A CXCL1 Paracrine Network Links Cancer Chemoresistance and Metastasis

被引：915

作者：

Acharyya, Swarnali ^{[1
]}

Oskarsson, Thordur ^{[1
]}

Vanharanta, Sakari ^{[1
]}

Malladi, Srinivas ^{[1
]}

Kim, Juliet ^{[1
]}

Morris, Patrick G. ^{[2
]}

Manova-Todorova, Katia ^{[3
]}

Leversha, Margaret ^{[4
]}

Hogg, Nancy ^{[7
]}

Seshan, Venkatraman E. ^{[6
]}

Norton, Larry ^{[2
]}

Brogi, Edi ^{[5
]}

Massague, Joan ^{[1
,8
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, New York, NY 10065 USA

[2] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA

[3] Mem Sloan Kettering Canc Ctr, Mol Cytol Core Facil, New York, NY 10065 USA

[4] Mem Sloan Kettering Canc Ctr, Mol Cytogenet Core Facil, New York, NY 10065 USA

[5] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA

[6] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10065 USA

[7] Canc Res UK London Res Inst, Leukocyte Adhes Lab, London WC2A 3PX, England

[8] Howard Hughes Med Inst, Chevy Chase, MD 21205 USA

来源：

CELL | 2012年 / 150卷 / 01期

关键词：

BREAST-CANCER; SUPPRESSOR-CELLS; MYELOID CELLS; TUMOR; RESISTANCE; CHEMOKINE; THERAPY; GENES; CHEMOTHERAPY; INFLAMMATION;

D O I：

10.1016/j.cell.2012.04.042

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：

Metastasis and chemoresistance in cancer are linked phenomena, but the molecular basis for this link is unknown. We uncovered a network of paracrine signals between carcinoma, myeloid, and endothelial cells that drives both processes in breast cancer. Cancer cells that overexpress CXCL1 and 2 by transcriptional hyperactivation or 4q21 amplification are primed for survival in metastatic sites. CXCL1/2 attract CD11b(+)Gr1(+) myeloid cells into the tumor, which produce chemokines including S100A8/9 that enhance cancer cell survival. Although chemotherapeutic agents kill cancer cells, these treatments trigger a parallel stromal reaction leading to TNF-alpha production by endothelial and other stromal cells. TNF-alpha via NF-kB heightens the CXCL1/2 expression in cancer cells, thus amplifying the CXCL1/2-S100A8/9 loop and causing chemoresistance. CXCR2 blockers break this cycle, augmenting the efficacy of chemotherapy against breast tumors and particularly against metastasis. This network of endothelial-carcinoma-myeloid signaling interactions provides a mechanism linking chemoresistance and metastasis, with opportunities for intervention.

引用

页码：165 / 178

页数：14

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