Cell lines:
Tumors:
- KDR mRNA is upregulated in invasive primary and metastatic comedo-type ductal breast cancers (Brown L.F. et al., 1995).
- In 13/13 breast carcinomas examined by immunohistochemistry and Western-blot analysis, functional KDR was present independent of tumor type, tumor stage and histological grade as demonstrated by tyrosine phosphorylation analysis of KDR. When malignant tissues were compared with their neighboring non-neoplastic regions, activated KDR was found to be expressed to a much higher extent within the malignant tissue samples. Immunostaining of KDR was localized to endothelium and epithelium of mammary ducts in malignant and benign breast tissue, while VEGF-A immunoreactivity was primarily found in the endothelium and also in tumor cells and macrophages (Kranz A. et al., 1999).
- Production of VEGF and expression of its receptors Flt-1 and KDR was determined in primary cultures of separated epithelial and stromal-enriched cultures derived from primary human breast carcinomas. By ELISA, stromal cells were found to produce significantly greater VEGF amount than the amount produced by similar cultures derived from normal breast tissue. Flt-1 and KDR receptors were analysed by semi-quantitative RT-PCR. Flt-1 was expressed by 4/6 epithelial and 5/6 stromal cultures. When expressed by both cell types, Flt-1 appeared to be significantly more abundant on stromal cells compared with epithelial cultures. Only a single tumour, a lobular carcinoma, failed to express Flt-1 on either cell type. With KDR, the reverse was true with constitutive expression of this receptor by epithelial cultures and zero or reduced (3/6) expression by stromal cultures. Differences in the expression pattern of VEGF receptors may reflect a differential response to VEGF by specific cell types (Speirs V. and Atkin S.L., 1999).
- Expression of the angiogenic factor
VEGF; the
VEGF receptors flt-1 and KDR;
thrombospondin-1, which has been reported to inhibit angiogenesis; and the stromal components collagen type I, total fibronectin, ED-A+ fibronectin, versican, and decorin was investigated by mRNA
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 metastatic carcinomas. A characteristic expression profile emerged that was remarkably similar in invasive carcinoma, carcinoma in situ, and metastatic carcinoma, with the following characteristics: strong tumor cell expression of
VEGF; strong endothelial cell expression of
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 fibronectin, ED-A+ fibronectin, versican, and decorin. The formation of vascular stroma preceded invasion, raising the possibility that tumor cells invade not into normal breast stroma but rather into a richly vascular stroma that they have induced. Similarly, tumor cells at sites of metastasis appear to induce the vascular stroma in which they grow (Brown L.F. et al., 1999).
