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 journalArticle

469 Citations (Scopus)

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

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Cells
Neoplasm Metastasis
Tumors
Neoplasms
Myeloid Cells
Chemotherapy
NF-kappa B
Endothelial cells
Chemokines
Breast Neoplasms
Carcinoma
Amplification
Stromal Cells
Cell Survival
Endothelial Cells
Drug Therapy
Therapeutics

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Acharyya, S., Oskarsson, T., Vanharanta, S., Malladi, S., Kim, J., Morris, P. G., ... Massagué, J. (2012). A CXCL1 paracrine network links cancer chemoresistance and metastasis. Cell, 150(1), 165-178. https://doi.org/10.1016/j.cell.2012.04.042

A CXCL1 paracrine network links cancer chemoresistance and metastasis. / Acharyya, Swarnali; Oskarsson, Thordur; Vanharanta, Sakari; Malladi, Srinivas; Kim, Juliet; Morris, Patrick G.; Manova-Todorova, Katia; Leversha, Margaret; Hogg, Nancy; Seshan, Venkatraman E.; Norton, Larry; Brogi, Edi; Massagué, Joan.

In: Cell, Vol. 150, No. 1, 06.07.2012, p. 165-178.

Research output: Contribution to journalArticle

Acharyya, S, Oskarsson, T, Vanharanta, S, Malladi, S, Kim, J, Morris, PG, Manova-Todorova, K, Leversha, M, Hogg, N, Seshan, VE, Norton, L, Brogi, E & Massagué, J 2012, 'A CXCL1 paracrine network links cancer chemoresistance and metastasis', Cell, vol. 150, no. 1, pp. 165-178. https://doi.org/10.1016/j.cell.2012.04.042
Acharyya S, Oskarsson T, Vanharanta S, Malladi S, Kim J, Morris PG et al. A CXCL1 paracrine network links cancer chemoresistance and metastasis. Cell. 2012 Jul 6;150(1):165-178. https://doi.org/10.1016/j.cell.2012.04.042
Acharyya, Swarnali ; Oskarsson, Thordur ; Vanharanta, Sakari ; Malladi, Srinivas ; Kim, Juliet ; Morris, Patrick G. ; Manova-Todorova, Katia ; Leversha, Margaret ; Hogg, Nancy ; Seshan, Venkatraman E. ; Norton, Larry ; Brogi, Edi ; Massagué, Joan. / A CXCL1 paracrine network links cancer chemoresistance and metastasis. In: Cell. 2012 ; Vol. 150, No. 1. pp. 165-178.
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