Author/Authors :
Swarnali Acharyya، نويسنده , , Thordur Oskarsson، نويسنده , , Sakari Vanharanta، نويسنده , , Srinivas Malladi، نويسنده , , Juliet Kim، نويسنده , , Patrick G. Morris، نويسنده , , Katia Manova-Todorova، نويسنده , , Margaret Leversha، نويسنده , , Nancy Hogg، نويسنده , , Venkatraman E. Seshan، نويسنده , , Larry Norton، نويسنده , , Edi Brogi، نويسنده , , Joan Massagué، نويسنده ,
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.
