TY - JOUR
T1 - A CXCL1 paracrine network links cancer chemoresistance and metastasis
AU - Acharyya, Swarnali
AU - Oskarsson, Thordur
AU - Vanharanta, Sakari
AU - Malladi, Srinivas
AU - Kim, Juliet
AU - Morris, Patrick G.
AU - Manova-Todorova, Katia
AU - Leversha, Margaret
AU - Hogg, Nancy
AU - Seshan, Venkatraman E.
AU - Norton, Larry
AU - Brogi, Edi
AU - Massagué, Joan
N1 - Funding Information:
We would like to thank J. Joyce, J. Bromberg, E. Pamer, H.G. Wendel, I. Ferrero, Z. Granot, R. Downey and members of Massague laboratory for insightful discussions, J. Howard for her help with clinical cases, D. Macalinao, W. Shu, M. Akram, K. Chadalavada, T. Tong, M. Turkekul, A. Barlas, and E. de Stanchina for technical advice and support. This work was funded by NIH grants CA94060 and U54 CA163167 and the Alan and Sandra Gerry Metastasis Research Initiative. S.A. is supported by a Department of Defense Era of Hope postdoctoral fellowship. J.M. is an Investigator of the Howard Hughes Medical Institute.
PY - 2012/7/6
Y1 - 2012/7/6
N2 - 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.
AB - 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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U2 - 10.1016/j.cell.2012.04.042
DO - 10.1016/j.cell.2012.04.042
M3 - Article
C2 - 22770218
AN - SCOPUS:84863625224
SN - 0092-8674
VL - 150
SP - 165
EP - 178
JO - Cell
JF - Cell
IS - 1
ER -