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.

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.

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 α(1–2)fucosyltransfer-ase activity, a key enzyme for the biosynthesis of these antigens. Yet the biological significance of α(1–2)fucosylated structures is not well defined. We have trans-fected a poorly tumorigenic rat colon carcinoma cell line with the human H blood group α(1–2)fucosyltransferase cDNA. This resulted in cell surface expression of H antigens with a concomitant decrease of sialic acid substituted and free β-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, α(1–2)fucosyltransferase transfectants were able to form progressive tumors. Increased tumorigenicity was also visible in nude mice. These results demonstrate that α(1–2)fucosylated antigens contribute directly to aggressiveness of colon carcinoma cells. This could occur by altering a function of CD44 variants.

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 α1,2fucosyl­transferase activity, a key enzyme for synthesis of these antigens. Using a model of colon carcinoma, we previously showed that α1,2fucosylation 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 α1,2fucosyltransferase 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 α1,2fucosylated glycans, became more sensitive to apoptosis after transfection with a fragment of the FTA cDNA in the antisense orientation. Expression of α1,2fucosyl­transferase in poorly tumorigenic REG cells dramatically enhanced their tumorigenicity in syngeneic rats. However, in immunodeficient animals, both control and α1,2fuco­syltransferase transfected REG cells were fully tumorigenic and metastatic, indicating that the presence of α1,2fucosylated antigens allowed REG tumor cells to escape immune control. Taken together, the results show that increased tumorigenicity mediated by α1,2fucosyl­ation is associated to increased resistance to apoptosis and to escape from immune control.

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.