Research ArticleCancer

Semaphorin 3D autocrine signaling mediates the metastatic role of annexin A2 in pancreatic cancer

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Sci. Signal.  04 Aug 2015:
Vol. 8, Issue 388, pp. ra77
DOI: 10.1126/scisignal.aaa5823

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Semaphorin signals guide metastases

Semaphorin signaling directs the migration of developing neurons, as well as new blood vessels. The abundance of semaphorin 3D (Sema3D) is increased in the tumors of patients with metastatic pancreatic ductal adenocarcinoma (PDA), and antibodies against the protein annexin A2 are present in patient sera. Using cells from a genetic mouse model of PDA, Foley et al. found that annexin A2 increased the release of Sema3D from PDA cells and promoted migratory behavior in cultured PDA cells. Secreted Sema3D activated its co-receptor plexin D1 in an autocrine manner on the surface of PDA cells. Knocking down annexin A2 decreased the colonization of injected PDA cells in the liver and lungs of mice. These prometastatic effects of annexin A2 did not involve changes in tumor growth or vascularization. Targeting annexin A2 may prevent metastatic PDA.


Most patients with pancreatic ductal adenocarcinoma (PDA) present with metastatic disease at the time of diagnosis or will recur with metastases after surgical treatment. Semaphorin–plexin signaling mediates the migration of neuronal axons during development and of blood vessels during angiogenesis. The expression of the gene encoding semaphorin 3D (Sema3D) is increased in PDA tumors, and the presence of antibodies against the pleiotropic protein annexin A2 (AnxA2) in the sera of some patients after surgical resection of PDA is associated with longer recurrence-free survival. By knocking out AnxA2 in a transgenic mouse model of PDA (KPC) that recapitulates the progression of human PDA from premalignancy to metastatic disease, we found that AnxA2 promoted metastases in vivo. The expression of AnxA2 promoted the secretion of Sema3D from PDA cells, which coimmunoprecipitated with the co-receptor plexin D1 (PlxnD1) on PDA cells. Mouse PDA cells in which SEMA3D was knocked down or ANXA2-null PDA cells exhibited decreased invasive and metastatic potential in culture and in mice. However, restoring Sema3D in AnxA2-null cells did not entirely rescue metastatic behavior in culture and in vivo, suggesting that AnxA2 mediates additional prometastatic mechanisms. Patients with primary PDA tumors that have abundant Sema3D have widely metastatic disease and decreased survival compared to patients with tumors that have relatively low Sema3D abundance. Thus, AnxA2 and Sema3D may be new therapeutic targets and prognostic markers of metastatic PDA.

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