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 4

LH2 expression has prognostic value in cancer patients.

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LH2 expression has prognostic value in cancer patients. (A) Human lung c...
(A) Human lung cancers that are negative (upper panel) or positive (lower panel) for LH2 expression. LH2 expression (brown) in the stroma serves as a positive control for staining in the LH2-negative tumor. Scale bars: 200 μm. (B) Box plots representing the median and 25th and 75th percentiles of LH2 protein levels in lung adenocarcinoma and squamous cell carcinoma. P value, 2-tailed t test on log-transformed data. (C) Box plots representing the median and 5th and 95th percentiles of the LH2 protein levels in lung tumors of different grades. P value, 2-tailed t test on log-transformed data. (D) Kaplan-Meier survival analysis. Tumors classified as positive or negative for LH2 expression on the basis of immunohistochemical staining (A). P value, log-rank (Mantel-Cox) test (LH2-positive versus -negative). (E and F) Kaplan-Meier survival analysis of human lung cancers on the basis of different tumor histologies (E) and tumor grades (F). P values, log-rank (Mantel-Cox) test of differences between the LH2-positive and -negative groups. (G) Kaplan-Meier plot (P values, log-rank test) of publically available data from patient cohorts with lung adenocarcinoma (lung), breast adenocarcinoma (breast), or renal cell carcinoma (kidney). Analysis compares top third (highest expression), bottom third (lowest expression), and middle third (intermediate expression) of LH2 mRNA levels. Breast and lung tumor cohorts each represent a compendium of multiple datasets. Sample sizes in each cohort are indicated.