Ruan Jia, Hyjek Elizabeth, Kermani Pouneh, Christos Paul J, Hooper Andrea T, Coleman Morton, Hempstead Barbara, Leonard John P, Chadburn Amy, Rafii Shahin
Center for Lymphoma and Myeloma, Division of Hematology-Oncology, Department of Medicine, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021, USA.
Clin Cancer Res. 2006 Oct 1;12(19):5622-31. doi: 10.1158/1078-0432.CCR-06-1204.
Tumor stromal microenvironment promotes neoplastic growth and angiogenesis. We have previously shown that recruitment of marrow-derived vascular endothelial growth factor receptor-1(+) (VEGFR-1(+)) proangiogenic hematopoietic progenitors contributes instructively and structurally to neoangiogenesis in mouse models. Here, we investigated whether stromal incorporation of CD68(+) hemangiogenic cells and alpha-smooth muscle actin(+) (alpha-SMA(+)) stromal cells correlates with neoangiogenesis and progression in human non-Hodgkin's lymphoma subtypes.
Spatial localizations of vascular and stromal cells expressing CD34, VEGFR-1, alpha-SMA, and CD68 were examined by immunohistochemistry in 42 cases of non-Hodgkin's lymphoma, including diffuse large B-cell lymphoma, Burkitt lymphoma, follicular lymphoma, and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), and compared with benign follicular hyperplasia.
Compared with indolent lymphomas, there was a profound increase in recruitment of CD68(+) cells and VEGFR-1(+) neovessels in aggressive subtypes (including those transformed from indolent subtypes), where CD68(+) cells were localized to the perivascular region of neovessels as well as the stromal compartment. The perivascular CD68(+) cells expressed VEGFR-1 and VEGF-A. In contrast, there was a diffuse increase in alpha-SMA incorporation throughout the stromal compartment of indolent subtype of CLL/SLL compared with the scant perivascular pattern in aggressive subtypes. Overall, there was no correlation between CD34(+) microvessel density and lymphoma histologic subtype.
Heightened stromal hemangiogenesis as marked by infiltration of proangiogenic VEGFR-1(+)CD68(+)VEGF-A(+) cells and their paracrine cross-talk with neovasculature appears to be a distinct feature of aggressive lymphoma, providing novel targets for antiangiogenic therapy, whereas alpha-SMA(+) stromal vascular network may be differentially targeted in CLL/SLL.
肿瘤基质微环境促进肿瘤生长和血管生成。我们之前已经表明，骨髓源性血管内皮生长因子受体1阳性（VEGFR-1+）促血管生成造血祖细胞的募集在小鼠模型中对新生血管生成具有指导性和结构性作用。在此，我们研究了CD68+血管生成细胞和α平滑肌肌动蛋白阳性（α-SMA+）基质细胞在基质中的掺入是否与人类非霍奇金淋巴瘤亚型中的新生血管生成和进展相关。
通过免疫组织化学检查了42例非霍奇金淋巴瘤（包括弥漫性大B细胞淋巴瘤、伯基特淋巴瘤、滤泡性淋巴瘤以及慢性淋巴细胞白血病/小淋巴细胞淋巴瘤（CLL/SLL））中表达CD34、VEGFR-1、α-SMA和CD68的血管和基质细胞的空间定位，并与良性滤泡增生进行了比较。
与惰性淋巴瘤相比，侵袭性亚型（包括由惰性亚型转化而来的那些）中CD68+细胞和VEGFR-1+新生血管的募集显著增加，其中CD68+细胞定位于新生血管的血管周围区域以及基质区室。血管周围的CD68+细胞表达VEGFR-1和VEGF-A。相比之下，与侵袭性亚型中稀少的血管周围模式相比，惰性亚型CLL/SLL的整个基质区室中α-SMA的掺入呈弥漫性增加。总体而言，CD34+微血管密度与淋巴瘤组织学亚型之间无相关性。
以促血管生成的VEGFR-1+CD68+VEGF-A+细胞浸润及其与新生血管的旁分泌相互作用为标志的基质血管生成增强似乎是侵袭性淋巴瘤的一个独特特征，为抗血管生成治疗提供了新的靶点，而α-SMA+基质血管网络在CLL/SLL中可能有不同的靶向作用。
