Vascular stroma formation in carcinoma in situ, invasive carcinoma, and metastatic carcinoma of the breast

The generation of vascular stroma is essential for solid tumor growth and i nvolves stimulatory and inhibiting factors as well as stromal components th at regulate functions such as cellular adhesion, migration, and gene expres sion. In an effort to obtain a more integrated understanding of vascular st roma formation in breast carcinoma, we examined expression of the angiogeni c factor vascular permeability factor (VPF)/vascular endothelial growth fac tor (VEGF); the VPF/VEGF receptors flt-1 and KDR; thrombospondin-l, which h as been reported to inhibit angiogenesis; and the stromal components collag en type I, total fibronectin, ED-AS fibronectin, versican, and decorin by m RNA in situ hybridization on frozen sections of 113 blocks of breast tissue from 68 patients including 28 sections of breast tissue without malignancy , 18 with in situ carcinomas, 56 with invasive carcinomas, and 8 with metas tatic carcinomas. A characteristic expression profile emerged that was rema rkably similar in invasive carcinoma, carcinoma in situ, and metastatic car cinoma, with the following characteristics: strong tumor cell expression of VPF/VEGF; strong endothelial cell expression of VPF/VEGF receptors; strong expression of thrombospondin-1 by stromal cells and occasionally by tumor cells; and strong stromal cell expression of collagen type I, total fibrone ctin, ED-AS fibronectin, versican, and decorin, The formation of vascular s troma preceded invasion, raising the possibility that tumor cells invade no t into normal breast stroma but rather into a richly vascular stroma that t hey have induced. Similarly, tumor cells at sites of metastasis appear to i nduce the vascular stroma in which they grow, We conclude that a distinct p attern of mRNA expression characterizes the generation of vascular stroma i n breast cancer and that the formation of vascular stroma may play a role n ot only in growth of the primary tumor but also in invasion and metastasis.