Endothelial cells and normal breast epithelial cells enhance invasion of breast carcinoma cells by CXCR-4-dependent up-regulation of urokinase-type plasminogen activator receptor (uPAR, CD87) expression

• Published in: The Journal of pathology Vol. 214; no. 5; pp. 545 - 554
• Main Authors: Serratì, S, Margheri, F, Fibbi, G, Di Cara, G, Minafra, L, Pucci-Minafra, I, Liotta, F, Annunziato, F, Pucci, M, Del Rosso, M
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01-04-2008; Wiley
• Subjects: angiogenesis; Biological and medical sciences; Breast - metabolism; breast cancer; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Communication; Cell Line; Chemokine CXCL12 - metabolism; Culture Media, Conditioned; CXCL12; CXCR4; Endothelium, Vascular - metabolism; Epithelial Cells - metabolism; Female; Fibrinolysis; Gynecology. Andrology. Obstetrics; Humans; invasion; Investigative techniques, diagnostic techniques (general aspects); JNK; Mammary gland diseases; MAP Kinase Kinase 4 - metabolism; Medical sciences; microenvironment; Neoplasm Invasiveness; Neoplasm Proteins - metabolism; Neovascularization, Pathologic; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Phosphorylation; Receptors, Cell Surface - metabolism; Receptors, CXCR4 - physiology; Receptors, Urokinase Plasminogen Activator; Reverse Transcriptase Polymerase Chain Reaction - methods; SDF1; Tumor Cells, Cultured; Tumors; Up-Regulation; uPAR; Endothelial cell; u-Plasminogen activator; Breast disease; JNK; CXCR4; Tumorous infiltration; Chemokine receptor; Metastasis; Microenvironment; Angiogenesis; Breast carcinoma; Regulation(control); SDF1; uPAR; Mammary gland; Neovascularization; CXC chemokine; Tumor cell; CXCR4 chemokine receptor; Biological receptor; Serine endopeptidases; Enzyme; Transferases; Mitogen-activated protein kinase; Breast cancer; Malignant tumor; Normal; Invasion; stromal-derived factor-1α; Mammary gland diseases; Peptidases; Stromal cell derived factor 1; Anatomic pathology; CXCL12; Breast; Hydrolases; Epithelial cell; Cancer
• ISSN: 0022-3417; 1096-9896
• DOI: 10.1002/path.2309

Here we show the increase of invasion of three breast cancer cell lines (8701-BC, MDA-MB-231 and SKBR3) upon long-term co-incubation with culture medium of normal microvascular endothelial cells (MVEC) and normal breast epithelial cells (HB2). The enhancement of invasion relied on the interaction of microvascular endothelial cell and normal breast epithelial cell CXCL12 (SDF1) chemokine, whose expression by breast cancer cells was very low, with the cognate CXCR4 receptor of malignant cells, which resulted in over-expression of the urokinase-type plasminogen activator receptor (uPAR) on their surfaces. uPAR over-expression, showed by RT-PCR and Western blotting, was paralleled by increased urokinase-type plasminogen activator (uPA) partitioning on the cell surface with respect to the fluid phase, as demonstrated by zymography. Long-term interaction of SDF1 with CXCR4 stimulated sustained activation of JNK phosphorylation. Blocking antibodies to CXCR4 were able to block the endothelial/epithelial cell-dependent enhancement of invasion, as well as to inhibit SDF1-CXCR4-dependent JNK phosphorylation and uPAR over-expression of malignant cells. We suggest that acquisition of the angiogenic phenotype by breast cancer cells triggers an amplification loop, in which endothelial cells and normal breast epithelial cells of the tumour cooperate to provide facilitated routes to cell invasion and metastasis and to enhance the aggressive phenotype of cancer cells. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.