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A Subset of Host B Lymphocytes Controls Melanoma Metastasis through a Melanoma Cell Adhesion Molecule/MUC18-Dependent Interaction: Evidence from Mice and Humans

¹ The University of Texas M. D. Anderson Cancer Center, Houston, Texas; ² Surgery Branch, National Cancer Institute, Bethesda, Maryland; and ³ São Paulo Federal University, São Paulo, Brazil

Requests for reprints: Wadih Arap and Renata Pasqualini, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-792-3873; Fax: 713-745-2999; E-mail: warap{at}mdanderson.org and rpasqual{at}mdanderson.org or José Daniel Lopes, Federal University of São Paulo, Rua Botucatu 862, São Paulo 04023-062, Brazil. Phone: 55-011-5576-4532; Fax: 55-011-5571-1095; E-mail: jdlopes{at}unifesp.br.

Key Words: Melanoma • B lymphocytes • melanoma cell adhesion molecule/MUC18 • Phage display

Host immunity affects tumor metastasis but the corresponding cellular and molecular mechanisms are not entirely clear. Here, we show that a subset of B lymphocytes (termed B-1 population), but not other lymphocytes, has prometastatic effects on melanoma cells in vivo through a direct heterotypic cell-cell interaction. In the classic B16 mouse melanoma model, one mechanism underlying this phenomenon is a specific up-regulation and subsequent homophilic interaction mediated by the cell surface glycoprotein MUC18 (also known as melanoma cell adhesion molecule). Presence of B-1 lymphocytes in a panel of tumor samples from melanoma patients directly correlates with MUC18 expression in melanoma cells, indicating that the same protein interaction exists in humans. These results suggest a new but as yet unrecognized functional role for host B-1 lymphocytes in tumor metastasis and establish a biochemical basis for such observations. Our findings support the counterintuitive central hypothesis in which a primitive layer of the immune system actually contributes to tumor progression and metastasis in a mouse model and in melanoma patients. Given that monoclonal antibodies against MUC18 are in preclinical development but the reason for their antitumor activity is not well understood, these translational results are relevant in the setting of human melanoma and perhaps of other cancers. [Cancer Res 2008;68(20):8419–28]

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