Assessing the Role of the VCAM1-VLA4 Interaction in Macrophage Polarization in Pulmonary Metastatic Osteosarcoma

Macrophages are key members of the innate immune system involved in phagocytosis, antigen presentation and other immunological functions. Macrophages are also important players in response to tumor. Their polarization states determine the role that they play in the tumor microenvironment (TME) and are generally regarded as M1-like and M2-like tumor associated macrophages (TAMs). Subsequently, the TME influences how macrophages function in that environment. Osteosarcoma is an aggressive solid tumor and about 20% of patients present with lung metastasis at the time of diagnosis. Pulmonary metastatic osteosarcoma has a low 5-year survival rate of less than 20%. The ability for osteosarcoma to metastasize to the lungs is due, in part, by the expression of Vascular Cell Adhesion Molecule 1 (VCAM1) on its surface. However, it is not well-known how expression of this protein contributes to tumor metastasis. We speculate that the binding interaction between VCAM1 and its integrin α4β1 (VLA4) has some role in this process. Recently, our lab has obtained preliminary data suggesting one of the methods osteosarcomas use to shape macrophages into a pro-tumor (M2-like) phenotype is through the interaction between VCAM1 on its surface and the VLA4 integrin on macrophages. Our data shows that this interaction upregulates expression of the enzyme Arginase 1, (Arg1) a well-accepted marker of M2-polarized macrophages. We speculate that this phenomenon may be, in part, regulated by the protein, suppressor of cytokine signaling 1 (SOCS1), as it inhibits the phosphorylation of the transcription factor, signal transducer and activator of transcription 1 (STAT1); thus, allowing STAT3 to phosphorylate and upregulate M2-associated genes such as Arg1. St Baldricks Foundation, Keira Kilbane Foundation, Steven G. AYA Cancer Research Fund, Theresa G. & Stuart F. Kline Family Foundation