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International audience; Innate and acquired resistances to therapeutic agents are responsible for the failure of cancer treatments. Due to the multifactorial nature of resistance, the identification of new therapeutic targets is required to improve cancer treatment. Calcium is a universal second messenger that regulates many cellular functions such as proliferation, migration, and survival. Calcium channels, pumps and exchangers tightly regulate the duration, location and magnitude of calcium signals. Many studies have implicated dysregulation of calcium signaling in several pathologies, including cancer. Abnormal calcium fluxes due to altered channel expression or activation contribute to carcinogenesis and promote tumor development. However, there is limited information on the role of calcium signaling in cancer resistance to therapeutic drugs. This review discusses the role of calcium signaling as a mediator of cancer resistance, and assesses the potential value of combining anticancer therapy with calcium signaling modulators to improve the effectiveness of current treatments.

BACKGROUND Several studies have recently highlighted important roles for adipose tissue in cancer. However, few have examined adipose tissue cholesterol, and no study has been performed in breast adipose tissue associated with breast tumors. OBJECTIVES The present work was designed to determine if breast adipose tissue cholesterol from the tumor-surrounding area is associated with breast cancer aggressiveness. METHODS Between 2009 and 2011, 215 breast adipose tissue samples were collected at the Tours University Hospital (France) during surgery of women (aged 28-89 y) with invasive breast cancer. Associations of free cholesterol (FC), esterified cholesterol (EC), and total cholesterol (TC) amounts with clinical variables (age, BMI, and treated or untreated hypercholesterolemia) and tumor aggressiveness parameters [phenotype, grade, presence of inflammatory breast cancer (IBC), and multifocality] were tested using Student's t test and after ANOVA. RESULTS The predominant form of cholesterol in adipose tissue was FC, and 50% of patients had no detectable EC. The adipose tissue FC content (μg/mg total lipid) was 18% greater in patients >70 y old than in those 40-49 y old (P

Prognostic factors for epithelial ovarian cancers (EOCs) are in particular clinical factors such as pathology staging at diagnosis (FIGO stages), genetic mutation, or histological phenotypes. In the present study, FIGO stage, tumor residue after surgery, and body mass index were clinical predictors of recurrence-free survival (RFS). Nonetheless, a number of studies support a lipid metabolism disorder in ovarian cancer patients. The objective of this pilot study was to explore whether fatty acid composition of adipose reflecting the qualitative dietary intake and fatty acids metabolism may be associated with RFS. Forty-six women with EOCs and six with borderline ovarian tumors between March 2017 and January 2020 were included in this prospective study at Tours university teaching hospital (central France). The patients involved in the present study are part of the METERMUS trial (clinicaltrials.gov NCT03027479). Adipose tissue specimens from four abdominal locations (superficial and deep subcutaneous, visceral (pericolic), and omental) were collected during surgery or exploratory laparoscopy. A fatty acid profile of adipose tissue triglycerides was established by gas chromatography. Fatty acids composition was compared among the four locations using nonparametric Friedman’s ANOVA test for repeated measures. Median follow-up of EOC patients was 15 months and patients’ RFS was analyzed using Kaplan–Meier survival curves and log-rank test by separating patients into two groups according to median fatty acid levels. The content of long-chain saturated fatty acids (SFAs) was increased and that of long-chain polyunsaturated fatty acids (PUFAs) decreased in deep versus superficial subcutaneous adipose tissue in EOC patients. Nevertheless, the content of total SFAs was ~28%, monounsaturated fatty acids (MUFAs) ~55%, PUFAs n-6 ~11.5%, and PUFAs n-3 about 1.3%, whatever the adipose tissue. When EOC patients were separated into two groups by median fatty acid content, total PUFAs (n-6+n-3) levels, whatever the adipose tissue, were positively and independently associated with RFS. RFS was about two times longer in EOC patients with high versus low total PUFA content (median survival: 12 vs. 27 months, p = 0.01 to

Objective The use of autologous fat grafting in the context of breast reconstruction is still a matter of controversy. The objective of this study was to compare the local relapse rate in women who had a fat grafting session in the context of breast reconstruction after breast cancer management, to those who had breast reconstruction without fat grafting. Methods We performed a retrospective, monocentric, case-control study from January 2007 to December 2017 in our hospital. The cases included women who underwent breast reconstruction with autologous fat grafting and controls, undergoing breast reconstruction without fat grafting. We compared survival and local recurrence between the two groups. Results 412 women were included: 109 (26.5%) in the lipofilling group and 303 women (73.5%) in the “no lipofilling” group. In the overall study population, lipofilling did not appear to be a predictive factor for recurrence, HR = 1.39 [0.63 - 3.06], p = 0.41; or a predictive factor for overall survival, HR = 0.84 [0.23 - 3.02], p = 0.79, or for distant metastases, HR = 1.10 [0.43 - 2.79], p = 0.84. In contrast, in the subgroup of women treated for invasive cancer, the multivariate analysis showed that lipofilling in this context was an independent predictive factor for local recurrence (HR= 5.06 [1.97 – 10.6], p = 0.04). Conclusion we found an increased risk of local recurrence after lipofilling in women who were managed for invasive breast cancer. This suggests that special consideration should be given to women who have had invasive breast cancer before lipofilling.

Loss of epithelial polarity and gain in invasiveness by carcinoma cells are critical events in the aggressive progression of cancers and depend on phenotypic transition programs such as the epithelial-to-mesenchymal transition (EMT). Many studies have reported the aberrant expression of voltage-gated sodium channels (NaV) in carcinomas and specifically the NaV1.5 isoform, encoded by the SCN5A gene, in breast cancer. NaV1.5 activity, through an entry of sodium ions, in breast cancer cells is associated with increased invasiveness, but its participation to the EMT has to be clarified. In this study, we show that reducing the expression of NaV1.5 in highly aggressive human MDA-MB-231 breast cancer cells reverted the mesenchymal phenotype, reduced cancer cell invasiveness and the expression of the EMT-promoting transcription factor SNAI1. The heterologous expression of NaV1.5 in weakly invasive MCF-7 breast cancer cells induced their expression of both SNAI1 and ZEB1 and increased their invasive capacities. In MCF-7 cells the stimulation with the EMT-activator signal TGF-β1 increased the expression of SCN5A. Moreover, the reduction of the salt-inducible kinase 1 (SIK1) expression promoted NaV1.5-dependent invasiveness and expression of EMT-associated transcription factor SNAI1. Altogether, these results indicated a prominent role of SIK1 in regulating NaV1.5-dependent EMT and invasiveness.

