title: 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.
authors: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors: Swarnali
authors: S
authors: Acharyya
authors: Thordur
authors: T
authors: Oskarsson
authors: Sakari
authors: S
authors: Vanharanta
authors: Srinivas
authors: S
authors: Malladi
authors: Juliet
authors: J
authors: Kim
authors: Patrick G
authors: PG
authors: Morris
authors: Katia
authors: K
authors: Manova-Todorova
authors: Margaret
authors: M
authors: Leversha
authors: Nancy
authors: N
authors: Hogg
authors: Venkatraman E
authors: VE
authors: Seshan
authors: Larry
authors: L
authors: Norton
authors: Edi
authors: E
authors: Brogi
authors: Joan
authors: J
authors: Massagué
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D040501:Calgranulin A / Q000378:metabolism; D040502:Calgranulin B / Q000378:metabolism; D002277:Carcinoma / Q000378:metabolism / Q000473:pathology*; D054360:Chemokine CXCL1 / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary; D008198:Lymph Nodes / Q000473:pathology; D008207:Lymphatic Metastasis; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000378:metabolism; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D019899:Paracrine Communication; D014183:Transplantation, Heterologous
chemical_list: D040501:Calgranulin A; D040502:Calgranulin B; D054360:Chemokine CXCL1