Hypoxia-inducible factor-dependent breast cancer-mesenchymal stem cell bidirectional signaling promotes metastasis

被引：249

作者：

Chaturvedi, Pallavi ^{[1
,2
]}

Gilkes, Daniele M. ^{[1
,2
]}

Wong, Carmen Chak Lui ^{[1
,2
,3
]}

Kshitiz ^{[1
,4
]}

Luo, Weibo ^{[1
,2
]}

Zhang, Huafeng ^{[1
,5
]}

Wei, Hong ^{[1
,2
]}

Takano, Naoharu ^{[1
,2
]}

Schito, Luana ^{[1
,2
]}

Levchenko, Andre ^{[1
,4
]}

Semenza, Gregg L. ^{[1
,2
,6
,7
,8
,9
,10
]}

机构：

[1] Johns Hopkins Univ, Sch Med, Inst Cell Engn, Vasc Program, Baltimore, MD USA

[2] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA

[3] Univ Hong Kong, Dept Pathol, Hong Kong, Hong Kong, Peoples R China

[4] Johns Hopkins Univ, Sch Med, Dept Biomed Engn, Baltimore, MD 21205 USA

[5] Univ Sci & Technol China, Sch Life Sci, Hefei 230026, Anhui, Peoples R China

[6] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA

[7] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA

[8] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA

[9] Johns Hopkins Univ, Sch Med, Dept Radiat Oncol, Baltimore, MD USA

[10] Johns Hopkins Univ, Sch Med, Dept Biol Chem, Baltimore, MD 21205 USA

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2013年 / 123卷 / 01期

关键词：

LYSYL OXIDASE; GROWTH-FACTOR; TUMOR STROMA; EXPRESSION; OVEREXPRESSION; FACTOR-1-ALPHA; RECRUITMENT; HIF-1-ALPHA; FACTOR-2-ALPHA; ANGIOGENESIS;

D O I：

10.1172/JCI64993

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Metastasis involves critical interactions between cancer and stromal cells. Intratumoral hypoxia promotes metastasis through activation of hypoxia-inducible factors (HIFs). We demonstrate that HIFs mediate paracrine signaling between breast cancer cells (BCCs) and mesenchymal stein cells (MSCs) to promote metastasis. In a mouse orthotopic implantation model, MSCs were recruited to primary breast tumors and promoted BCC metastasis to LNs and lungs in a HIF-dependent manner. Coculture of MSCs with BCCs augmented HIF activity in BCCs. Additionally, coculture induced expression of the chemokine CXCL10 in MSCs and the cognate receptor CXCR3 in BCCs, which was augmented by hypoxia. CXCR3 expression was blocked in cocultures treated with neutralizing antibody against CXCL10. Conversely, CXCL10 expression was blocked in MSCs cocultured. with BCCs that did not express CXCR3 or HIFs. MSC coculture did not enhance the metastasis of HIF-deficient BCCs. BCCs and MSCs expressed placental growth factor (PGF) and its cognate receptor VEGFR1, respectively, in a HIF-dependent manner, and CXCL10 expression by MSCs was dependent on PGF expression by BCCs. PGF promoted metastasis of BCCs and also facilitated homing of MSCs to tumors. Thus, HIFs mediate complex and bidirectional paracrine signaling between BCCs and MSCs that stimulates breast cancer metastasis.

引用

页码：189 / 205

页数：17

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[1] Levels of hypoxia-inducible factor-1α independently predict prognosis in patients with lymph node negative breast carcinoma [J].