Platelet-Derived Growth Factor-D and Rho GTPases Regulate Recruitment of Cancer-Associated Fibroblasts in Cholangiocarcinoma

被引：140

作者：

Cadamuro, Massimiliano ^{[1
,2
]}

Nardo, Giorgia ^{[3
]}

Indraccolo, Stefano ^{[3
]}

Dall'Olmo, Luigi ^{[1
]}

Sambado, Luisa ^{[4
]}

Moserle, Lidia ^{[1
,3
]}

Franceschet, Irene ^{[1
]}

Colledan, Michele ^{[2
]}

Massani, Marco ^{[5
]}

Stecca, Tommaso ^{[5
]}

Bassi, Nicolo ^{[1
,5
]}

Morton, Stuart ^{[1
]}

Spirli, Carlo ^{[6
]}

Fiorotto, Romina ^{[6
]}

Fabris, Luca ^{[1
,2
,6
,7
]}

Strazzabosco, Mario ^{[2
,6
,7
]}

机构：

[1] Univ Padua, Dept Surg Oncol & Gastroenterol, I-35128 Padua, Italy

[2] Osped Riuniti Bergamo, Ctr Liver Res CeLiveR, I-24100 Bergamo, Italy

[3] IRCCS, Ist Oncol Veneto, Padua, Italy

[4] Univ Padua, Dept Med, I-35128 Padua, Italy

[5] Treviso Reg Hosp, Surg Div 4, I-31100 Treviso, Italy

[6] Yale Univ, Sect Digest Dis, New Haven, CT USA

[7] Univ Milano Bicocca, Dept Surg & Interdisciplinary Med, Milan, Italy

来源：

HEPATOLOGY | 2013年 / 58卷 / 03期

基金：

美国国家卫生研究院;

关键词：

HEPATIC STELLATE CELLS; PDGF-D; FACTOR-RECEPTOR; BETA-RECEPTOR; PROGRESSION; EXPRESSION; MIGRATION; OVEREXPRESSION; ACTIVATION; CARCINOMA;

D O I：

10.1002/hep.26384

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

Cholangiocarcinoma (CCA) is characterized by an abundant stromal reaction. Cancer-associated fibroblasts (CAFs) are pivotal in tumor growth and invasiveness and represent a potential therapeutic target. To understand the mechanisms leading to CAF recruitment in CCA, we studied (1) expression of epithelial-mesenchymal transition (EMT) in surgical CCA specimens and CCA cells, (2) lineage tracking of an enhanced green fluorescent protein (EGFP)-expressing human male CCA cell line (EGI-1) after xenotransplantation into severe-combined-immunodeficient mice, (3) expression of platelet-derived growth factors (PDGFs) and their receptors in vivo and in vitro, (4) secretion of PDGFs by CCA cells, (5) the role of PDGF-D in fibroblast recruitment in vitro, and (6) downstream effectors of PDGF-D signaling. CCA cells expressed several EMT biomarkers, but not alpha smooth muscle actin (-SMA). Xenotransplanted CCA masses were surrounded and infiltrated by -SMA-expressing CAFs, which were negative for EGFP and the human Y-probe, but positive for the murine Y-probe. CCA cells were strongly immunoreactive for PDGF-A and -D, whereas CAFs expressed PDGF receptor (PDGFR). PDGF-D, a PDGFR agonist, was exclusively secreted by cultured CCA cells. Fibroblast migration was potently induced by PDGF-D and CCA conditioned medium and was significantly inhibited by PDGFR blockade with Imatinib and by silencing PDGF-D expression in CCA cells. In fibroblasts, PDGF-D activated the Rac1 and Cdc42 Rho GTPases and c-Jun N-terminal kinase (JNK). Selective inhibition of Rho GTPases (particularly Rac1) and of JNK strongly reduced PDGF-D-induced fibroblast migration. Conclusion: CCA cells express several mesenchymal markers, but do not transdifferentiate into CAFs. Instead, CCA cells recruit CAFs by secreting PDGF-D, which stimulates fibroblast migration through PDGFR and Rho GTPase and JNK activation. Targeting tumor or stroma interactions with inhibitors of the PDGF-D pathway may offer a novel therapeutic approach. (Hepatology 2013;53:1042-1053)

引用

页码：1042 / 1053

页数：12

共 32 条

[1] Imatinib blocks migration and invasion of medulloblastoma cells by concurrently inhibiting activation of platelet-derived growth factor receptor and transactivation of epidermal growth factor receptor [J].