Downregulation of CXCL12 in mesenchymal stromal cells by TGFβ promotes breast cancer metastasis.
Mesenchymal stromal cells (MSCs) are one of major components of the tumour microenvironment. Recent studies have shown that MSC tumour residence and their close interactions with inflammatory factors are important factors that affect tumour progression. Among tumour-associated inflammatory factors, transforming growth factor β (TGFβ) is regarded as a key determinant of malignancy. By employing a lung metastasis model of a murine breast cancer, we show here that the prometastatic effect of MSCs was dependent on their response to TGFβ. Interestingly, we found that MSC-produced CXCL12, an important chemokine in tumour metastasis, was markedly inhibited by TGFβ. Furthermore, silencing of CXCL12 in TGFβ-unresponsive MSCs restored their ability to promote tumour metastasis. We found that 4T1 breast cancer cells expressed high levels of CXCR7, but not of CXCR4, both of which are CXCL12 receptors. In presence of CXCL12, CXCR7 expression on tumour cells was decreased. Indeed, when CXCR7 was silenced in breast cancer cells, their metastatic ability was inhibited. Therefore, our data demonstrated that sustained expression of CXCL12 by MSCs in the primary tumour site inhibits metastasis through reduction of CXCR7, while, in the presence of TGFβ, this CXCL12 effect of MSCs on tumour cells is relieved. Importantly, elevated CXCR7 and depressed CXCL12 expression levels were prominent features of clinical breast cancer lesions and were related significantly with poor survival. Our findings reveal a novel mechanism of MSC effects on malignant cells through which crosstalk between MSCs and TGFβ regulates tumour metastasis.
Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, China.
P F
PF
Yu
Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, China.
Y
0000-0001-5602-9871
Y
Huang
Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, China.
C L
CL
Xu
Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, China.
L Y
LY
Lin
Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, China.
Y Y
YY
Han
Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, China.
W H
WH
Sun
Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, China.
G H
GH
Hu
Child Health Institute of New Jersey, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
A B
AB
Rabson
Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, China.
Y
Y
Wang
Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, China.|The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, Soochow University, Suzhou, China.
Y F
YF
Shi
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D005260:Female; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D054387:Receptors, CXCR / Q000096:biosynthesis; D015398:Signal Transduction; D014162:Transfection
C501896:ACKR3 protein, human; D054377:Chemokine CXCL12; C501897:Cmkor1 protein, mouse; C515256:Cxcl12 protein, mouse; D054387:Receptors, CXCR
Br J Cancer. 2008 Nov 4;99(9):1493-501
18854833
Clin Cancer Res. 2007 Sep 1;13(17):5020-7
17785552
Cancer Res. 2004 Dec 1;64(23):8604-12
15574767
J Exp Med. 2014 Jul 28;211(8):1503-23
25071162
Nat Rev Immunol. 2011 Aug 25;11(9):597-606
21866172
Blood. 2003 Sep 15;102(6):1978-84
12775566
J Biol Chem. 2005 Oct 21;280(42):35760-6
16107333
Nat Commun. 2013;4:1795
23653207
Oncogene. 2016 Mar 24;35(12):1602-8
26119942
Cell Stem Cell. 2012 Dec 7;11(6):812-24
23168163
Cancer Metastasis Rev. 2006 Dec;25(4):573-87
17165132
Proc Natl Acad Sci U S A. 2007 Oct 2;104(40):15735-40
17898181
Annu Rev Immunol. 2013;31:285-316
23298209
Cell. 2010 Mar 19;140(6):883-99
20303878
Breast Cancer Res. 2012 Feb 07;14(1):R23
22314082
J Exp Med. 2006 Sep 4;203(9):2201-13
16940167
Cancer Res. 2010 Dec 15;70(24):10411-21
21056990
Nat Rev Cancer. 2010 Jun;10(6):415-24
20495575
Oncogene. 2015 Apr 16;34(16):2043-51
24909174
Cancer Cell. 2013 Oct 14;24(4):410-21
24135279
J Cell Biochem. 2012 Nov;113(11):3363-70
22644871
Exp Cell Res. 2010 Dec 10;316(20):3417-24
20633553
Oncogene. 2016 Mar 3;35(9):1122-33
25982273
Stem Cells. 2009 Jun;27(6):1366-75
19489099
Oncogene. 2016 Mar 31;35(13):1716-24
26119946
Haematologica. 2014 Jun;99(6):997-1005
24584347
Cancer Cell. 2011 Sep 13;20(3):300-14
21907922
Sci Signal. 2015 Jul 28;8(387):re9
26221054
Proc Natl Acad Sci U S A. 2015 Mar 17;112(11):3499-504
25739959
J Immunol. 2014 Jan 1;192(1):103-9
24293629
Nat Rev Cancer. 2013 Nov;13(11):788-99
24132110
Clin Cancer Res. 2010 Jun 1;16(11):2927-31
20484021
Nature. 2007 Oct 4;449(7162):557-63
17914389
Cancer Res. 2014 Apr 1;74(7):2038-49
24520074
Cancer Cell. 2008 Sep 9;14(3):263-73
18772115
Cell. 2005 May 6;121(3):335-48
15882617