The intracellular Ca

In a previous pilot study, we showed that polyunsaturated n-3 fatty acids of breast adipose tissues were associated with breast cancer multifocality. In the present study, we investigated biochemical, clinical and histological factors associated with breast cancer focality in a large cohort of women with positive hormone-receptors tumors. One hundred sixty-one consecutive women presenting with positive hormone-receptors breast cancer underwent breast-imaging procedures including a Magnetic Resonance Imaging prior to treatment. Breast adipose tissue specimens were collected during surgery of tumors. A biochemical profile of breast adipose tissue fatty acids was established by gas chromatography. Clinicopathologic characteristics were correlated with multifocality. We assessed whether these factors were predictive of breast cancer focality. We found that tumor size (OR = 1.06 95%CI [1.02-1.09], p 0.001) and decreased levels in breast adipose tissue of long-chain polyunsaturated n-3 fatty acids (OR = 0.11 95%CI [0.01-0.98], p = 0.03), were independent predictive factors of multifocality. Low levels of long chain polyunsaturated n-3 fatty acids in breast adipose tissue appear to contribute to breast cancer multifocality. The present results reinforce the link between dietary habits and breast cancer clinical presentation.

International audience

The intracellular Ca2+ concentration is mainly controlled by Ca2+ channels. These channels form complexes with K+ channels, which function to amplify Ca2+ flux. In cancer cells, voltage-gated/voltage-dependent Ca2+ channels and non-voltage-gated/voltage-independent Ca2+ channels have been reported to interact with K+ channels such as Ca2+-activated K+ channels and voltage-gated K+ channels. These channels are activated by an increase in cytosolic Ca2+ concentration or by membrane depolarization, which induces membrane hyperpolarization, increasing the driving force for Ca2+ flux. These complexes, composed of K+ and Ca2+ channels, are regulated by several molecules including lipids (ether lipids and cholesterol), proteins (e.g. STIM), receptors (e.g. S1R/SIGMAR1), and peptides (e.g. LL-37) and can be targeted by monoclonal antibodies, making them novel targets for cancer research.

Lipids such as cholesterol, triacylglycerols, and fatty acids play important roles in the regulation of cellular metabolism and cellular signaling pathways and, as a consequence, in the development of various diseases. It is therefore important to understand how their metabolism is regulated to better define the components involved in the development of various human diseases. In the present work, we describe the development and validation of a high-performance thin layer chromatography (HPTLC) method allowing the separation and quantification of free cholesterol, cholesteryl esters, nonesterified fatty acids, and triacylglycerols. This method will be of interest as the quantification of these lipids in one single assay is difficult to perform.

Lipids such as cholesterol, triglycerides, and fatty acids play important roles in the regulation of cellular metabolism and cellular signaling pathways and, as a consequence, in the development of various diseases. It is therefore important to understand how their metabolism is regulated to better define the components involved in the development of various human diseases. In the present work, we described the development and validation of an HPTLC method allowing the separation and quantification of free cholesterol, cholesteryl esters, non-esterified fatty acids, and triglycerides. This method will be of interest as the quantification of these lipids in one single assay is difficult to perform.

International audience; Epithelial Ovarian cancer (EOC) is the deadliest gynecologic malignancy and represents the fifth leading cause of all cancer-related deaths in women. The majority of patients are diagnosed at an advanced stage of the disease that has spread beyond the ovaries to the peritoneum or to distant organs (stage FIGO III-IV) with a 5-year overall survival of about 29%. Consequently, it is necessary to understand the pathogenesis of this disease. Among the factors that contribute to cancer development, lipids and ion channels have been described to be associated to cancerous diseases particularly in breast, colorectal and prostate cancers. Here, we reviewed the literature data to determine how lipids or lipid metabolites may influence EOC risk or progression. We also highlighted the role and the expression of the calcium (Ca2+) and calcium-activated potassium (KCa) channels in EOC and how lipids might regulate them. Although lipids and some subclasses of nutritional lipids may be associated to EOC risk, lipid metabolism of LPA (lysophosphatidic acid) and AA (arachidonic acid) emerges as an important signaling network in EOC. Clinical data showed that they are found at high concentrations in EOC patients and in vitro and in vivo studies referred to them as triggers of the Ca2+entry in the cancer cells inducing their proliferation, migration or drug resistance. The cross-talk between lipid mediators and Ca2+ and/or KCa channels needs to be elucidated in EOC in order to facilitate the understanding of its outcomes and potentially suggest novel therapeutic strategies including treatment and prevention.

Objective Since it is thought that breast adipose tissue could influence breast cancer clinical presentation, we wanted to characterize specifically the relationship between breast adipose tissue fatty acid profile and Inflammatory Breast cancer (IBC). Methods Two hundred thirty-four women presenting with breast cancer were managed in our centre between January 2009 and December 2011. Breast adipose tissue specimens were collected during breast surgery. We established the biochemical profile of adipose tissue fatty acids (FA) by gas chromatography and assessed whether there were differences in function of the presence of breast inflammation or not. Results We found that IBC was associated with decreased levels in breast adipose tissue of eicosapentaenoic acid (EPA), one of the two main polyunsaturated n-3 fatty acids (n-3 PUFA) of marine origin, but also with decreased levels of Gamma Linolenic acid (GLA). Inversely, an increase in palmitic acid levels was associated with IBC. Conclusion These differences in lipid content may contribute to the occurrence of breast cancer inflammation.

International audience; The fatty acids composition of adipose tissue may provide information on the nutritional part of the risk or evolution of breast cancer. To determine whether 1H NMR of adipose tissue provides information on the nature of the diet consumed, a dietary intervention with increasing percentage of polyunsaturated n-3 docosahexaenoic acid (DHA 22:6n-3, provided as DHASCO oil) was applied to a rat model of N-nitroso-N-methylurea-induced mammary tumors. Spectra of the lipid extracts were obtained from adipose tissues in five groups of Sprague–Dawley rats fed with a diet containing 7% peanut/rapeseed enriched with 8% (w/w) of an oil without (palm oil) or with low (1%), moderate (3%), or high (8%) DHASCO content. A control group received a basal diet with 15% peanut/rapeseed representative of the “Western” diet. After 5 months of those five controlled diets, adipose tissue was collected for analysis of the lipid extract using both 1H NMR analysis on an 11.7 T spectrometer and gas chromatography considered as gold standard. 1H NMR analysis showed a dose-dependent increase in DHA in the lipid extract of adipose tissues and a commensurate decrease in n-6 polyunsaturated fatty acids in the three DHA groups, which allowed one to follow n-6/n-3 ratio changes. The highest n-6/n-3 ratio was observed in the control Western diet group compared to the other diet groups. The integrated spectral regions showed separation between groups, thereby documenting a specific NMR lipid profile corresponding to each dietary intervention. Those diet-dependent NMR lipid profiles were consistent with that obtained with gas chromatography analyses of the same samples. This study is a proof of concept highlighting the potential use of the 1H NMR approach to evaluate dietary intervention in biopsies of adipose tissues.

