Emmanuel Blot

Intratumoural level of SDF-1 correlates with survival in head and neck squamous cell carcinoma

The SDF-1/CXCR4 pathway has been suggested to play a role in the metastatic dissemination of various tumours. We assessed the prognostic impact of SDF-1 and CXCR4 expression in head and neck squamous cell carcinoma (HNSCC). Seventy-one HNSCC samples collected at the time of initial diagnosis were retrospectively analysed. SDF-1 and CXCR4 expression levels were measured using real-time RT-PCR and correlated to survival. After a median follow-up of 45 months, 25 patients (35%) died of cancer (group D), and 46 patients (65%) were alive or dead without evidence of HSNCC evolution (group A). The median level of CXCR4 expression was 0.33 and 0.29 in groups A and D, respectively (P=0.93), showing no correlation with recurrence or survival. By contrast, the median level of SDF-1 expression was significantly different in the A and D groups (2.41 vs 1.16, respectively, P=0.018). Using the median level as a cut-off, patients with low SDF-1 had poorer metastasis-free (P=0.026), disease-free (P=0.006) and overall specific survival rates (P=0.002). The prognostic value of SDF-1 was confirmed by a multivariate analysis. In this series of 71 HNSCC patients, the SDF-1 expression level correlated significantly with metastatic evolution and overall survival.

Ovarian cancer: Stat3, RhoA and IGF-IR as therapeutic targets

Seeking to improve ovarian cancer therapy, we compared biological characteristics of the moderately-aggressive OVCAR-3 cell line with two highly aggressive ovarian cancer cell populations: the SK-OV-3 cell line, and HASCJ primary cells isolated from the ascitic fluid of a patient with FIGO stage IV ovarian cancer. Secretion of angiogenic factors was not discriminative, whereas cell invasion through Matrigel and vasculogenic mimicry were much greater in the more aggressive cells. Among 10 agents tested for their ability to decrease cancer cell aggressivity using these two models, inhibitors of Stat3, IGF-IR and Rho GTPase were found to be the most promising.

Stimulation of angiogenesis resulting from cooperation between macrophages and MDA-MB-231 breast cancer cells: proposed molecular mechanism and effect of tetrathiomolybdate

BackgroundInfiltration by macrophages (Mφ) indicates a poor prognosis in breast cancers, in particular by inducing angiogenesis. Our study aimed 1) to investigate the mechanism by which cooperation between Mφ and aggressive breast cancer cells (MDA-MB-231) induces angiogenesis; 2) to examine the effect of tetrathiomolybdate (TM) on this angiogenic activity.MethodsMφ coincubated with MDA-MB-231 were used as a model to mimic the inflammatory microenvironment. Angiogenesis induced by the culture media was tested in the chick chorioallantoic membrane (CAM). Mφ phenotype was evaluated by 1) expression of the M1 marker CD80, and secretion of interleukin 10 (IL-10), an M2 marker; 2) capacity to secrete Tumour Necrosis Factor α (TNFα) when stimulated by lipopolysaccharide/interferon γ (LPS/IFNγ); 3) ability to induce MDA-MB-231 apoptosis. To explore the molecular mechanisms involved, cytokine profiles of conditioned media from MDA-MB-231, Mφ and the coculture were characterised by an antibody cytokine array. All experiments were carried out both in presence and in absence of TM.ResultsIncubation of Mφ with MDA-MB-231 induced a pro-angiogenic effect in the CAM. It emerged that the angiogenic activity of the coculture is due to the capacity of Mφ to switch from M1 Mφ towards M2, probably due to an increase in Macrophage Colony Stimulating Factor. This M1-M2 switch was shown by a decreased expression of CD80 upon LPS/IFNγ stimulation, an increased secretion of IL-10, a decreased secretion of TNFα in response to LPS/IFNγ and an inability to potentiate apoptosis. At the molecular level, the angiogenic activity of the coculture medium can be explained by the secretion of CXC chemokines/ELR+ and CC chemokines. Although TM did not modify either the M2 phenotype in the coculture or the profile of the secreted chemokines, it did decrease the angiogenic activity of the coculture medium, suggesting that TM inhibited angiogenic activity by interfering with the endothelial cell signalling induced by these chemokines.ConclusionsCooperation between Mφ and MDA-MB-231 transformed M1 Mφ to an angiogenic, M2 phenotype, attested by secretion of CXC chemokines/ELR+ and CC chemokines. TM inhibited this coculture-induced increase in angiogenic activity, without affecting either Mφ phenotype or cytokine secretion profiles.

CXCR4 membrane expression in node-negative breast cancer.

Abstract:  CXC chemokine receptor 4 (CXCR4) has been reported to be involved in organ‐specific homing of breast cancer‐derived metastasis. We investigated CXCR4 expression by immunohistochemistry as a possible new prognostic factor for primary breast cancer. Two groups of women treated for breast cancer in 1991 at the Centre for the fight against cancer of Upper Normandy—France (Centre de Lutte contre le Cancer de Haute Normandie) were assessed retrospectively. CXCR4 expression was evaluated using standard immunohistochemistry. Usual prognostic factors were recorded in the computer database. Final date of follow‐up was December 31, 2001. Tissues were available for 110 node‐positive and 84 node‐negative breast cancer patients treated in 1991. CXCR4 membrane staining was considered a strong prognostic factor for both 10‐year metastasis‐free‐ (p < 0.0001) and overall survival (p < 0.0001) in node‐negative but not in node‐positive breast cancer patients. CXCR4 cytoplasmic staining was not considered a significant prognostic factor. Our results suggest that CXCR4 membrane staining could be considered a new prognostic factor. Moreover, targeting CXCR4 in primary breast cancer patients may be a new therapeutic concept. However, these results warrant further investigation.