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- Title
Lysyl hydroxylase 2 induces a collagen cross-link switch in tumor stroma.
- Authors
Yulong Chen; Masahiko Terajima; Yanan Yang; Li Sun; Young-Ho Ahn; Pankova, Daniela; Puperi, Daniel S.; Takeshi Watanabe; Kim, Min P.; Blackmon, Shanda H.; Rodriguez, Jaime; Hui Liu; Behrens, Carmen; Wistuba, Ignacio I.; Minelli, Rosalba; Scott, Kenneth L.; Sanchez-Adams, Johannah; Guilak, Farshid; Pati, Debananda; Nishan Thilaganathan
- Abstract
Epithelial tumor metastasis is preceded by an accumulation of collagen cross-links that heighten stroma l 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 crosslinks. Utilizing resected human lung cancertissues 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.
- Subjects
HYDROXYLASES; OXYGENASES; STROMAL cells; CONNECTIVE tissue cells; MESENCHYMAL stem cells
- Publication
Journal of Clinical Investigation, 2015, Vol 125, Issue 3, p1147
- ISSN
0021-9738
- Publication type
Article
- DOI
10.1172/JCI74725