Editors' ChoiceCancer

Pressured to Metastasize

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Science Signaling  16 Apr 2013:
Vol. 6, Issue 271, pp. ec83
DOI: 10.1126/scisignal.2004246

In the central nervous system, the N-methyl-D-aspartate receptor (NMDAR) plays an important role in learning and memory. Functional NMDARs are present in various human tumors, and the NMDAR agonist glutamate has been implicated in cancer growth and progression. Having previously identified NMDAR as potentially involved in the invasion of pancreatic neuroendocrine tumors (PNET), Li and Hanahan investigated the role of this receptor in PNET biology. Both the NR1 and NR2b subunits of NMDAR were present in tumors from mouse models of PNET, pancreatic ductal adenocarcinoma, and breast cancer, and NR2b was especially prevalent at the invasion fronts of tumors. Vesicular glutamate transporters (vGluts), which are required for glutamate secretion, were present in PNET cells. NR2b was expressed in several types of human tumors, and poor patient prognosis correlated with greater abundance of NR2b and vGlut2. The βTC-3 line of cultured mouse PNET cells were only weakly invasive in traditional transwell migration assays, but they were more invasive when hydrostatic pressure was applied to mimic in vivo interstitial fluid pressure. Inhibiting NMDAR with the antagonist MK801 (i) blocked the invasiveness of βTC-3 cells in the modified in vitro invasion assay that incorporated hydrostatic pressure, (ii) reduced βTC-3 cell proliferation and survival under static culture conditions, (iii) inhibited the invasiveness of various human NR2b-positive tumor cell lines in vitro, and (iv) reduced the tumor burden in the mouse PNET model. Under conditions of hydrostatic flow, the amount of glutamate present in βTC-3 cell medium increased, suggesting that fluid flow promoted the secretion of glutamate, which could then act as an autocrine signal in these cells. Fluid flow also enhanced the surface localization of NMDAR and triggered activation of Ca2+/calmodulin kinase (CaMK) and MEK-MAPK (mitogen-activated or extracellular signal–regulated protein kinase–mitogen-activated protein kinase) signaling pathways downstream of NMDAR in βTC-3 cells as compared to cells under static conditions. These results suggest that in vivo hydrostatic pressure may induce some cancer cells to secrete glutamate, which can act in autocrine fashion to activate signaling pathways downstream of NMDAR that promote tumor cell proliferation and invasion.

L. Li, D. Hanahan, Hijacking the neuronal NMDAR signaling circuit to promote tumor growth and invasion. Cell 153, 86–100 (2013). [PubMed]