A CXCL1 Paracrine Network Links Cancer Chemoresistance and Metastasis

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2012 Jul 10

PMID 22770218

Citations 615

Authors

Swarnali Acharyya

Thordur Oskarsson

Sakari Vanharanta

Srinivas Malladi

Juliet Kim

Patrick G Morris

Katia Manova-Todorova

Margaret Leversha

Nancy Hogg

Venkatraman E Seshan

Larry Norton

Edi Brogi

Joan Massague

Affiliations

Soon will be listed here.

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.

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