Background: Long chain n-3 Polyunsaturated Fatty Acids (n-3 PUFA) of marine origin (docosahexaenoic acid, DHA and eicosapentaenoic acid, EPA) have been shown to increase sensitivity of cell lines to anthracyclins or taxanes. Preclinical studies and a phase II clinical trial have shown that increasing DHA level in the body tissues through a dietary supplementation improves chemotherapy efficacy. We have set up a phase III controlled, double blind study to determine whether a dietary supplementation with n-3 PUFA would increase PFS in patients receiving chemotherapy for metastatic breast cancer (MBC). Methods: Inclusion criteria were patients with a ductal or lobular breast carcinoma, positive hormone receptors, Her2 (-), who have developed visceral metastasis, and were due to receive a 1st or 2d line chemotherapy. Dietary intervention was carried out during chemotherapy. Patients had to take daily at each meal a can* (medical food) containing either fish oil (1.56 g/d of DHA and 2.64 g/d EPA, experimental arm) or coprah oil (short chains fatty acids, control arm). Principal endpoint was PFS, secondary were objective response, overall survival, dietary tolerance to cans, lipids plasma levels of n-3 PUFA. Results: Sixty five patients with MBC have been prospectively enrolled in the DHALYA trial (NTC01548534). The first 45 patients who completed chemotherapy along with dietary supplementation are evaluable. Plasma fatty acid level was measured at baseline, at C1 after 10 days loading dose, at C3, and at C6 or at withdrawal. Level of EPA and DHA increased in half of the patients, thus allowing a putative allocation into either arm: arm A with induced elevation of PUFA levels (N=22), and arm B without any change in PUFA levels (N=23). No difference was observed in the quality of the dietary intervention (number of cans, duration) among arms. Distribution of patients according to demographics (age, menopausal status, histology, SBR grade), or type or quality of chemotherapy received (anthracycline- or taxane-based, number of cycles, length) was similar between arms. However a significantly greater proportion of patients with poor prognosis at staging (larger tumor size and greater axillary lymph nodes involvement) were observed in arm A. There was no difference in side effects (grade ≥2) between arms. In terms of efficacy, median PFS was 14.3 (arm A) and 12.5 (arm B) months, not statistically different yet. Conclusion: A dietary intervention targeted on marine-derived PUFA during systemic chemotherapy for MBC is safe and feasible. A longer follow-up is required in order to know whether chemotherapy efficacy can be increased. This study was supported by a grant from the French Ministry of Health, PHRC-11-153. *Cans were graciously provided by Nutrialys Medical Nutrition, Saint Grégoire, France. Citation Format: Philippe Bougnoux, Jacques Bonneterre, Anne Mercier-Blas, Patrick Soulié, Hélène Simon, Franck Priou, Christine Piprot-Choffat, Christelle Levy, Caroline Goupille, Virginie Berger. Modification of the response to chemotherapy of HER2 negative metastatic breast cancer by lipids of marine origin: A controlled, randomized, double blind dietary supplementation trial [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-13-08.

The aim of this study is to identify high performance thin layer chromatography (HPTLC) conditions allowing the separation and quantification of mammalian cellular phospholipids (PLs) (sphingomyelin, phosphatidylcholine, phosphatidylserine, phosphatidylinositol, phosphatidylethanolamine, and especially phosphatidic acid, cardiolipin, and monolysocardiolipin, these latter two being specifically located in mitochondria membranes). In order to make this method faster and easier, a 1D HPTLC method is chosen, testing several eluents as well as several staining methods. A pre‐conditioning of HPTLC plates with boric acid and a copper staining reagent followed by carbonization are selected for the quality of PL separation and homogeneity of staining. The selected conditions are discussed and the method validation is performed according to the International Conference on Harmonization guidelines. Linearity is effective between 1 and 8 µg and limit of quantification is between 0.5 and 2.3 µg depending on PL classes. Precision measurements show coefficients of variation

The effect of numerous anticancer drugs on breast cancer cell lines and rodent mammary tumors can be enhanced by a treatment with long-chain n-3 polyunsaturated fatty acids (n-3 PUFA) such as docosahexaenoic acid (DHA, 22:6n-3) which is a natural ligand of peroxisome proliferator-activated receptors (PPAR). In order to identify the PPAR regulating breast cancer cell growth, we tested the impact of siRNA, selected to suppress PPARα, PPARβ or PPARγ mRNA in MDA-MB-231 and MCF-7 breast cancer cell lines. The siPPARβ was the most effective to inhibit breast cancer cell growth in both cell lines. Using PPARα, PPARβ and PPARγ pharmacological antagonists, we showed that PPARβ regulated DHA-induced inhibition of growth in MDA-MB-231 and MCF-7 cells. In addition, the expressions of all 3 PPAR mRNA were co-regulated in both cell lines, upon treatments with siRNA or PPAR antagonists. PPAR mRNA expression was also examined in the NitrosoMethylUrea (NMU)-induced rat mammary tumor model. The expressions of PPARα and PPARβ mRNAs were correlated in the control group but not in the n-3 PUFA group in which the expression of PPARβ mRNA was reduced. Although PPARα expression was also increased in the n-3 PUFA-enriched diet group under docetaxel treatment, it is only the expression of PPARβ mRNA that correlated with the regression of mammary tumors: those that most regressed displayed the lowest PPARβ mRNA expression. Altogether, these data identify PPARβ as an important player capable of modulating other PPAR mRNA expressions, under DHA diet, for inhibiting breast cancer cell growth and mammary tumor growth.

International audience; Expression of the antimicrobial peptide hCAP18/LL-37 is associated to malignancy in various cancer forms, stimulating cell migration and metastasis. We report that LL-37 induces migration of three cancer cell lines by activating the TRPV2 calcium-permeable channel and recruiting it to pseudopodia through activation of the PI3K/AKT pathway. Ca2+ entry through TRPV2 cooperated with a K+ efflux through the BKCa channel. In a panel of human breast tumors, the expression of TRPV2 and LL-37 was found to be positively correlated. The D-enantiomer of LL-37 showed identical effects as the L-peptide, suggesting that no binding to a specific receptor was involved. LL-37 attached to caveolae and pseudopodia membranes and decreased membrane fluidity, suggesting that a modification of the physical properties of the lipid membrane bilayer was the underlying mechanism of its effects.

