Abnormal Integrin Activity Promotes Tumor Metastasis into the Lymph Nodes

Cancer metastasis from the site of a primary tumor into the lymph nodes is driven, at least in part, by activation of the integrin alpha4beta in the lymph node endothelium.

Integrins are transmembrane receptors that mediate the attachment between a cell and the tissues that surround it, such as other cells or the extracellular matrix (ECM). One such integrin is alpha4beta1, a dimer composed of CD49d (alpha 4) and CD29 (beta 1). Vascular cell adhesion molecule-1 (VCAM-1 - an integrin receptor) located on an endothelial cell, binds to alpha4beta1, which is normally expressed on leukocyte plasma membranes. However, integrin molecules do not adhere to their appropriate ligands until the leukocytes are activated by chemotactic agents or other stimuli. Only then do the integrins undergo the conformational change necessary to confer high binding affinity for the endothelial adhesion molecules

Investigators at the University of California, San Diego (USA) reported in a paper published in the May 13, 2013, online edition of the journal Proceedings of the National Academy of Sciences of the United States of America (PNAS) that activated integrin alpha4beta1 promoted expansion of the lymphatic endothelium in lymph nodes and served as an adhesive ligand that captured VCAM-1-positive metastatic tumor cells, thereby promoting lymph node metastasis.

Experimental induction of alpha4beta1 expression in lymph nodes was sufficient to promote tumor cell adhesion to lymphatic endothelium and lymph node metastasis in vivo, whereas genetic or pharmacological blockade of integrin alpha4beta1 or VCAM-1 inhibited it.

The presence of lymph node metastases accurately predicts poor disease outcome, and integrin alpha4beta1 is a biomarker of the lymphatic endothelium in tumor-draining lymph nodes. Thus, the results of this study indicate that targeting integrin alpha4beta1 or VCAM to inhibit the interactions of tumor cells with the lymph node microenvironment may be an effective strategy to suppress tumor metastasis.

Senior author Dr. Judith Varner, professor of medicine at the University of California, San Diego, said, "One of the most significant features of this work is that it highlights the way that tumors can have long-range effects on other parts of the body, which can then impact tumor metastasis or growth."

"Alpha4beta1 could prove to be a valuable biomarker for measuring cancer risk," said Dr. Varner, "since increased levels of the activated protein in lymph tissues is an indirect indicator that an undetected tumor may be nearby. The idea is that a radiolabeled or otherwise labeled anti-integrin alpha4beta1 antibody could be injected into the lymphatic circulation, and it would only bind to and highlight the lymphatic vessels that have been activated by the presence of a tumor."

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