A CXCL1 paracrine network links cancer chemoresistance and metastasis

By Swarnali Acharyya, Thordur Oskarsson, S. Vanharanta, S. Malladi, Juliet Y. Kim, P. Morris, K. Manova-Todorova, M. Leversha, N. Hogg, Venkatraman E. Seshan and 3 more. Cell, 2012

1,057 citations recorded by the source corpus.

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. While 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 heightens the expression of CXCL1/2 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.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/925990be27c66128df282d0f18c8f2ac8b6b6953

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In Immunology

1. Arthur W. Lambert
2. yang-xin fu
3. H. Liang
4. D. Garfield
5. Jianhua Wang
6. E. Keller
7. R. Weinberg
8. Y. Mao

In Oncology

1. D. Pattabiraman
2. Arthur W. Lambert
3. R. Weinberg
4. J. Massagué
5. E. Batlle
6. Thordur Oskarsson
7. yang-xin fu
8. H. Liang

Citations in the corpus

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• EMERGING BIOLOGICAL PRINCIPLES OF METASTASIS (2017, positive): “More generally, the effect of chemotherapy on either primary or metastatic growths may elicit the secretion of various paracrine mediators from the surrounding stromal cells that can promote resistance, including CXCL1/2 (Acharyya et al., 2012), IL-6 and Timp1 (Gilbert and Hemann, 2010), WNT16B (Sun”
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• Metastatic Stem Cells: Sources, Niches, and Vital Pathways (2014, background): “As metastatic lesions grow, the cancer cells recruit TAMs, myeloid precursors, and mesenchymal cells that establish paracrine loops feeding back to the cancer cells with various survival and self-renewal factors (Figure 7; Acharyya et al., 2012; Calón et al., 2012; Joyce and Pollard, 2009; Vermeulen”
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