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Cancer-associated fibroblasts induce a collagen cross-link switch in tumor stroma

Title
Cancer-associated fibroblasts induce a collagen cross-link switch in tumor stroma
Authors
Pankova D.Chen Y.Terajima M.Schliekelman M.J.Baird B.N.Fahrenholtz M.Sun L.Gill B.J.Vadakkan T.J.Kim M.P.Ahn Y.-H.Roybal J.D.Liu X.Cuentas E.R.P.Rodriguez J.Wistuba I.I.Creighton C.J.Gibbons D.L.Hicks J.M.Dickinson M.E.West J.L.Grande-Allen K.J.Hanash S.M.Yamauchi M.Kurie J.M.
Ewha Authors
안영호
SCOPUS Author ID
안영호scopus
Issue Date
2016
Journal Title
Molecular Cancer Research
ISSN
1541-7786JCR Link
Citation
vol. 14, no. 3, pp. 287 - 295
Publisher
American Association for Cancer Research Inc.
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
Intratumoral collagen cross-links heighten stromal stiffness and stimulate tumor cell invasion, but it is unclear how collagen cross-linking is regulated in epithelial tumors. To address this question, we used KrasLA1 mice, which develop lung adenocarcinomas from somatic activation of a KrasG12D allele. The lung tumors in KrasLA1 mice were highly fibrotic and contained cancerassociated fibroblasts (CAF) that produced collagen and generated stiffness in collagen gels. In xenograft tumors generated by injection of wild-type mice with lung adenocarcinoma cells alone or in combination with CAFs, the total concentration of collagen cross-links was the same in tumors generated with or without CAFs, but coinjected tumors had higher hydroxylysine aldehyde-derived collagen cross-links (HLCC) and lower lysine-aldehyde-derived collagen cross-links (LCCs). Therefore, we postulated that an LCC-to-HLCC switch induced by CAFs promotes the migratory and invasive properties of lung adenocarcinoma cells. To test this hypothesis, we created coculture models in which CAFs are positioned interstitially or peripherally in tumor cell aggregates, mimicking distinct spatial orientations of CAFs in human lung cancer. In both contexts, CAFs enhanced the invasive properties of tumor cells in three-dimensional (3D) collagen gels. Tumor cell aggregates that attached to CAF networks on a Matrigel surface dissociated and migrated on the networks. Lysyl hydroxylase 2 (PLOD2/LH2), which drives HLCC formation, was expressed in CAFs, and LH2 depletion abrogated the ability of CAFs to promote tumor cell invasion and migration. Implications: CAFs induce a collagen cross-link switch in tumor stroma to influence the invasive properties of tumor cells. © 2016 American Association for Cancer Research.
DOI
10.1158/1541-7786.MCR-15-0307
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의학전문대학원 > 의학과 > Journal papers
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