A CXCL1 paracrine network links cancer chemoresistance and metastasis Journal Article
| Authors: | Acharyya, S.; Oskarsson, T.; Vanharanta, S.; Malladi, S.; Kim, J.; Morris, P. G.; Manova-Todorova, K.; Leversha, M.; Hogg, N.; Seshan, V. E.; Norton, L.; Brogi, E.; Massague, J. |
| Article 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. © 2012 Elsevier Inc. |
| Keywords: | controlled study; human tissue; doxorubicin; nonhuman; paclitaxel; lymph nodes; lymphatic metastasis; mouse; animals; mice; cell survival; breast cancer; lung neoplasms; animal experiment; animal model; cyclophosphamide; immunoglobulin enhancer binding protein; drug resistance, neoplasm; breast neoplasms; mice, inbred c57bl; cancer resistance; endothelium cell; endothelial cells; lung metastasis; tumor necrosis factor alpha; cd11b antigen; carcinoma; neoplasm metastasis; transplantation, heterologous; paracrine signaling; bone marrow cell; molecular interaction; neoplasm transplantation; tissue microarray; tumor growth; disease models, animal; cxcl2 chemokine; stroma cell; breast carcinogenesis; gene knockdown techniques; cxcl1 chemokine; chromosome 4q; myeloid cells; calgranulin a; paracrine communication; calgranulin b; chemokine cxcl1; chemokine receptor cxcr2 antagonist |
| Journal Title: | Cell |
| Volume: | 150 |
| Issue: | 1 |
| ISSN: | 0092-8674 |
| Publisher: | Cell Press |
| Date Published: | 2012-07-06 |
| Start Page: | 165 |
| End Page: | 178 |
| Language: | English |
| DOI: | 10.1016/j.cell.2012.04.042 |
| PROVIDER: | scopus |
| PUBMED: | 22770218 |
| PMCID: | PMC3528019 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 1 August 2012" - "CODEN: CELLB" - "Source: Scopus" |
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