The Semaphorin 7A Receptor Plexin C1 Is Lost During Melanoma Metastasis

Abstract

The transformation of normal melanocytes, or melanocyte stem cells, to melanoma, is a complex process involving multiple mechanisms. Loss of tumor suppressor proteins, which function as brakes on cell growth, migration, or cell survival, was recognized early on as an important mechanism for initiation and progression of melanoma. Semaphorins and their cognate receptors, Plexins and neuropilins, are involved in neuronal pathfinding, immune function, and tumor progression through effects on blood vessel growth and cell migration. Semaphorin 7A (Sema7A) is a membrane-linked semaphorin that is expressed by human keratinocytes, and we have shown that Sema7A binds to human melanocytes through beta1-integrins and the Plexin C1 receptor. Functional studies showed that Sema7A stimulates cytoskeletal reorganization in human melanocytes, resulting in adhesion and dendrite formation. Downstream targets of Plexin C1 signaling in human melanocytes include cofilin and LIM kinase II, both of which are critical mediators of cell adhesion and migration. In this report, we analyzed the expression of Plexin C1 using immunohistochemistry on sections of primary and matched metastatic lesions from 19 subjects and in a large melanoma tumor microarray. Our data show a significant loss of Plexin C1 in metastatic melanoma compared with primary melanoma, suggesting the possibility that the Plexin C1 receptor is a tumor suppressor protein for melanoma.

Endothelial Semaphorin 7A promotes neutrophil migration during hypoxia

“…Semaphorin 7A can act through the activation of two different receptors, Plexin C1 and α1β1-integrin. As regards to the SEMA7A receptor(s) involved in the transmigration process, most of the published works associate α1β1-integrin receptors with immunomodulatory functions (8,20), whereas Plexin C1 receptors have been associated with adhesion, dendricity, and changes in the cytoskeleton (7,9). In in vitro studies, we were able to demonstrate that SEMA7A facilitates increased transendothelial migration of neutrophils depending on the Plexin C1 receptor, although further studies must be carried out to elucidate this finding in vivo.…”

“…These experiments confirm Sema7a as a potent mediator of PMN transmigration during hypoxia in vivo. Reorganization of the cytoskeleton and changes in cell morphology has been associated with the activation of semaphorin 7A receptor Plexin C1 in melanocytes and monocytes (7,9,10). (14).…”

“…A member of this family, Semaphorin 7A (SEMA7A), holds the ability to induce the production of cytokines in macrophages and monocytes, which play a significant role during the effector phase of the inflammatory immune response (7,8). Furthermore, SEMA7A also stimulates cytoskeletal reorganization in melanocytes and monocytes, which translates into cell morphology changes that can result in spreading and migration of these types of cells (9)(10)(11). However, to date, the role and expression of SEMA7A during hypoxia was unknown.…”

Semaphorins in Angiogenesis and Tumor Progression

“…In metastatic melanomas, the plexin-C1 receptor is lost, suggesting that sema7A may function as an inhibitor of tumor metastasis (Scott et al 2008;Lazova et al 2009). Sema6A: Sema6A is a membrane-bound semaphorin that signals via the plexin-A2 and plexin-A4 receptors (Suto et al 2007).…”

Semaphorin 7A Promotes Chemokine-Driven Dendritic Cell Migration

“…Thus, Sema7A on DCs acts by controlling the balance between adhesion/ deadhesion, similar to Sema7A function on tumor cells and melanocytes (15,17,38). A prominent role for the actin-binding protein cofilin was shown in these studies.…”