期刊
NPJ BREAST CANCER
卷 2, 期 -, 页码 1-10出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/npjbcancer.2016.33
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资金
- Associazione Italiana Ricerca sul Cancro [6251]
- Fondazione Italiana Ricerca sul Cancro (FIRC fellowship) [18328]
- Associazione Italiana Ricerca sul Cancro (AIRC)
- Associazione Italiana Ricerca sul Cancro (AIRC 5x1000)
- La Caixa Foundation
- Redes Tematicas de Investigacion en Cancer [RD12/0036/0072]
A subgroup of triple-negative breast cancer (TNBC) shows epithelial-to-mesenchymal transition (EMT) features, which are sustained by the interaction between cancer cells and tumor-associated macrophages (TAMs). In this study, the clinical relevance of 30 EMT-related kinases and the potential cross-talk with TAMs were investigated in a cohort of 203 TNBC patients treated with adjuvant chemotherapy. The prognostic value of the evaluated markers was validated in two independent cohorts of TNBC patients treated with adjuvant chemotherapy (N = 95; N = 137). In vitro, we investigated the potential synergism between cancer cells and TAMs. We found that the EMT-related kinase AXL showed the highest correlation with the frequency of CD163-positive macrophages (r(S) = 0.503; P < 0.0001). Relapsing TNBC patients presented high expression of AXL (P < 0.0001) and CD163 (P < 0.018), but only AXL retained independent prognostic significance in multivariate analysis (relapse-free survival, P = 0.002; overall survival P = 0.001). In vitro analysis demonstrated that AXL-expressing TNBC cells were able to polarize human macrophages towards an M2-like phenotype, and modulate a specific pattern of pro-tumor cytokines and chemokines. Selective AXL inhibition impaired the activity of M2-like macrophages, reducing cancer cell invasiveness, and restoring the sensitivity of breast cancer cells to chemotherapeutic drugs. These data suggest that the EMT-related kinase AXL overexpressed in cancer cells has prognostic significance, and contributes to the functional skewing of macrophage functions in TNBC. AXL inhibition may represent a novel strategy to target cancer cells, as well as tumor-promoting TAMs in TNBC.
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