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.
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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

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Figure 1

p21 loss confers metastatic capacity to lung adenocarcinomas in K-rasLA1 mice.

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p21 loss confers metastatic capacity to lung adenocarcinomas in K-rasLA1...
(A) Kaplan-Meier survival analysis of a single experiment in which mouse cohorts were generated with the indicated genotypes and sample sizes. The P value was calculated with the log-rank (Mantel-Cox) test of the difference between mean survival times in the p21-replete (K-rasLA1/+ Cdkn1a+/+) and p21-deficient (K-rasLA1/+ Cdkn1a–/– [KC]) groups. (B) Examples of invasive lung adenocarcinomas in KC mice. Arrowheads indicate invasive front at the edge of (left to right) a primary tumor, peribronchial invasion, and perivascular invasion. Scale bars: 200 μm (left), 100 μm (middle and right). (C) Examples of metastatic foci in KC mice. Images (left to right) of metastases to chest wall, diaphragm, subcutaneous space, kidney, and liver. H&E staining of adjacent tissue sections (lower panels). Scale bars: 100 μm. (D) A pleural implant subjected to immunofluorescence staining with antibodies against SPC (top), a marker of type II alveolar cells. Scale bars: 100 μm.