Pericytes limit tumor cell metastasis
Xiaojie Xian, Joakim Håkansson, Anders Ståhlberg, Per Lindblom, Christer Betsholtz, Holger Gerhardt, Henrik Semb
Xiaojie Xian, Joakim Håkansson, Anders Ståhlberg, Per Lindblom, Christer Betsholtz, Holger Gerhardt, Henrik Semb
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Research Article Oncology

Pericytes limit tumor cell metastasis

Abstract

Previously we observed that neural cell adhesion molecule (NCAM) deficiency in β tumor cells facilitates metastasis into distant organs and local lymph nodes. Here, we show that NCAM-deficient β cell tumors grew leaky blood vessels with perturbed pericyte-endothelial cell-cell interactions and deficient perivascular deposition of ECM components. Conversely, tumor cell expression of NCAM in a fibrosarcoma model (T241) improved pericyte recruitment and increased perivascular deposition of ECM molecules. Together, these findings suggest that NCAM may limit tumor cell metastasis by stabilizing the microvessel wall. To directly address whether pericyte dysfunction increases the metastatic potential of solid tumors, we studied β cell tumorigenesis in primary pericyte-deficient Pdgfbret/ret mice. This resulted in β tumor cell metastases in distant organs and local lymph nodes, demonstrating a role for pericytes in limiting tumor cell metastasis. These data support a new model for how tumor cells trigger metastasis by perturbing pericyte-endothelial cell-cell interactions.

Authors

Xiaojie Xian, Joakim Håkansson, Anders Ståhlberg, Per Lindblom, Christer Betsholtz, Holger Gerhardt, Henrik Semb

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Figure 2

Pathological organization of periendothelial α-SMA+ cells correlates with increased tumor vessel leakage in RTNC/KO angiogenic islets.

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Pathological organization of periendothelial α-SMA+ cells correlates wit...
Pancreas sections from 8-week-old mice were double-immunostained with antibodies against PECAM (red) and α-SMA (A–E, green; F, red). In WT (A) and NCAM–/– (B) islets, α-SMA+ cells were closely attached to the endothelium. Premature abnormal organization of periendothelial α-SMA+ cells, including detachment of α-SMA+ cells from endothelial cells (arrow in C) and multiple layers of α-SMA+ cells with an apparent loose attachment to the endothelium (D), and presence of fibroblast-like α-SMA+ cells in RTNCAM+/– angiogenic islets (E), were observed in RTNCAM+/– islets. The dashed lines and arrows in D indicate the borders of the endothelium and α-SMA+ cells stretching away from the vessel, respectively. (F) Pancreas section of an 8-week-old RTNCAM+/– mouse perfused with FITC-dextran (green), immunostained with anti–α-SMA (red). Increased leakage correlated with severely disorganized α-SMA+ periendothelial cells. The inset in C shows coexpression of NG2 (green) and α-SMA (red). (G) Analysis of blood vessel density revealed no difference between RT and RTNC/KO islets. Average values ± SEM are shown. Scale bars: 50 μm (A–F).