| First Author | Eisinger-Mathason TS | Year | 2013 |
| Journal | Cancer Discov | Volume | 3 |
| Issue | 10 | Pages | 1190-205 |
| PubMed ID | 23906982 | Mgi Jnum | J:204376 |
| Mgi Id | MGI:5532427 | Doi | 10.1158/2159-8290.CD-13-0118 |
| Citation | Eisinger-Mathason TS, et al. (2013) Hypoxia-dependent modification of collagen networks promotes sarcoma metastasis. Cancer Discov 3(10):1190-205 |
| abstractText | Intratumoral hypoxia and expression of hypoxia-inducible factor-1alpha (HIF-1alpha) correlate with metastasis and poor survival in patients with sarcoma. We show here that hypoxia controls sarcoma metastasis through a novel mechanism wherein HIF-1alpha enhances expression of the intracellular enzyme procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2). We show that loss of HIF-1alpha or PLOD2 expression disrupts collagen modification, cell migration, and pulmonary metastasis (but not primary tumor growth) in allograft and autochthonous LSL-Kras(G12D/+); Trp53(fl/fl) murine sarcoma models. Furthermore, ectopic PLOD2 expression restores migration and metastatic potential in HIF-1alpha-deficient tumors, and analysis of human sarcomas reveals elevated HIF1A and PLOD2 expression in metastatic primary lesions. Pharmacologic inhibition of PLOD enzymatic activity suppresses metastases. Collectively, these data indicate that HIF-1alpha controls sarcoma metastasis through PLOD2-dependent collagen modification and organization in primary tumors. We conclude that PLOD2 is a novel therapeutic target in sarcomas and successful inhibition of this enzyme may reduce tumor cell dissemination. SIGNIFICANCE: Undifferentiated pleomorphic sarcoma (UPS) is a commonly diagnosed and particularly aggressive sarcoma subtype in adults, which frequently and fatally metastasizes to the lung. Here, we show the potential use of a novel therapeutic target for the treatment of metastatic UPS, specifi cally the collagen-modifying enzyme PLOD2. |
