Predicting and Treating Cancer Metastasis Before the Formation of Pre-metastatic Clusters
- 詳細技術說明
- This invention provides a method of predictingcancer metastases by monitoring VEGFR1+ bone marrow derived cells(BMDCs) in cancer patients and a method of inhibiting and treating tumormetastasis by preventing the formation of pre-metastatic clusters of VEGFR1+BMDCs at the site distant from the primary site.
- *Abstract
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Bone marrow-derivedcells (BMDCs) can contribute to malignant conversion, tumor vascularization andneoplastic cell migration. Previously, asmall population of BMDCs that express vascular endothelial growth factor I(VEGFR1) have been identified and found to enhance primary tumor growth andpromote tumor spread. However, their precise contribution to metastasis wasunclear.
Investigators at theWeill Cornell Medical College have found in animal studies that tumormetastasis is a well-defined sequence: prior to arrival of the tumor cells, primarytumor induces VEGFR1+ bone marrow derived cells to migrate toorgan-specific pre-metastatic sites; in the target organs, these VEGFR1+ hematopoieticcells form clusters of hematopoietic progenitor cells. The inactivation or removal of these cellsfrom the bone marrow prevents the formation of pre-metastatic clusters andtherefore metastases.
This is the firstdirect evidence that a non-neoplastic cell population can portend a futuremetastatic site. Furthermore, the identification of these hematopoieticclusters in human tissues prior to evidence of tumor spread clearly demonstratesthe applicability of monitoring these cells to identify and prevent metastasisin the clinical setting.
The investigatorshave also demonstrated that VEGFR1+ BMDCs at the pre-metastatic clusters express VLA-4 and MMP9;inhibiting the expression of VLA-4 reduces cluster formation; VEGFR1+cell cluster formation is reduced in MMP9 knockout mice.
Therefore, blockingthe establishment of these clusters with various existing antagonists, such asa VEGFR1 inhibitor, a VLA-4 inhibitor, and an MMP-9 inhibitor, may preventtumor cell adhesion, proliferation and metastatic spread. These discoveries offer possible treatmentoptions for preventing future metastases.
Worldwide patentapplications have been filed for this invention. Patents in the United Stateshave been issued and patents in Europe, China and Japan are currently pending.
PotentialApplications
- Inhibittumor formation at a site distant from the site of prior tumor formation usinga VEGFR1 inhibitor, a VLA-4 inhibitor and/or an MMP-9 inhibitor
- Predicttumor metastasis by monitoring VEGFR1+ Hematopoietic ProgenitorCells
Advantages
- Predictand treat patients before the presentation of metastasis or recurrent disease
- Anovel method for the treatment and prevention of metastasis
- *Licensing
- Brian J. Kellybjk2003@med.cornell.edu212-746-6186
- 其他
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- IssuedUS Patent 7,598,043.
- IssuedUS Patent 8,465,738.
- VEGFR1-positive haematopoietic bone marrowprogenitors initiate the pre-metastatic niche. Nature, 2005, 438,820-7.
- News and Views. Cancer biology: emissaries set upnew sites. Nature, 2005, 438, 750-1.
- Migratory neighbors and distant invaders:tumor-associated niche cells. Genes Dev, 2008,22, 559-74.
- Bone marrow cells in the 'pre-metastatic niche':within bone and beyond. Cancer MetastasisRev. 2006, 25, 521-9.
- Preparing the "soil": the premetastaticniche. Cancer Res, 2006, 66, 11089-93.
- Niche-to-niche migration of bone-marrow-derivedcells. Trends Mol Med, 2007,13, 72-81.
- 國家/地區
- 美國