International audience; Taxanes can induce drug resistance by increasing signaling pathways such as PI3K/Akt and ERK, which promote survival and cell growth in human cancer cells. We have previously shown that long chain n-3 polyunsaturated fatty acids, such as docosahexaenoic acid (DHA, 22:6n-3) decrease resistance of experimental mammary tumors to anticancer drugs. Our objective was to determine whether DHA could increase tumor sensitivity to docetaxel by down-regulating these survival pathways. In docetaxel-treated MDA-MB-231 cells, phosphorylated-ERK1/2 levels were increased by 60% in membrane and nuclear compartments, compared to untreated cells. Our data showed that ERK1/2 activation depended on PKC activation since: i) enzastaurin (a pan-PKC inhibitor) blocked docetaxel-induced ERK1/2 phosphorylation ii) docetaxel increased PKC activity by 30% and phosphatidic acid level by 1.6-fold iii) inhibition of PKCε and PKCδ by siRNA resulted in reduced phosphorylated ERK1/2 levels. In DHA-supplemented cells, docetaxel was unable to increase PKCε and δ levels in membrane and nuclear fractions, resulting in diminished ERK1/2 phosphorylation and increased docetaxel efficacy. Reduced membrane level of PKCε and PKCδ was associated with significant incorporation of DHA in all phospholipids, including phosphatidylcholine which is a major source of phosphatidic acid. Additionally, examination of the Akt pathway showed that DHA could repress docetaxel-induced Ser473Akt phosphorylation. In rat mammary tumors, dietary DHA supplementation during docetaxel chemotherapy repressed ERK and Akt survival pathways and in turn strongly improved taxane efficacy. The P-ERK level was negatively correlated with tumor regression. These findings are of potential clinical importance in treating chemotherapy-refractory cancer.

International audience; The aim of this study was to evaluate the effects of a fish oil (FO) diet (rich in long chain, n-3, polyunsaturated fatty acid) on cancer cachexia symptoms in rats. To this end, peritoneal carcinosis (PC) was generated by an intraperitoneal injection of cancer cells in BDIX rats fed FO or standard (Std) diets. Food intake and body weight were recorded throughout the study until sacrifice. PC rats were sacrificed when food intake was significantly and severely reduced. Fat and skeletal muscles masses were weighed and serum inflammatory cytokines concentration measured at sacrifice. Occurrence of anorexia in PC rats was delayed in the FO diet group (median time was multiplied by 2.5) in comparison with Std diet. At the time of sacrifice, PC rats displayed a lower body weight gain as well as lower muscle and fat masses than pair-fed rats, suggesting the presence of a hypermetabolism state. Serum TNF-alpha was significantly increased in PC rats compared with controls rats. There was no effect of FO diet on tissue mass (skeletal muscle and fat) or on TNF-alpha concentration. In conclusion, FO diet delays the appearance of anorexia induced by PC in rats.

The important factor determining breast cancer outcome is tumor cell sensitivity to cytotoxic agents. Most anticancer drugs lack intrinsic anti-tumor selectivity, provoking adverse effects in healthy nontumor tissues. As a result, drugs cannot always be delivered to the tumor at doses sufficient to induce tumor shrinkage, increasing the risk of the development of cellular drug resistance by tumor cells. Two main approaches are currently being investigated to reduce the toxicity in nontumor tissue by using a prodrug locally delivered through biochemical activation in the tumor environment, and for specifically increasing the sensitivity of tumors to anticancer drugs by modifying the tumor tissue through dietary supplementation. Both approaches have their own limitations that would be alleviated by combining them in order to better treat breast cancers. Specifically, the potential benefit of bringing together a glucuronide prodrug with dietary supplementation using polyunsaturated fatty acids, and in partic...

International audience; Cardiolipin (CL) content accumulation leads to an increase in energy wasting in liver mitochondria in a rat model of cancer cachexia in which tumor necrosis factor alpha (TNFα) is highly expressed. In this study we investigated the mechanisms involved in liver mitochondria CL accumulation in cancer cachexia and examined if TNFα was involved in this process leading to mitochondrial bioenergetics alterations. We studied gene, protein expression and activity of the main enzymes involved in CL metabolism in liver mitochondria from a rat model of cancer cachexia and in HepaRG hepatocyte-like cells exposed to 20 ng/ml of TNFα for 12 h. Phosphatidylglycerolphosphate synthase (PGPS) gene expression was increased 2.3-fold (p < 0.02) and cardiolipin synthase (CLS) activity decreased 44% (p < 0.03) in cachectic rat livers compared to controls. CL remodeling enzymes monolysocardiolipin acyltransferase (MLCL AT-1) activity and tafazzin (TAZ) gene expression were increased 30% (p < 0.01) and 50% (p < 0.02), respectively, in cachectic rat livers compared to controls. Incubation of hepatocytes with TNFα increased CL content 15% (p < 0.05), mitochondrial oxygen consumption 33% (p < 0.05), PGPS gene expression 44% (p < 0.05) and MLCL AT-1 activity 20% (p < 0.05) compared to controls. These above findings strongly suggest that in cancer cachexia, TNFα induces a higher energy wasting in liver mitochondria by increasing CL content via upregulation of PGPS expression.

The presence of α1,2-fucosylated glycans at the surface of rat colon carcinoma cells has been associated with an increased tumorigenicity and resistance to natural killer/lymphokine activated killer (NK/LAK) cytotoxicity. We now report that transfection of rat α1,2-fucosyltransferases cDNA (FTA and FTB) into REG cells, which are spontaneously devoid of this enzymatic activity, allows expression of histo-blood group H antigen and increases their resistance to LAK, but not NK cell lysis. Conversely, transfection of PRO cells, which spontaneously express α1,2-fucosyltransferase activity, with the FTA cDNA in the antisense orientation decreases expression of the H antigen together with their resistance to LAK cell lysis, but again, not to NK cell lysis. Furthermore, REG cells that are rejected by immunocompetent syngeneic rats are similarly rejected by rats depleted of NK cells by antibody 3.2.3, directed against the NKR-P1 molecule. Thus, the rejection of REG cells by immunocompetent rats and their earlier reported increased tumorigenicity after transfection with an α1,2-fucosyltransferase cDNA cannot be ascribed to NK cell sensitivity or resistance, respectively. The increased resistance to LAK cell lysis, however, may be relevant to tumor progression. Int. J. Cancer 86:713–717, 2000. © 2000 Wiley-Liss, Inc.

