Lysyl hydroxylase 2 induces a collagen cross-link switch in tumor stroma
Yulong Chen, … , Mitsuo Yamauchi, Jonathan M. Kurie
Yulong Chen, … , Mitsuo Yamauchi, Jonathan M. Kurie
Published February 9, 2015
Citation Information: J Clin Invest. 2015;125(3):1147-1162. https://doi.org/10.1172/JCI74725.
View: Text | PDF
Research Article Oncology

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.

Authors

Yulong 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

×

Figure 9

Ectopic LH2 increases KC4 tumor size and metastasis.

Options: View larger image (or click on image) Download as PowerPoint
Ectopic LH2 increases KC4 tumor size and metastasis. (A) Q-PCR analysis ...
(A) Q-PCR analysis (bar graph) and immunoblot analysis (gels) of KC4 cells stably transfected with murine LH2 cDNA expression vector or empty vector control. Mean ± SD of triplicate samples. Actin was used as a loading control. P values, 2-tailed Student’s t test. (B) Images show migrating and invading KC4 cells stably transfected with murine LH2 cDNA expression vector or empty vector control in Boyden chambers. Scale bars: 200 μm. Mean ± SD of triplicate wells from a single experiment are expressed as the fold change relative to control transfectants, which were set at 1.0. P values, 2-tailed Student’s t test. (C) Scatter plots of primary tumor weights (left) and total numbers of lung metastases (right) from a single experiment in which mice were injected subcutaneously with KC4 cells stably transfected with LH2 expression vector or empty vector control. Dot, single mouse; bars and whiskers, mean ± SD. P values, Mann-Whitney U test.