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Cancer Discov. 2013 Oct;3(10):1190-205. doi: 10.1158/2159-8290.CD-13-0118. Epub 2013 Aug 1.

Hypoxia-dependent modification of collagen networks promotes sarcoma metastasis.

Author information

1
1Abramson Family Cancer Research Institute; 2Perelman School of Medicine, University of Pennsylvania; 3The Wistar Institute, Philadelphia, Pennsylvania; Departments of 4Pharmacology and Cancer Biology and 5Radiation Oncology, Duke University Medical Center, Durham, North Carolina; 6Howard Hughes Medical Institute; 7Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts; and 8Memorial Sloan-Kettering Cancer Center, New York, New York.

Abstract

Intratumoral hypoxia and expression of hypoxia-inducible factor-1α (HIF-1α) correlate with metastasis and poor survival in patients with sarcoma. We show here that hypoxia controls sarcoma metastasis through a novel mechanism wherein HIF-1α enhances expression of the intracellular enzyme procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2). We show that loss of HIF-1α 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-1α-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-1α 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.

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PMID:
23906982
PMCID:
PMC3822914
DOI:
10.1158/2159-8290.CD-13-0118
[Indexed for MEDLINE]
Free PMC Article

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