Contribution of CXCL12 secretion to invasion of breast cancer cells.
BACKGROUND
Neu (HER2/ErbB2) is overexpressed in 25% to 30% of human breast cancer, correlating with a poor prognosis. Researchers in previous studies who used the mouse mammary tumor virus Neu-transgenic mouse model (MMTV-Neu) demonstrated that the Neu-YB line had increased production of CXCL12 and increased metastasis, whereas the Neu-YD line had decreased metastasis. In this study, we examined the role of increased production of CXCL12 in tumor cell invasion and malignancy.


METHODS
We studied invasion in the tumor microenvironment using multiphoton intravital imaging, in vivo invasion and intravasation assays. CXCL12 signaling was altered by using the CXCR4 inhibitor AMD3100 or by increasing CXCL12 expression. The role of macrophage signaling in vivo was determined using a colony-stimulating factor 1 receptor (CSF-1R) blocking antibody.


RESULTS
The Neu-YD strain was reduced in invasion, intravasation and metastasis compared to the Neu-YB and Neu deletion mutant (activated receptor) strains. Remarkably, in the Neu-YB strain, in vivo invasion to epidermal growth factor was dependent on both CXCL12-CXCR4 and CSF1-CSF-1R signaling. Neu-YB tumors had increased macrophage and microvessel density. Overexpression of CXCL12 in rat mammary adenocarcinoma cells increased in vivo invasion as well as microvessel and macrophage density.


CONCLUSIONS
Expression of CXCL12 by tumor cells results in increased macrophage and microvessel density and in vivo invasiveness.
Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, 1301 Morris Park Ave, Bronx, NY, 10461, USA.
Pamela J
PJ
Boimel
Tatiana
T
Smirnova
Zhen Ni
ZN
Zhou
Jeffrey
J
Wyckoff
Haein
H
Park
Salvatore J
SJ
Coniglio
Bin-Zhi
BZ
Qian
E Richard
ER
Stanley
Dianne
D
Cox
Jeffrey W
JW
Pollard
William J
WJ
Muller
John
J
Condeelis
Jeffrey E
JE
Segall
D000230:Adenocarcinoma / Q000098:blood supply / Q000378:metabolism / Q000556:secondary*; D000818:Animals; D002465:Cell Movement; D054377:Chemokine CXCL12 / Q000378:metabolism* / Q000502:physiology; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000556:secondary*; D008262:Macrophage Activation; D008264:Macrophages / Q000378:metabolism / Q000502:physiology; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018715:Microscopy, Video; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D009360:Neoplastic Cells, Circulating / Q000473:pathology; D019899:Paracrine Communication; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D015398:Signal Transduction; D047368:Tumor Burden; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment
D054377:Chemokine CXCL12; D018719:Erb-b2 Receptor Tyrosine Kinases; D019718:Receptors, CXCR4; C514936:CXCR4 protein, mouse; C515256:Cxcl12 protein, mouse; C524056:Erbb2 protein, mouse