A CXCL1 Paracrine Network Links Cancer Chemoresistance and Metastasis
Menée à l'aide d'un modèle murin, cette étude met en évidence le rôle joué par la voie de signalisation de la chimiokine CXCL1 dans le processus métastatique d'un cancer du sein et la résistance thérapeutique
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-± production by endothelial and other stromal cells. TNF-± 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. º CXCL1/2 mediate breast cancer metastasis through myeloid cell recruitment º CXCL1/2 promote breast cancer cell survival through myeloid-cell-derived S100A8/9 º Chemotherapeutic agents induce TNF-± to hyperactivate the CXCL1/2 S100A8/9 axis º Blocking CXCL1 signaling improves chemotherapy efficacy and diminishes metastasis A paracrine cascade that triggers the production of survival factors by surrounding stromal cells, enabling the survival of metastatic cancer cells, is also elicited by chemotherapeutic agents and is central to chemoresistance. Blocking this chemokine axis may improve the efficacy of chemotherapy and reduce metastatic burden in breast cancer.
Cell 2012