From Memorial Sloan-Kettering: VCAM-1 as a potential therapeutic target in metastasis

http://www.ncbi.nlm.nih.gov/pubmed/22879387

Clin Cancer Res. 2012 Aug 9. [Epub ahead of print]

Molecular pathways: VCAM-1 as a potential therapeutic target in metastasis.

Chen Q, Massagué J.

Source

Department of Medical Physics, Memorial Sloan-Kettering Cancer Center.

Abstract

Interactions between disseminated tumor cells (DTCs) and stromal cells in the microenvironment are critical for tumor colonization of distal organs. Recent studies have shown that vascular cell adhesion molecule-1 (VCAM-1) is aberrantly expressed in breast cancer cells and mediates pro-metastatic tumor-stromal interactions. Moreover, the usefulness of VCAM-1 to DTCs in two different organs -lung and bone- is based on distinct mechanisms. In the lungs, VCAM-1 on the surface of cancer cells binds to its counter-receptor, the α4β1 integrin (also known as very-late antigen, VLA-4), on metastasis-associated macrophages, triggering VCAM-1 mediated activation of the PI3K growth and survival pathway in the cancer cells. In the bone marrow, cancer cell VCAM-1 attracts and tethers α4 integrin-expressing osteoclast progenitors to facilitate their maturation into multinucleated osteoclasts that mediate osteolytic metastasis. These findings highlight the importance of direct interactions between DTCs and stromal cells during tumor dissemination and draw attention to the possibility of targeting the α4 integrin-VCAM-1 interactions in metastatic breastcancer. Anti-α4 integrin inhibitors have been developed to treat various diseases driven by massive leukocyte infiltrates and have gained FDA approval or are undergoing clinical trials. Testing these drugs against tumor-stromal leukocyte interactions may provide a new strategy to suppress lung and bone relapse of breast cancer.