之，这项研究表明肿瘤相关巨噬细胞在促进肿瘤血管生成方面发挥着关键作用，这是肿瘤进展为恶性肿瘤的重要步骤。
The development of a tumor vasculature or access to the host vasculature is a crucial step for the survival and metastasis of malignant tumors. Although therapeutic strategies attempting to inhibit this step during tumor development are being developed, the biological regulation of this process is still largely unknown. Using a transgenic mouse susceptible to mammary cancer, PyMT mice, we have characterized the development of the vasculature in mammary tumors during their progression to malignancy. We show that the onset of the angiogenic switch, identified as the formation of a high-density vessel network, is closely associated with the transition to malignancy. More importantly, both the angiogenic switch and the progression to malignancy are regulated by infiltrated macrophages in the primary mammary tumors. Inhibition of the macrophage infiltration into the tumor delayed the angiogenic switch and malignant transition whereas genetic restoration of the macrophage population specifically in these tumors rescued the vessel phenotype. Furthermore, premature induction of macrophage infiltration into premalignant lesions promoted an early onset of the angiogenic switch independent of tumor progression. Taken together, this study shows that tumor-associated macrophages play a key role in promoting tumor angiogenesis, an essential step in the tumor progression to malignancy.