[CXCR4 expression increases liver and lung metastasis in a mouse model of pancreatic cancer.]
>>Gastroenterology. 2005 Oct;129(4):1237-50.
Comment on:
Gastroenterology. 2005 Oct;129(4):1344-7.
CXCR4 expression increases liver and lung metastasis in a mouse model of pancreatic cancer.
Saur D, Seidler B, Schneider G, Algul H, Beck R, Senekowitsch-Schmidtke R, Schwaiger M, Schmid RM.
Department of Internal Medicine 2, Technical University of Munich, Germany. Dieter.Saur@lrz.tu-muenchen.de
BACKGROUND & AIMS: Expression of the Gi-protein-coupled chemokine receptor CXCR4 has recently been linked to increased proliferation, invasion, and migration of human pancreatic cancer cell lines. However, the relevance of CXCR4 for organ-specific pancreatic cancer metastasis in vivo remains unclear. Here, we have studied the role of CXCR4 in vivo using noninvasive imaging of targeted metastasis in a mouse model of pancreatic cancer. METHODS: Functional expression of the chemokine receptors CXCR4 and CCR7 was achieved by stable transfection of murine TD-2 pancreatic cancer cells and analyzed by flow cytometry, calcium flux, migration, and proliferation assays. The metastatic potential of the different stable TD-2 cell clones was assessed by tail vein metastatic assays in nude mice using in vivo bioluminescent imaging. RESULTS: Native TD-2 cells display very low abundant CXCR4 and CCR7 expression and show poor metastatic potential after tail vein injection. To study the role of CXCR4 in pancreatic cancer metastasis, we selected stable TD-2 cell clones with similar CXCR4 expression levels as human pancreatic cancer cell lines derived from metastatic lesions. CXCR4, but not CCR7, expression dramatically increased the in vivo metastatic potential of TD-2 cells, resulting in liver and lung metastasis in nude mice. Systemic administration of the selective CXCR4 inhibitor AMD 3100 effectively blocked the enhanced metastatic potential of CXCR4-expressing pancreatic cancer cells. CONCLUSIONS: These results indicate that CXCR4 expression mediates organ-specific metastasis of pancreatic cancer cells and provide preclinical evidence that blockade of the CXCL12/CXCR4 axis is a target for antimetastatic therapy.<<
AMD 3100 is Mozobil. So while CXCR4 inhibition might not be a big deal in HIV, it looks as though recent research is indeed pointing to a major role in many cancers (there's abstracts out there regarding HER-2 and CXCR4 in breast cancer, for example). And there might well be synergies with other drugs. Drugs that hit the primary tumor often don't do that much for survival. Stopping metastasis would be hot. Of course, MLNM is a long ways from market in those indications, but it looks intriguing. Their purchase of COR didn't work out so well, but the buy of Leukosite gave them Velcade. They may not be much better at internal drug development than PDLI, but they are batting .500 on acquisitions. Here's hoping it eventually goes to .667.
As an aside, the technique used in this study seems to involve Xenogen's system. They got munched by Caliper, a long time Millenium collaborator. I've gotten on my animal rights soapbox at SI several times regarding Xenogen, so here I'll just say that I hope Caliper does well with it.
Cheers, Tuck |
