Skip to main content

Hypoxia-dependent modification of collagen networks promotes sarcoma metastasis.

Publication ,  Journal Article
Eisinger-Mathason, TSK; Zhang, M; Qiu, Q; Skuli, N; Nakazawa, MS; Karakasheva, T; Mucaj, V; Shay, JES; Stangenberg, L; Sadri, N; Puré, E ...
Published in: Cancer Discov
October 2013

UNLABELLED: 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.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Cancer Discov

DOI

EISSN

2159-8290

Publication Date

October 2013

Volume

3

Issue

10

Start / End Page

1190 / 1205

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Sarcoma, Experimental
  • Sarcoma
  • Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase
  • Neoplasm Metastasis
  • Molecular Targeted Therapy
  • Minoxidil
  • Mice, Transgenic
  • Mice
  • Hypoxia-Inducible Factor 1, alpha Subunit
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Eisinger-Mathason, T. S. K., Zhang, M., Qiu, Q., Skuli, N., Nakazawa, M. S., Karakasheva, T., … Simon, M. C. (2013). Hypoxia-dependent modification of collagen networks promotes sarcoma metastasis. Cancer Discov, 3(10), 1190–1205. https://doi.org/10.1158/2159-8290.CD-13-0118
Eisinger-Mathason, TS Karin, Minsi Zhang, Qiong Qiu, Nicolas Skuli, Michael S. Nakazawa, Tatiana Karakasheva, Vera Mucaj, et al. “Hypoxia-dependent modification of collagen networks promotes sarcoma metastasis.Cancer Discov 3, no. 10 (October 2013): 1190–1205. https://doi.org/10.1158/2159-8290.CD-13-0118.
Eisinger-Mathason TSK, Zhang M, Qiu Q, Skuli N, Nakazawa MS, Karakasheva T, et al. Hypoxia-dependent modification of collagen networks promotes sarcoma metastasis. Cancer Discov. 2013 Oct;3(10):1190–205.
Eisinger-Mathason, TS Karin, et al. “Hypoxia-dependent modification of collagen networks promotes sarcoma metastasis.Cancer Discov, vol. 3, no. 10, Oct. 2013, pp. 1190–205. Pubmed, doi:10.1158/2159-8290.CD-13-0118.
Eisinger-Mathason TSK, Zhang M, Qiu Q, Skuli N, Nakazawa MS, Karakasheva T, Mucaj V, Shay JES, Stangenberg L, Sadri N, Puré E, Yoon SS, Kirsch DG, Simon MC. Hypoxia-dependent modification of collagen networks promotes sarcoma metastasis. Cancer Discov. 2013 Oct;3(10):1190–1205.

Published In

Cancer Discov

DOI

EISSN

2159-8290

Publication Date

October 2013

Volume

3

Issue

10

Start / End Page

1190 / 1205

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Sarcoma, Experimental
  • Sarcoma
  • Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase
  • Neoplasm Metastasis
  • Molecular Targeted Therapy
  • Minoxidil
  • Mice, Transgenic
  • Mice
  • Hypoxia-Inducible Factor 1, alpha Subunit