Accumulation of histo-blood group antigens such as Lewis b, Lewis Y and H increases tumor cell motility and tumorigenesis. α1,2-Fucosylation is a key step in the synthesis of these antigens. Two α1,2-fucosyltransferases, expressed in colorectal carcinomas, have been characterized (FUT1 and FUT2 in humans, FTA and FTB in rats). To define the relative contribution of each of these enzymes in tumor cell behavior, we have used an anti-sense transfection approach in rat colon carcinoma PROb cells, which synthesize mRNA encoding for both enzymes. We have previously reported that anti-sense transfection of a cDNA fragment of the FTB enzyme decreased H antigenic cell-surface levels and concomitantly decreased tumorigenicity. H antigens, detected by antibodies specific for H type 1, 3 or 4, were detected only on a splice variant of CD44 containing the product of exon v6. We now report the anti-sense transfection of an FTA cDNA fragment into PROb cells, which resulted in decreased enzymatic activity on a type 2 precursor and decreased cell-surface H type 2 antigen exclusively. Compared to controls, FTA anti-sense-transfected cells were significantly more tumorigenic in syngeneic animals but not in immunodeficient SCID mice. The UEA-I lectin, specific for H type 2, revealed that these structures were present on the CD44v6 variant and on an uncharacterized 80-kDa glycoprotein. Our results indicate that FTA and FTB fucosylate distinct glycan chains in the same cell, leading to opposite effects, under control of the immune system. Int. J. Cancer 80:606–611, 1999. © 1999 Wiley-Liss, Inc.

Clones either strongly or barely expressing the Tn and Sialyl-Tn antigens were isolated from a rat colon carcinoma cell line. Expression of the antigens in normal rat tissues was very restricted and vaccination using Ovine Submaxillary Mucin as the immunogen could delay growth of the Sialyl-Tn positive cells, but not of the Sialyl-Tn negative cells in syngeneic rats. The model should be useful for testing new anti-Tn or Sialyl-Tn vaccination protocols.

Up-regulation of the synthesis of carbohydrate tumor-associated antigens terminated by the disaccharide Fucα1-2Gal is frequent in colon carcinoma and associated with poor prognosis. There is evidence that Fucα1-2Gal (H-disaccharide) structures increase cancer-cell motility and tumorigenicity by as-yet unknown mechanisms. Using polyacrylamide-based neoglycoconjugates, we looked for a potential receptor for this disaccharide, and observed that a neoglycoconjugate probe containing the H-disaccharide could bind rat colon-carcinoma cells in a dose-dependent manner, whereas very little binding was evidenced when a probe containing glucose was used. Binding of the H-disaccharide probe could be inhibited by the free H-disaccharide as well as by unlabeled neoglycoconjugates containing a terminal H-disaccharide. The best inhibitor was the H-type-1 trisaccharide neoglycoconjugate. Histochemical detection of the potential H-receptor was performed on rat normal tissues and in situ 1,2-dimethylhydrazine-induced colon carcinomas. A strong binding of the H-disaccharide probe was evidenced on most tumors that could be partly inhibited by the trisaccharide Fucα1-2Galβ1-4Glc and by the unlabeled H-disaccharide neoglycoconjugate, indicating carbohydrate specificity of the binding. Staining of normal colonic mucosa was much weaker. Strong staining was also observed on some normal tissues, such as the spleen or lymph nodes, while others, such as lungs or liver, were negative. Probes containing glucose or the Lewis-a trisaccharide did not stain tumors or normal tissues. These results provide preliminary evidence for the existence of H-specific binding sites, the number of which increases in colon carcinoma. Int. J. Cancer 76:136–140, 1998.© 1998 Wiley-Liss, Inc.

Using an experimental model of rat colon adenocarcinoma, we have recently shown that the presence of H blood-group antigen on variants of the CD44 adhesion molecule carrying amino acids encoded by exon v6 (CD44v6), increased the cells' tumorigenicity. In the present study, colon adenocarcinomas were induced by 1,2-dimethylhydrazine treatment in rats. Using immunohistochemistry, biopsies of normal, precancerous and carcinomatous colon mucosa were evaluated for expression A and H blood group antigens and CD44s and CD44v6 antigens. Normal rat colon showed strong and homogeneous expression of blood-group antigen A, but weak expression of H antigen. Several weeks before the appearance of tumours, dysplastic glands were strongly stained with anti-H reagents, while their A antigen was lost. Expression of CD44v6 was weak and restricted to some cells at the bottom of normal crypts. No obvious change was observed before appearance of severe dysplasia. In carcinomas, a strong but irregular expression of A, H and CD44v6 antigens was observed. In moderately differentiated carcinomas, A and H antigens were present at the apical surface of cells, whereas CD44v6 was found at the basolateral side. Only carcinomatous cells with loss of polarity, found in poorly differentiated cancers or infiltrated in the muscularis mucosae, were found to coexpress blood-group H or A and CD44v6 antigens at their surface.

Fucosylated histo-blood group antigens such as Lewis b, Lewis Y, and H accumulate in colon carcinoma and this is accompanied by a clear increase in alpha(1-2)fucosyltransferase activity, a key enzyme for the biosynthesis of these antigens. Yet the biological significance of alpha(1-2) fucosylated structures is not well defined. We have transfected a poorly tumorigenic rat colon carcinoma cell line with the human H blood group alpha(1-2)fucosyltransferase cDNA. This resulted in cell surface expression of H antigens with a concomitant decrease of sialic acid substituted and free beta-galactosides. Immunoprecipitation experiments showed that H antigens were essentially borne by variants of CD44 carrying amino acid sequences encoded by exon v6. The transfected cells showed increased motility in a wound healing assay, without changing their proliferation rates. Parental and control cells transfected with an empty vector formed small tumors that always regressed after 30 days when injected subcutaneously to syngeneic rats. In contrast, alpha(1-2)fucosyltransferase transfectants were able to form progressive tumors. Increased tumorigenicity was also visible in nude mice. These results demonstrate that alpha(1-2)fucosylated antigens contribute directly to aggressiveness of colon carcinoma cells. This could occur by altering a function of CD44 variants.

