Lysyl hydroxylase 2 induces a collagen cross-link switch in tumor stroma

被引：145

作者：

Chen, Yulong ^{[1
]}

Terajima, Masahiko ^{[2
]}

Yang, Yanan ^{[3
]}

Sun, Li ^{[1
]}

Ahn, Young-Ho ^{[1
,4
]}

Pankova, Daniela ^{[1
]}

Puperi, Daniel S. ^{[5
]}

Watanabe, Takeshi ^{[2
]}

Kim, Min P. ^{[6
]}

Blackmon, Shanda H. ^{[6
]}

Rodriguez, Jaime ^{[7
]}

Liu, Hui ^{[7
]}

Behrens, Carmen ^{[7
]}

Wistuba, Ignacio I. ^{[7
]}

Minelli, Rosalba ^{[8
]}

Scott, Kenneth L. ^{[8
]}

Sanchez-Adams, Johannah ^{[9
]}

Guilak, Farshid ^{[9
]}

Pati, Debananda ^{[10
]}

Thilaganathan, Nishan ^{[1
]}

Burns, Alan R. ^{[11
]}

Creighton, Chad J. ^{[12
,13
,14
]}

Martinez, Elisabeth D. ^{[15
,16
]}

Zal, Tomasz ^{[17
]}

Grande-Allen, K. Jane ^{[5
]}

Yamauchi, Mitsuo ^{[2
]}

Kurie, Jonathan M. ^{[1
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Thorac Head & Neck Med Oncol, Houston, TX 77030 USA

[2] Univ N Carolina, NC Oral Hlth Inst, Chapel Hill, NC 27599 USA

[3] Mayo Clin, Ctr Canc, Dept Biochem & Mol Biol, Div Pulm & Crit Care Med, Rochester, MN USA

[4] Ewha Womans Univ, Sch Med, Dept Mol Med, Seoul, South Korea

[5] Rice Univ, Dept Bioengn, Houston, TX USA

[6] Houston Methodist Res Inst, Dept Surg, Houston, TX USA

[7] Univ Texas MD Anderson Canc Ctr, Dept Translat Mol Pathol, Houston, TX 77030 USA

[8] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA

[9] Duke Univ, Med Ctr, Dept Orthopaed Surg, Durham, NC USA

[10] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA

[11] Univ Houston, Coll Optometry, Houston, TX USA

[12] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA

[13] Baylor Coll Med, Dept Med, Houston, TX 77030 USA

[14] Baylor Coll Med, Dan L Duncan Canc Ctr, Houston, TX 77030 USA

[15] Univ Texas SW Med Ctr Dallas, Hamon Ctr Therapeut Oncol Res, Dallas, TX 75390 USA

[16] Univ Texas SW Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA

[17] Univ Texas MD Anderson Canc Ctr, Dept Immunol, Houston, TX 77030 USA

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2015年 / 125卷 / 03期

关键词：

LUNG-CANCER; ADJUVANT CHEMOTHERAPY; LYSINE HYDROXYLATION; EXPRESSION; OXIDASE; GENES; IDENTIFICATION; P21; OVEREXPRESSION; NETWORKS;

D O I：

10.1172/JCI74725

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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.

引用

页码：1147 / 1162

页数：16

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