Description:
Princeton University Invention #
09-2550
In breast cancer
patients, disseminated tumor cells from the primary site can remain in a dormant
state in the secondary organ for a long period before starting to grow into
life-threatening metastasis. However, the molecular understanding of this
process is still very limited.
Researchers in
Molecular Biology, Princeton University have demonstrated that Vascular Cell
Adhesion Molecule-1 (VCAM1) is essential for the conversion from dormancy to
macrometastasis in a xenograft mouse model of breast cancer bone metastasis. A
weakly bone-metastatic subline of the human breast cancer cell MDA-MB-231 was
found to give rise to strongly metastatic derivatives after six-month in vivo
dormancy in nude mice. When differentially expressed genes identified by
microarray profiling were evaluated by silencing their expression in the highly
metastatic derivatives and tested in vivo, VCAM1 silencing dramatically reduced
bone metastasis ability. Ectopic overexpression of VCAM1 in dormancy-prone
breast cancer cell lines allowed the outgrowth of bone metastasis. Our work
shows that VCAM1 mediates metastasis transition by promoting osteoclastogenesis
via binding to the receptor integrin VLA-4 expressed on osteoclast precursors.
VCAM1 was also found to promote tumor growth in the orthotopic site by
increasing angiogenesis. Functional assays showed VCAM1 mediates recruitment of
endothelial cells which express VLA-4. We also successfully blocked the
initiation and progression of bone metastasis using purified monoclonal
antibodies for VCAM1 or VLA-4. Tissue array analysis using primary tumor samples
showed VCAM1 was upregulated in breast tumor epithelial cells and is associated
with early relapse. Overall, our study established VCAM1 and its receptor VLA-4
as a promising therapeutic target for inhibiting the aggressive conversion from
dormancy to overt bone metastasis in breast cancer. They may also have
cytostatic effect on primary tumor growth.
Princeton is
currently seeking commercial partners for the further development and
commercialization of this opportunity. Patent protection is pending.
For more information on Princeton
University invention # 09-2550 please contact:
Laurie Tzodikov
Office of Technology Licensing and Intellectual Property
Princeton University
4 New South Building
Princeton, NJ 08544-0036
(609) 258-7256
(609) 258-1159 fax
tzodikov@princeton.edu
