A CXCL1 paracrine network links cancer chemoresistance and metastasis
- PMID: 22770218
- PMCID: PMC3528019
- DOI: 10.1016/j.cell.2012.04.042
A CXCL1 paracrine network links cancer chemoresistance and metastasis
Abstract
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-α production by endothelial and other stromal cells. TNF-α 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.
Copyright © 2012 Elsevier Inc. All rights reserved.
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Comment in
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Domino effect.Nat Rev Cancer. 2012 Jul 24;12(8):506. doi: 10.1038/nrc3332. Nat Rev Cancer. 2012. PMID: 22825210 No abstract available.
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Cell signalling: Stuck in the middle of chemoresistance and metastasis.Nat Rev Clin Oncol. 2012 Sep;9(9):490. doi: 10.1038/nrclinonc.2012.129. Epub 2012 Jul 31. Nat Rev Clin Oncol. 2012. PMID: 22850753 No abstract available.
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