期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 125, 期 3, 页码 1147-1162出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI74725
关键词
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资金
- NIH [R01 CA109478, CA125123, R01 CA125269, R01 CA157450, R21AR060978, 1R21 CA184817-01, P30 EY007551]
- Cancer Prevention Research Institute of Texas Multi-Investigator Research Award [RP120713]
- UT Lung Specialized Programs of Research Excellence [P50 CA70907]
- Department of Defense PROSPECT grant [W81XWH-07-1-0306]
- MD Anderson Cancer Center Support Grant [CA016672]
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 p21(CIP1/WAF1)-deficient, K-ras(G12D)-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.
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