Journal Article

AXL-associated tumor inflammation as a poor prognostic signature in chemotherapy-treated triple-negative breast cancer patients

Győrffy, Balázs, Torrisi, Rosalba, Caruso, Michele, Di Tommaso, Luca, Ács, Balázs, Losurdo, Agnese, Mantovani, Alberto, Santarpia, Libero, Kulka, Janina, Karachaliou, Niki, Santoro, Armando, Raschioni, Carlotta, Tőkés, Tímea, Székely, Borbála, Roncalli, Massimo, Rosell, Rafael, Reis-Filho, Jorge S, Bottai, Giulia, Szász, Attila M

2016

Overview

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. Immunology: Invasiveness kinase linked to tumor-promoting immune cells Targeting a kinase involved in cancer progression could help block the crosstalk between cancer cells and tumor-promoting immune cells. A team led by Libero Santarpia from the Humanitas Clinical and Research Institute in Milan, Italy, looked for several kinases linked to high levels of tumor-associated macrophages in tumor samples taken from women with triple-negative breast cancer treated with adjuvant chemotherapy. The researchers found that a kinase called AXL was the strongest driver of these pro-tumor immune cells and that high AXL expression levels were a good indicator of poor patient outcomes. Lab experiments with breast cancer cell lines revealed that AXL helps coax macrophages to adopt a form that fuels tumor development through the release of various immune modulators. Inhibiting AXL activity impaired the activity of tumor-associated macrophages, reduced cell invasiveness and restored drug sensitivity in the cancer cells.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 692/4028/67/1347 / 692/53/2422 / Biomedical and Life Sciences / Biomedicine / Cancer Research / Cell Biology / Human Genetics / Oncology