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Lysyl hydroxylase 2 induces a collagen cross-link switch in tumor stroma.

Abstract
Epithelial tumor metastasis is preceded by an accumulation of collagen cross-links that heighten stromal stiffness and stimulate the invasive properties of tumor cells. However, the biochemical nature of collagen cross-links in cancer is still unclear. Here, we postulated that epithelial tumorigenesis is accompanied by changes in the biochemical type of collagen cross-links. Utilizing resected human lung cancer tissues and a p21CIP1/WAF1-deficient, K-rasG12D-expressing murine metastatic lung cancer model, we showed that, relative to normal lung tissues, tumor stroma contains higher levels of hydroxylysine aldehyde-derived collagen cross-links (HLCCs) and lower levels of lysine aldehyde-derived cross-links (LCCs), which are the predominant types of collagen cross-links in skeletal tissues and soft tissues, respectively. Gain- and loss-of-function studies in tumor cells showed that lysyl hydroxylase 2 (LH2), which hydroxylates telopeptidyl lysine residues on collagen, shifted the tumor stroma toward a high-HLCC, low-LCC state, increased tumor stiffness, and enhanced tumor cell invasion and metastasis. Together, our data indicate that LH2 enhances the metastatic properties of tumor cells and functions as a regulatory switch that controls the relative abundance of biochemically distinct types of collagen cross-links in the tumor stroma.
AuthorsYulong Chen, Masahiko Terajima, Yanan Yang, Li Sun, Young-Ho Ahn, Daniela Pankova, Daniel S Puperi, Takeshi Watanabe, Min P Kim, Shanda H Blackmon, Jaime Rodriguez, Hui Liu, Carmen Behrens, Ignacio I Wistuba, Rosalba Minelli, Kenneth L Scott, Johannah Sanchez-Adams, Farshid Guilak, Debananda Pati, Nishan Thilaganathan, Alan R Burns, Chad J Creighton, Elisabeth D Martinez, Tomasz Zal, K Jane Grande-Allen, Mitsuo Yamauchi, Jonathan M Kurie
JournalThe Journal of clinical investigation (J Clin Invest) Vol. 125 Issue 3 Pg. 1147-62 (Mar 02 2015) ISSN: 1558-8238 [Electronic] United States
PMID25664850 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Collagen
  • PLOD2 protein, human
  • Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase
Topics
  • Adenocarcinoma (enzymology, mortality, secondary)
  • Animals
  • Carcinoma, Squamous Cell (enzymology, mortality, secondary)
  • Cell Line, Tumor
  • Cells, Cultured
  • Collagen (metabolism)
  • Enzyme Induction
  • Extracellular Matrix (metabolism)
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Kaplan-Meier Estimate
  • Lung Neoplasms (enzymology, mortality, pathology)
  • Male
  • Mice, 129 Strain
  • Mice, Transgenic
  • Neoplasm Transplantation
  • Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase (physiology)
  • Promoter Regions, Genetic
  • STAT3 Transcription Factor (metabolism)
  • Tumor Microenvironment
  • Up-Regulation

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