International audience; New ultrasound parameters, potentially predictive of tumor response to chemotherapy, were sought after analyzing details of vascular architecture of mammary tumors during chemotherapy. Tumor-bearing rats were separated into untreated or docetaxel-treated group (6 mg/kg/week). Power Doppler Index and vascular contrast-enhanced ultrasound (CEUS) reference endpoints (Peak, area under the curve (AUC), blood flow) were evaluated at the beginning (W (0)), and after 2 and 6 weeks of docetaxel treatment (W (+2) and W (+6)). An improved CEUS image analysis, taking advantage of individual pixel intensity, was developed to quantify large, medium, and small vessels of tumors. Standard immunohistochemistry validated this new methodology analyzing tumor vascular architecture. In rats, there was an enrichment of vascularization with large vessels during tumor growth indicative of a vascular adjustment to tumor size. Docetaxel stopped tumor growth, and showed a sequential effect on vascular parameters. After an initial enrichment in larger vessels (by threefold) at W (+2), docetaxel led to a diminution of vascular parameters at W (+6) (-46 % for peak, -55 % for AUC -31 % compared to W (0)) and a vascular remodeling in favor of small vessels. One of the CEUS parameters measured before chemotherapy, the so-called global contrast-enhanced pixels density, was predictive of rat tumor response to treatment (r = 0.80; p < 0.01). The method was then applied in a clinical setting to detect changes of vascular architecture during chemotherapy of human breast carcinoma. The docetaxel chemotherapy of breast carcinomas induced a similar sequential effect, with vessel enlargement after two cycles of docetaxel treatment and an antiangiogenic effect after six cycles. Such vascular remodeling was not noticed when patients were treated with 5-fluorouracil-epirubicin-cyclophosphamide. Taken together, the sharpened analysis of CEUS pixel intensity presented here strengthened the monitoring of breast tumor vasculature with the potential to improve the prediction of docetaxel efficacy.

Background Cancer cachexia is a complex syndrome related to a negative energy balance resulting in muscle wasting. Implication of muscle mitochondrial bioenergetics alterations during cancer cachexia was suggested. Therefore, the aim of this study was to explore the efficiency of oxidative phosphorylation in skeletal muscle mitochondria in a preclinical model of cancer cachexia. Methods Berlin–Druckrey IX rats with peritoneal carcinosis (PC) were used as a model of cancer cachexia with healthy pair-fed rats (PF) as control. Hindlimb muscle morphology and fibre type composition were analysed in parallel with ubiquitin ligases and UCP gene expression. Oxidative phosphorylation was investigated in isolated muscle mitochondria by measuring oxygen consumption and ATP synthesis rate. Results PC rats underwent significant muscle wasting affecting fast glycolytic muscles due to a reduction in fibre cross-sectional area. MuRF1 and MAFbx gene expression were significantly increased (9- and 3.5-fold, respectively) in the muscle of PC compared to PF rats. Oxygen consumption in non-phosphorylating state and the ATP/O were similar in both groups. Muscle UCP2 gene was overexpressed in PC rats. State III and the uncoupled state were significantly lower in muscle mitochondria from PC rats with a parallel reduction in complex IV activity (−30 %). Conclusion This study demonstrated that there was neither alteration in ATP synthesis efficiency nor mitochondrial uncoupling in skeletal muscle of cachectic rats despite UCP2 gene overexpression. Muscle mitochondrial oxidative capacities were reduced due to a decrease in complex IV activity. This mitochondrial bioenergetics alteration could participate to insulin resistance, lipid droplet accumulation and lactate production.

International audience; The aim of this study was to determine how n-3 polyunsaturated fatty acid (PUFAs) counteracted tumor chemoresistance by restoring a functional vascularization. Rats with chemically induced mammary tumors were divided into two nutritional groups: a control group and a group fed with an n-3 PUFA-enriched diet. Both groups were treated with docetaxel. Functional vascular parameters (ultrasounds, interstitial fluid pressure) were determined for both nutritional groups before (W(0)) and during docetaxel treatment [every 2 h up to 1 week (W(+1)) for interstitial fluid pressure, at W(+1) for Evans blue extravasation and at W(+2) and W(+6) for ultrasounds]. In vitro n-3 PUFA-induced changes in endothelial cell migration, permeability and phosphorylation of endothelial nitric oxide synthase were evaluated using human umbilical vein endothelial cells. Whereas docetaxel stabilized tumor growth in the rat control group, it induced a 50% tumor regression in the n-3 PUFA group. Ultrasounds parameters were consistently lower in the n-3 PUFA group at all time points measured, down to ∼50% at W(+6). A single dose of docetaxel in the n-3 PUFA group markedly reduced interstitial fluid pressure from 2 h after injection up to W(+1) when Evans blue extravasation was increased by 3-fold. A decreased activation of endothelial nitric oxide synthase in tumors of the n-3 PUFA group, and in human umbilical vein endothelial cell cultured with n-3 PUFA, points toward a PUFA-induced disruption of nitric oxide signaling pathway. This normalization of tumor vasculature functions under n-3 PUFA diet indicates that such a supplementation, by improving drug delivery in mammary tumors, could be a complementary clinical strategy to decrease anticancer drug resistance.

International audience; Background & aims: Cancer cachexia is a dynamic process characterized by a negative energy balance induced by anorexia and hypermetabolism. The mechanisms leading to hypermetabolism are not totally elucidated. This study examines the efficiency of oxidative phosphorylation and energy wasting in liver mitochondria isolated from rats with cancer cachexia induced by peritoneal carcinosis (PC).Methods: PC was generated by an intraperitoneal injection of cancer cells (PROb) in BDIX rats. The efficiency of oxidative phosphorylation and energy wasting as well as the role played by reactive oxygen species (ROS) and cardiolipin (mitochondrial inner membrane phospholipid) in these processes were assessed in liver mitochondria of PC and pair-fed control rats.Results: The efficiency of oxidative phosphorylation decreased (-26%) while energy wasting increased (+22%) in liver mitochondria from PC compared to control rats. The increased energy wasting was associated with a higher cardiolipin content (+55%, p

International audience; Docosahexaenoic acid (DHA, a lipid of marine origin) has been found to enhance the activity of several anticancer drugs through an oxidative mechanism. To examine the relation between chemosensitization by DHA and tumor cells antioxidant status, we used two breast cancer cell lines: MDA-MB-231, in which DHA increases sensitivity to doxorubicin, and MCF-7, which does not respond to DHA. Under these conditions, reactive oxygen species (ROS) level increased on anthracycline treatment only in MDA-MB-231. This was concomitant with a decreased cytosolic glutathione peroxidase (GPx1) activity, a crucial enzyme for protection against hydrogen and lipid peroxides, while major antioxidant enzyme activities increased in both cell lines in response to ROS. GPx-decreased activity was accompanied by an accumulation of glutathione, the GPx cosubstrate, and resulted from a decreased amount of GPx protein. In rat mammary tumors, when a DHA dietary supplementation led to an increased tumor sensitivity to anthracyclines, GPx1 activity was similarly decreased. Furthermore, vitamin E abolished both DHA effects on chemotherapy efficacy enhancement and on GPx1 inhibition. Thus, loss of GPx response to an oxidative stress in transformed cells may account for the ability of peroxidizable targets such as DHA to enhance tumor sensitivity to ROS-generating anticancer drugs.

