A CXCL1 paracrine network links cancer chemoresistance and metastasis

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 Massagué

Research output: Contribution to journalArticlepeer-review

660 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)165-178
Number of pages14
JournalCell
Volume150
Issue number1
DOIs
StatePublished - Jul 6 2012

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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