BackgroundIncreased numbers of tumour-associated macrophages correlate with shortened survival in some cancers. The molecular bases of this correlation are not thoroughly understood. Events triggered by CXCL12 may play a part, as CXCL12 drives the migration of both CXCR4-positive cancer cells and macrophages and may promote a molecular crosstalk between them.ResultsSamples of HER1-positive colon cancer metastases in liver, a tissue with high expression of CXCL12, were analysed by immunohistochemistry. In all of the patient biopsies, CD68-positive tumour-associated macrophages presented a mixed CXCL10 (M1)/CD163 (M2) pattern, expressed CXCR4, GM-CSF and HB-EGF, and some stained positive for CXCL12. Cancer cells stained positive for CXCR4, CXCL12, HER1, HER4 and GM-CSF. Regulatory interactions among these proteins were validated via experiments in vitro involving crosstalk between human mononuclear phagocytes and the cell lines DLD-1 (human colon adenocarcinoma) and HeLa (human cervical carcinoma), which express the above-mentioned ligand/receptor repertoire. CXCL12 induced mononuclear phagocytes to release HB-EGF, which activated HER1 and triggered anti-apoptotic and proliferative signals in cancer cells. The cancer cells then proliferated and released GM-CSF, which in turn activated mononuclear phagocytes and induced them to release more HB-EGF. Blockade of GM-CSF with neutralising antibodies or siRNA suppressed this loop.ConclusionsCXCL12-driven stimulation of cancer cells and macrophages may elicit and reinforce a GM-CSF/HB-EGF paracrine loop, whereby macrophages contribute to cancer survival and expansion. The involvement of mixed M1/M2 GM-CSF-stimulated macrophages in a tumour-promoting loop may challenge the paradigm of tumour-favouring macrophages as polarized M2 mononuclear phagocytes.

Both preclinical and clinical investigations suggest that Notch signalling is critical for the development of many cancers and for their response to chemotherapy. We previously showed that Notch inhibition abrogates stromal-induced chemoresistance in lymphoid neoplasms. However, the role of Notch in acute myeloid leukemia (AML) and its contribution to the crosstalk between leukemia cells and bone marrow stromal cells remain controversial. Thus, we evaluated the role of the Notch pathway in the proliferation, survival and chemoresistance of AML cells in co-culture with bone marrow mesenchymal stromal cells expanded from both healthy donors (hBM-MSCs) and AML patients (hBM-MSCs*). As compared to hBM-MSCs, hBM-MSCs* showed higher level of Notch1, Jagged1 as well as the main Notch target gene HES1. Notably, hBM-MSCs* induced expression and activation of Notch signalling in AML cells, supporting AML proliferation and being more efficientin inducing AML chemoresistance than hBM-MSCs*. Pharmacological inhibition of Notch using combinations of Notch receptor-blocking antibodies or gamma-secretase inhibitors (GSIs), in presence of chemotherapeutic agents, significant lowered the supportive effect of hBM-MSCs and hBM-MSCs* towards AML cells, by activating apoptotic cascade and reducing protein level of STAT3, AKT and NF-κB.These results suggest that Notch signalling inhibition, by overcoming the stromal-mediated promotion of chemoresistance,may represent a potential therapeutic targetnot only for lymphoid neoplasms, but also for AML.

Some chemicals are known to enhance the effect of other chemicals beyond what can be predicted with standard mixture models, such as concentration addition and independent action. These chemicals are called synergists. Up until now, no models exist that can predict the joint effect of mixtures including synergists. The aim of the present study is to develop a mechanistic toxicokinetic (TK) and toxicodynamic (TD) model for the synergistic mixture of the azole fungicide, propiconazole (the synergist), and the insecticide, α-cypermethrin, on the mortality of the crustacean Daphnia magna. The study tests the hypothesis that the mechanism of synergy is the azole decreasing the biotransformation rate of α-cypermethrin and validates the predictive ability of the model on another azole with a different potency: prochloraz. The study showed that the synergistic potential of azoles could be explained by their effect on the biotransformation rate but that this effect could only partly be explained by the effect of the two azoles on cytochrome P450 activity, measured on D. magna in vivo. TKTD models of interacting mixtures seem to be a promising tool to test mechanisms of interactions between chemicals. Their predictive ability is, however, still uncertain.

Approximately 40% of patients affected by core binding factor (CBF) acute myeloid leukemia (AML) ultimately die from the disease. Few prognostic markers have been identified. We reviewed 192 patients with CBF AML, treated with curative intent (age, 15-79 years) in 11 Italian institutions. Overall, 10-year overall survival (OS), disease-free survival (DFS), and event-free survival were 63.9%, 54.8%, and 49.9%, respectively; patients with the t(8;21) and inv(16) chromosomal rearrangements exhibited significant differences at diagnosis. Despite similar high complete remission (CR) rate, patients with inv(16) experienced superior DFS and a high chance of achieving a second CR, often leading to prolonged OS also after relapse. We found that a complex karyotype (i.e., 4 cytogenetic anomalies) affected survival, even if only in univariate analysis; the KIT D816 mutation predicted worse prognosis, but only in patients with the t(8;21) rearrangement, whereas FLT3 mutations had no prognostic impact. We then observed increasingly better survival with more intense first-line therapy, in some high-risk patients including autologous or allogeneic hematopoietic stem cell transplantation. In multivariate analysis, age, severe thrombocytopenia, elevated lactate dehydrogenase levels, and failure to achieve CR after induction independently predicted longer OS, whereas complex karyotype predicted shorter OS only in univariate analysis. The achievement of minimal residual disease negativity predicted better OS and DFS. Long-term survival was observed also in a minority of elderly patients who received intensive consolidation. All considered, we identified among CBF AML patients a subgroup with poorer prognosis who might benefit from more intense first-line treatment.

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