Predicting and Treating Cancer Metastasis Before the Formation of Pre-metastatic Clusters

Bone marrow-derived cells (BMDCs) can contribute to malignant conversion, tumor vascularization and neoplastic cell migration. Previously, a small population of BMDCs that express vascular endothelial growth factor I (VEGFR1) have been identified and found to enhance primary tumor growth and promote tumor spread. However, their precise contribution to metastasis was unclear.

Investigators at the Weill Cornell Medical College have found in animal studies that tumor metastasis is a well-defined sequence: prior to arrival of the tumor cells, primary tumor induces VEGFR1+ bone marrow derived cells to migrate to organ-specific pre-metastatic sites; in the target organs, these VEGFR1+ hematopoietic cells form clusters of hematopoietic progenitor cells. The inactivation or removal of these cells from the bone marrow prevents the formation of pre-metastatic clusters and therefore metastases.

This is the first direct evidence that a non-neoplastic cell population can portend a future metastatic site. Furthermore, the identification of these hematopoietic clusters in human tissues prior to evidence of tumor spread clearly demonstrates the applicability of monitoring these cells to identify and prevent metastasis in the clinical setting.

The investigators have 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, blocking the establishment of these clusters with various existing antagonists, such as a VEGFR1 inhibitor, a VLA-4 inhibitor, and an MMP-9 inhibitor, may prevent tumor cell adhesion, proliferation and metastatic spread. These discoveries offer possible treatment options for preventing future metastases.

Worldwide patent applications have been filed for this invention. Patents in the United States have been issued and patents in Europe, China and Japan are currently pending.

Potential Applications

• Inhibit tumor formation at a site distant from the site of prior tumor formation using a VEGFR1 inhibitor, a VLA-4 inhibitor and/or an MMP-9 inhibitor
• Predict tumor metastasis by monitoring VEGFR1+ Hematopoietic Progenitor Cells

Advantages

• Predict and treat patients before the presentation of metastasis or recurrent disease
• A novel method for the treatment and prevention of metastasis