The Reprogramming of Tumor Stroma by HSF1 Is a Potent Enabler of Malignancy

被引：306

作者：

Scherz-Shouval, Ruth ^{[1
]}

Santagata, Sandro ^{[1
,2
,3
]}

Mendillo, Marc L. ^{[1
]}

Sholl, Lynette M. ^{[2
]}

Ben-Aharon, Irit ^{[4
,5
]}

Beck, Andrew H. ^{[6
]}

Dias-Santagata, Dora ^{[7
,8
]}

Koeva, Martina ^{[1
,9
]}

Stemmer, Salomon M. ^{[4
,5
]}

Whitesell, Luke ^{[1
]}

Lindquist, Susan ^{[1
,10
,11
]}

机构：

[1] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA

[2] Harvard Univ, Sch Med, Dept Pathol, Brigham & Womens Hosp, Boston, MA 02115 USA

[3] Dana Farber Canc Ctr, Dept Canc Biol, Boston, MA 02215 USA

[4] Rabin Med Ctr, Davidoff Ctr, Inst Oncol, IL-49100 Petah Tiqwa, Israel

[5] Tel Aviv Univ, Sackler Fac Med, IL-69978 Ramat Aviv, Israel

[6] Harvard Univ, Sch Med, Dept Pathol, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA

[7] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA

[8] Harvard Univ, Sch Med, Boston, MA 02215 USA

[9] MIT, Dept Biol Engn, Cambridge, MA 02142 USA

[10] MIT, Dept Biol, Cambridge, MA 02142 USA

[11] Howard Hughes Med Inst, Cambridge, MA 02142 USA

来源：

CELL | 2014年 / 158卷 / 03期

关键词：

HEAT-SHOCK FACTOR-1; TRANSCRIPTION FACTOR HSF1; BREAST-CANCER; TGF-BETA; GENE-EXPRESSION; LUNG-CANCER; FIBROBLASTS; MICROENVIRONMENT; PROGRESSION; GROWTH;

D O I：

10.1016/j.cell.2014.05.045

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Stromal cells within the tumor microenvironment are essential for tumor progression and metastasis. Surprisingly little is known about the factors that drive the transcriptional reprogramming of stromal cells within tumors. We report that the transcriptional regulator heat shock factor 1 (HSF1) is frequently activated in cancer-associated fibroblasts (CAFs), where it is a potent enabler of malignancy. HSF1 drives a transcriptional program in CAFs that complements, yet is completely different from, the program it drives in adjacent cancer cells. This CAF program is uniquely structured to support malignancy in a non-cell-autonomous way. Two central stromal signaling molecules-TGF-beta and SDF1-play a critical role. In early-stage breast and lung cancer, high stromal HSF1 activation is strongly associated with poor patient outcome. Thus, tumors co-opt the ancient survival functions of HSF1 to orchestrate malignancy in both cell-autonomous and non-cell-autonomous ways, with far-reaching therapeutic implications.

引用

页码：564 / 578

页数：15

共 44 条

[1] The fibromatosis signature defines a robust stromal response in breast carcinoma [J].

Beck, Andrew H. ;

Espinosa, Inigo ;

Gilks, C. Blake ;

van de Rijn, Matt ;

West, Robert B. .

LABORATORY INVESTIGATION, 2008, 88 (06) :591-601

[2] Why don't we get more cancer? A proposed role of the microenvironment in restraining cancer progression [J].

Bissell, Mina J. ;

Hines, William C. .

NATURE MEDICINE, 2011, 17 (03) :320-329

[3] Gene expression signature of fibroblast serum response predicts human cancer progression: Similarities between tumors and wounds [J].

Chang, HY ;

Sneddon, JB ;

Alizadeh, AA ;

Sood, R ;

West, RB ;

Montgomery, K ;

Chi, JT ;

van de Rijn, M ;

Botstein, D ;

Brown, PO .

PLOS BIOLOGY, 2004, 2 (02) :206-214

[4] Heat shock factor 1 is a powerful multifaceted modifier of carcinogenesis [J].

Dai, Chengkai ;

Whitesell, Luke ;

Rogers, Arlin B. ;

Lindquist, Susan .

CELL, 2007, 130 (06) :1005-1018

[5] Rapid targeted mutational analysis of human tumours: a clinical platform to guide personalized cancer medicine [J].

Dias-Santagata, Dora ;

Akhavanfard, Sara ;

David, Serena S. ;

Vernovsky, Kathy ;

Kuhlmann, Georgiana ;

Boisvert, Susan L. ;

Stubbs, Hannah ;

McDermott, Ultan ;

Settleman, Jeffrey ;

Kwak, Eunice L. ;

Clark, Jeffrey W. ;

Isakoff, Steven J. ;

Sequist, Lecia V. ;

Engelman, Jeffrey A. ;

Lynch, Thomas J. ;

Haber, Daniel A. ;

Louis, David N. ;

Ellisen, Leif W. ;

Borger, Darrell R. ;

Lafrate, A. John .

EMBO MOLECULAR MEDICINE, 2010, 2 (05) :146-158

[6]

DVORAK HF, 1986, NEW ENGL J MED, V315, P1650

[7] Cancer-Associated Fibroblasts Are Activated in Incipient Neoplasia to Orchestrate Tumor-Promoting Inflammation in an NF-κB-Dependent Manner [J].

Erez, Neta ;

Truitt, Morgan ;

Olson, Peter ;

Hanahan, Douglas .

CANCER CELL, 2010, 17 (02) :135-147

[8] Heat Shock Factor 1 Promotes Invasion and Metastasis of Hepatocellular Carcinoma In vitro and In Vivo [J].

Fang, Feng ;

Chang, Ruimin ;

Yang, Lianyue .

CANCER, 2012, 118 (07) :1782-1794

[9] Stromal gene expression predicts clinical outcome in breast cancer [J].

Finak, Greg ;

Bertos, Nicholas ;

Pepin, Francois ;

Sadekova, Svetlana ;

Souleimanova, Margarita ;

Zhao, Hong ;

Chen, Haiying ;

Omeroglu, Gulbeyaz ;

Meterissian, Sarkis ;

Omeroglu, Atilla ;

Hallett, Michael ;

Park, Morag .

NATURE MEDICINE, 2008, 14 (05) :518-527

[10] The IASLC lung cancer staging project: Proposals for the revision of he TNM stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours [J].

Goldstraw, Peter ;

Crowley, John ;

Chansky, Kari ;

Giroux, Dorothy J. ;

Groome, Patti A. ;

Rami-Porta, Ramon ;

Postmus, Pieter E. ;

Rusch, Valerie ;

Sobin, Leslie .

JOURNAL OF THORACIC ONCOLOGY, 2007, 2 (08) :706-714

← 1 2 3 4 5 →