Dependency of Colorectal Cancer on a TGF-β-Driven Program in Stromal Cells for Metastasis Initiation

被引：905

作者：

Calon, Alexandre ^{[1
]}

Espinet, Elisa ^{[1
]}

Palomo-Ponce, Sergio ^{[1
]}

Tauriello, Daniele V. F. ^{[1
]}

Iglesias, Mar ^{[4
,5
]}

Virtudes Cespedes, Maria ^{[6
,7
]}

Sevillano, Marta ^{[1
]}

Nadal, Cristina ^{[8
]}

Jung, Peter ^{[1
]}

Zhang, Xiang H. -F. ^{[9
]}

Byrom, Daniel ^{[2
]}

Riera, Antoni ^{[2
,10
]}

Rossell, David ^{[3
]}

Mangues, Ramon ^{[6
,7
]}

Massague, Joan ^{[9
,11
]}

Sancho, Elena ^{[1
]}

Batlle, Eduard ^{[1
,12
]}

机构：

[1] Inst Res Biomed, Oncol Programme, Barcelona 08028, Spain

[2] Inst Res Biomed, Chem & Mol Pharmacol Programme, Barcelona 08028, Spain

[3] Inst Res Biomed, Biostat & Bioinformat Unit, Barcelona 08028, Spain

[4] Hosp Mar, Dept Pathol, Inst Hosp Mar Invest Med, Barcelona 08004, Spain

[5] Autonomous Univ Barcelona, Barcelona 08004, Spain

[6] Hosp Santa Creu & Sant Pau, Biomed Res Inst St Pau, Barcelona 08025, Spain

[7] CIBER Bioingn Biomat & Nanomed, Barcelona 08025, Spain

[8] Hosp Clin CIBERehd, Inst Malalties Hematooncol, Barcelona 08036, Spain

[9] Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, New York, NY 10021 USA

[10] Univ Barcelona, Dept Quim Organ, E-08028 Barcelona, Spain

[11] Howard Hughes Med Inst, Chevy Chase, MD 20185 USA

[12] ICREA, Barcelona 08010, Spain

来源：

CANCER CELL | 2012年 / 22卷 / 05期

基金：

欧洲研究理事会; 美国国家卫生研究院;

关键词：

GROWTH-FACTOR; COLON-CANCER; TUMOR-SUPPRESSOR; POOR-PROGNOSIS; T-CELLS; RECEPTOR; INTERLEUKIN-11; CARCINOMA; SMAD4; TUMORIGENESIS;

D O I：

10.1016/j.ccr.2012.08.013

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

A large proportion of colorectal cancers (CRCs) display mutational inactivation of the TGF-beta pathway, yet, paradoxically, they are characterized by elevated TGF-beta production. Here, we unveil a prometastatic program induced by TGF-beta in the microenvironment that associates with a high risk of CRC relapse upon treatment. The activity of TGF-beta on stromal cells increases the efficiency of organ colonization by CRC cells, whereas mice treated with a pharmacological inhibitor of TGFBR1 are resilient to metastasis formation. Secretion of IL11 by TGF-beta-stimulated cancer-associated fibroblasts (CAFs) triggers GP130/STAT3 signaling in tumor cells. This crosstalk confers a survival advantage to metastatic cells. The dependency on the TGF-beta stromal program for metastasis initiation could be exploited to improve the diagnosis and treatment of CRC.

引用

页码：571 / 584

页数：14

共 50 条

[1] Nuclear CDKs Drive Smad Transcriptional Activation and Turnover in BMP and TGF-β Pathways [J].

Alarcon, Claudio ;

Zaromytidou, Alexia-Ileana ;

Xi, Qiaoran ;

Gao, Sheng ;

Yu, Jianzhong ;

Fujisawa, Sho ;

Barlas, Afsar ;

Miller, Alexandria N. ;

Manova-Todorova, Katia ;

Macias, Maria J. ;

Sapkota, Gopal ;

Pan, Duojia ;

Massague, Joan .

CELL, 2009, 139 (04) :757-769

[2] TGF-β suppresses tumor progression in colon cancer by inhibition of IL-6 trans-signaling [J].

Becker, C ;

Fantini, MC ;

Schramm, C ;

Lehr, HA ;

Wirtz, S ;

Nikolaev, A ;

Burg, J ;

Strand, S ;

Kiesslich, R ;

Huber, S ;

Ito, H ;

Nishimoto, N ;

Yoshizaki, K ;

Nishimoto, N ;

Galle, PR ;

Blessing, M ;

Rose-John, S ;

Neurath, MF .

IMMUNITY, 2004, 21 (04) :491-501

[3] The role of interleukin-11 to prevent chemotherapy-induced thrombocytopenia in patients with solid tumors, lymphoma, acute myeloid leukemia and bone marrow failure syndromes [J].

Bhatia, Monica ;

Davenport, Virginia ;

Cairo, Mitchell S. .

LEUKEMIA & LYMPHOMA, 2007, 48 (01) :9-15

[4] Genes that mediate breast cancer metastasis to the brain [J].

Bos, Paula D. ;

Zhang, Xiang H. -F. ;

Nadal, Cristina ;

Shu, Weiping ;

Gomis, Roger R. ;

Nguyen, Don X. ;

Minn, Andy J. ;

van de Vijver, Marc J. ;

Gerald, William L. ;

Foekens, John A. ;

Massague, Joan .

NATURE, 2009, 459 (7249) :1005-U137

[5] Semi-mechanistic modelling of the tumour growth inhibitory effects of LY2157299, a new type I receptor TGF-β kinase antagonist, in mice [J].

Bueno, Lorea ;

de Alwis, Dinesh P. ;

Pitou, Celine ;

Yingling, Jonathan ;

Lahn, Michael ;

Glatt, Sophie ;

Troconiz, Inaki F. .

EUROPEAN JOURNAL OF CANCER, 2008, 44 (01) :142-150

[6] The polarization of immune cells in the tumour environment by TGFβ [J].

Flavell, Richard A. ;

Sanjabi, Shomyseh ;

Wrzesinski, Stephen H. ;

Licona-Limon, Paula .

NATURE REVIEWS IMMUNOLOGY, 2010, 10 (08) :554-567

[7] Contribution of platelets to tumour metastasis [J].

Gay, Laurie J. ;

Felding-Habermann, Brunhilde .

NATURE REVIEWS CANCER, 2011, 11 (02) :123-134

[8] Genetic and epigenetic alterations in colon cancer [J].

Grady, WM ;

Markowitz, SD .

ANNUAL REVIEW OF GENOMICS AND HUMAN GENETICS, 2002, 3 :101-128

[9] Smad4 deficiency in T cells leads to the Th17-associated development of premalignant gastroduodenal lesions in mice [J].

Hahn, Jennifer Nancy ;

Falck, Vincent George ;

Jirik, Frank Robert .

JOURNAL OF CLINICAL INVESTIGATION, 2011, 121 (10) :4030-4042

[10]

Ikeda M, 2002, ANN SURG ONCOL, V9, P287, DOI 10.1245/aso.2002.9.3.287

← 1 2 3 4 5 →