Any factor affecting BRCA gene regulation may be of interest in the prevention of breast tumourigenesis. We studied the influence of dietary docosahexaenoic acid (DHA), a major omega-3 fatty acid present in marine products, on rat autochthonous mammary tumourigenesis. DHA-supplementation significantly reduced the incidence of tumours (30%, P=0.007) and led to a 60% increase (P=0.02) in BRCA1 protein level. Since DHA influences the product of a major tumour suppressor gene, this finding may contribute to the observation that high-fish consumption reduces the risk of breast cancer.

Purpose: To investigate whether dietary docosahexaenoic acid (DHA), a peroxidizable polyunsaturated ω-3 fatty acids, sensitizes rat mammary tumors to anthracyclines and whether its action interferes with tumor vascularization, a critical determinant of tumor growth. Experimental Design: Female Sprague-Dawley rats were initiated by N-methylnitrosourea to develop mammary tumors and then assigned to a control group (n = 18), receiving a supplementation of palm oil, or to a DHA group (n = 54), supplemented with a microalgae-produced oil (DHASCO, 1.5 g/d). The DHA group was equally subdivided into three subgroups with addition of different amounts of α-tocopherol. Epirubicin was injected weekly during 6 weeks after the largest tumor reached 1.5 cm2, and subsequent changes in the tumor surface were evaluated. Tumor vascularization was assessed by power Doppler sonography before and during chemotherapy. Results: DHA and α-tocopherol were readily absorbed and incorporated into rat tissues. Epirubicin induced a 45% mammary tumor regression in the DHA-supplemented group, whereas no tumor regression was observed in the control group. In the DHA group, before chemotherapy was initiated, tumor vascular density was 43% lower than in the control group and remained lower during chemotherapy. Enhancement of epirubicin efficacy by DHA was abolished in a dose-dependent manner by α-tocopherol, and the same trend was observed for DHA-induced reduction in tumor vascular density. Conclusions: Dietary DHA supplementation led to a reduction in tumor vascularization before the enhancement of any response to anthracyclines, suggesting that DHA chemosensitizes mammary tumors through an inhibition of the host vascular response to the tumor.

The proinflammatory chemokine CC chemokine ligand 5 (CCL5) is a potent chemoattractant of immature dendritic cells (iDCs). It remains to be elucidated whether CCL5 may also enhance iDC migration through the basement membrane by affecting matrix metalloproteinase (MMP)-9 secretion. In this study, iDCs were differentiated in vitro from human monocytes of healthy donors. Zymographic analysis of cellular membranes of nontreated iDCs revealed a basal secretion of the pro- and active MMP-9, whereas only pro-MMP-9 was detected in conditioned media. Increasing concentrations of CCL5 significantly enhanced MMP-9 secretion by iDCs, peaking at 100 ng/ml, which optimally increased iDC migration through a reconstituted basement membrane (Matrigel™) in vitro. The CCL5-enhanced secretion of MMP-9 occurred early (2 h) and was maintained at least for 10 h. A significant increase in MMP-9 mRNA synthesis was detected by reverse transcriptase-polymerase chain reaction, only at 6 h of CCL5 treatment, which suggests that the early effect of CCL5 (0–4 h) on MMP-9 secretion was independent of mRNA synthesis, whereas the more delayed effect (6–10 h) could be mediated through an increase in MMP-9 gene expression. In a Matrigel migration assay, the CCL5-enhanced iDC migration was reduced significantly by specific inhibitors of MMP-9, such as tissue inhibitor of metalloproteinase-1 or an anti-MMP-9 antibody, which indicates that iDC migration through the basement membrane depends on MMP-9. These results suggest that under inflammatory conditions, the chemokine CCL5 may enhance iDC migration through the basement membrane by rapidly increasing their MMP-9 secretion.

International audience; Polyunsaturated fatty acids (PUFAs) have been reported to enhance the efficacy of chemotherapeutic agents that produce reactive oxygen species such as anthracyclines. We previously reported in a human breast cancer cell line that the increased cytotoxic activity of anthracyclines by several PUFAs was abolished by antioxidants and enhanced by pro-oxidants, suggesting that lipid peroxidation was involved in this effect. To determine the relevance of this observation in vivo, we examined the effect of the oxidative status of the diet on the activity of epirubicin against N-methylnitrosourea-induced mammary tumors in Sprague-Dawley rats. Three groups of rats were fed a basal diet enriched with dietary n-3 PUFA (sardine oil, 15%) alone (control group), with addition of an antioxidant (alpha-tocopherol, 100 UI/kg diet), or with addition of an oxidant system (dehydroascorbate/naphthoquinone). When the first mammary tumor reached 1 cm2, epirubicin was administrated weekly for 3 wk, and subsequent change in tumor size was documented over time. Two weeks after the end of epirubicin injections, tumor size was increased by 34% in the control group. In the pro-oxidant group, tumor size was decreased by 50%. In contrast, tumor size was increased by 188% in the antioxidant group. Thus, addition of pro-oxidants in a fish oil-enriched diet increased the sensitization of mammary tumors to chemotherapy, whereas addition of alpha-tocopherol suppressed tumor response in vivo, indicating that interaction between components of the diet has to be carefully controlled during chemotherapy.

Interleukin-7 (IL-7) is a pleiotropic, non-redundant cytokine crucial for development of B and T lymphocytes. The cellular response to IL-7 is triggered by binding of the cytokine to its receptor, IL-7R. Until now the expression of the receptor was evidenced only in lymphoid and myeloid cell lineages. The receptor consists of two chains: IL-7 specific α chain (CD127) and the common γ c chain (CD132) which is a component of several other cytokine receptors: IL-2, IL-4, IL-9 and IL-15. The former observation that exogenous IL-7 is biologically active towards murine endothelial cell lines from secondary lymphoid organs was the starting point of our studies. This observation has prompted us to search for the presence of IL-7 receptor in human microvascular endothelial cells. We used in our studies a set of human endothelial cell lines established from various organs. Our results demonstrate the presence of IL-7R in human microvascular endothelial cells, mainly in the mesenteric but also in the peripheral and to a lesser extent, in the mucosa-associated lymph node endothelial cells. On the basis of the RT-PCR reaction, molecular weight estimated in Western blot and IL-7 binding activity the identified endothelial IL-7 receptor was identical to the lymphocyte-type IL7-R.

The prospect of a primary prevention of breast cancer by nutrition implies that population at risk is individualized. Previous identification of a composite indicator of the nutritional part (modifiable) of the risk of breast cancer in breast white adipose tissue theoretically offers this perspective (1), but the need for a biopsy and tedious biochemical analyses hampers this approach. 1H-NMR of adipose tissue lipids represents an attractive, non invasive approach, which could circumvent these limitations. The aim of the study was to determine whether 1H-NMR spectroscopy of adipose tissue may provide information on the nature of the diet received. We carried out a dietary intervention in rats with different enriched oils under isocaloric conditions, and examined spectra of the lipid extract of their adipose tissue according to diet. Two groups of Sprague-Dawley rats were fed a basal diet containing 7% of a mixture of peanut and rapeseed oils enriched with 8% of an oil without (palm oil) or with DHA (DHASCO, containing 40% docosahexaenoic acid, DHA). This DHA group was subdivided into 3 groups with low (1%), moderate (3%) or high (8%) DHASCO content. A third group (control diet) had a diet containing 15% of the mixture of peanut and rapeseed oils. All five groups (n=6 per group) received 15% lipids. At the end of the experiment (6 months), rats were sacrificed and mammary pad adipose tissue used for analysis of the lipid extract. 1H-NMR analysis was carried out on a Bruker DRX500 spectrometer operating at 11.7 T. Fatty acids were analyzed by gas chromatography. The fatty acid profile of adipose tissue differed among dietary groups. For example, expressed as peak area %, mean values for DHA ranged from undetectable (< 0.1%, , control or palm groups) to 0.7, 1.9, 5.9 % in the 3 DHA groups. Total monounsaturates (mainly oleic acid) were at 52.1% in the control group, 56.1% in the palm group, and 54.7, 52.3 and 48.9 %, respectively, for the 3 DHA groups. Total saturates (mainly palmitic and stearic acids) were 16.9 and 24.1 % in the control and palm groups, and 24.7, 26.3 and 26 % for the 3 DHA groups. Total n-6 PUFA (mainly linoleic acid) were at 26.3 in the control, 13.9 in the palm groups, and 15.5, 14.6, 14.2 % in the 3 DHA groups. Partial least squares (PLS) discriminant analysis was carried out on 1H-NMR spectra of the lipid extracts from adipose tissue. The integrated spectral regions showed separation between rat groups suggesting a different NMR lipid profile according to dietary interventions. The 1H-NMR spectroscopy approach used here was effective for identification of the impact of dietary interventions targeting lipids, and in turn, it could be tested for the evaluation of the lipid profile of human adipose tissues in relation with dietary habits. 1 - Bougnoux et al,. Diet, cancer and the lipidome. Cancer Epidemiol, Biomarkers & Prev 2006; 15(3):416-21. Citation Format: Lobna Ouldamer, Lydie Nadal-Desbarats, Stephan Chevalier, Caroline Goupille, Philippe Bougnoux. Nutrition and breast cancer prevention: adipose tissue proton magnetic resonance spectroscopy (1H-NMR) as biomarker of past dietary intake of lipids. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4100. doi:10.1158/1538-7445.AM2014-4100

Accumulation of histo-blood group antigens such as Lewis b, Lewis Y and H in colon cancer is indicative of poor prognosis. It is accompanied by increase in alpha1,2fucosyl-transferase activity, a key enzyme for synthesis of these antigens. Using a model of colon carcinoma, we previously showed that alpha1,2fucosylation increases tumorigenicity. We now show that tumorigenicity inversely correlates with the cells' sensitivity to apoptosis. In addition, poorly tumorigenic REG cells independently transfected with three different alpha1,2fucosyltransferase cDNAs, the human FUT1, the rat FTA and FTB were more resistant than control cells to apoptosis induced in vitro by serum deprivation. Inversely, PRO cells, spontaneously tumorigenic in immunocompetent syngeneic animals and able to synthesize alpha1,2fucosylated glycans, became more sensitive to apoptosis after transfection with a fragment of the FTA cDNA in the antisense orientation. Expression of alpha1,2fucosyl-transferase in poorly tumorigenic REG cells dramatically enhanced their tumorigenicity in syngeneic rats. However, in immunodeficient animals, both control and alpha1,2fuco-syltransferase transfected REG cells were fully tumorigenic and metastatic, indicating that the presence of alpha1,2fucosylated antigens allowed REG tumor cells to escape immune control. Taken together, the results show that increased tumorigenicity mediated by alpha1,2fucosyl-ation is associated to increased resistance to apoptosis and to escape from immune control.

Objectifs Les taxanes, comme le docetaxel, sont des traitements majeurs dans le cancer du sein. En sus de leur role dans la stabilisation de la polymerisation de la tubuline, elles presentent des proprietes antiangiogeniques. Il est important de pouvoir differencier les modifications de micro et macrovascularisation. Materiels et methodes Les tumeurs mammaires ont ete induites chez 24 rates par une injection sous cutanee N-nitrosouree et reparties en deux groupes controle et docetaxel. Le docetaxel (6 mg/kg, i. p.) a ete administre pendant 6 semaines de facon hebdomadaire. Ont ete evaluees la surface tumorale et la vascularisation tumorale par Doppler puissance et ECUS apres injection de SonoVue ® . La quantification de la macrovascularisation etait effectuee sur programme Matlab ® en pourcentage tumoral. En ce qui concerne la microvascularisation, la fraction sanguine et la perfusion tumorale etaient mesurees en fonction des modeles exponentiels obtenus a partir du logiciel Qontrast ® . La mesure isolee de la micovascularisation etait obtenue a partir de la formule : % microvascularization = % vascularisation globale par ECUS-% macrovascularisation, par Doppler Puissance. Resultats Les volumes tumoraux restaient stables sous Docetaxel. Par contre, la fraction sanguine circulante et la perfusion tumorale etaient diminuees par Docetaxel alors que la macrovascularisation n’etait pas modifiee. Le temps de transit moyen des microbulles n’etait pas modifie par le traitement. Conclusion Cette etude demontre la faisabilite de differencier l’effet de medicaments sur les micro-et macrovaisseaux par la combinaison Doppler Puissance et echographie de contraste.