PhD candidate, University of Alberta
Under cancer conditions the muscle tissue promotes a local and harmful inflammatory response
Patients with cancer are at high risk of losing muscle mass during the course of their disease, this has a huge negative impact on their treatment choices, quality of life and survival.
Inflammation is a protective response of our body, however, when it is not resolved it becomes harmful to the health. Systemic inflammation is a known factor that contributes to muscle loss during cancer, recently, we have acknowledged that the muscle itself is involved in promoting an inflammatory environment that leads to muscle loss.
The main goal is to explore the muscle environment of the cancer population. I will unmask cells from the immune system that could be changing the muscle environment towards a harmful profile. Also, communication signals between muscle and immune cells will be explored, to understand the synergic processes that influence muscle loss.
This knowledge is very valuable for clinicians around the world as it will provide evidence to make an informed decision about the patient’s treatments and prognosis. In addition, it will help to develop preventive/multimodal therapies cancer therapy and guidelines for cancer patients at risk of muscle loss with increased inflammatory profiles.
Abstract: Idiopathic inflammatory myopathies (IIMs), collectively termed myositis, include three major subgroups: polymyositis, dermatomyositis and inclusion body myositis. IIMs are characterized clinically by muscle weakness and reduced muscle endurance preferentially affecting the proximal skeletal muscle. In typical cases, inflammatory cell infiltrates and proinflammatory cytokines, alarmins and eicosanoids are present in muscle tissue. Treatment with glucocorticoids and other immunosuppressants results in improved performance, but complete recovery is rarely seen. The mechanisms that cause muscle weakness and reduced muscle endurance are multi-factorial, and different mechanisms predominate in different phases of disease. It is likely that a combination of immune-mediated and nonimmune-mediated mechanisms contributes to clinical muscle symptoms. Immune-mediated mechanisms include immune cell-mediated muscle fibre necrosis as well as direct effects of various cytokines on muscle fibre contractility. Among the nonimmune-mediated mechanisms, an acquired metabolic myopathy and so-called endoplasmic reticulum stress may be important. There is also a possibility of defective repair mechanisms, with an influence of both disease-related factors and glucocorticoid treatment. Several proinflammatory molecules observed in muscle tissue of myositis patients, including interleukin (IL)-1, IL-15, tumour necrosis factor, high-mobility group box-1 and eicosanoids, have a role in muscle fibre regeneration, and blocking these molecule may impair muscle repair and recovery. The delicate balance between immunosuppressive treatment to downregulate proinflammatory molecules and an inhibitory effect on muscle fibre regeneration needs to be further understood. This would also be relevant for other chronic inflammatory diseases.
Pub.: 06 Jan '11, Pinned: 31 Jul '17
Abstract: Skeletal muscle is able to restore contractile functionality after injury thanks to its ability to regenerate. Following muscle necrosis, debris is removed by macrophages, and muscle satellite cells (MuSCs), the muscle stem cells, are activated and subsequently proliferate, migrate, and form muscle fibers restoring muscle functionality. In most muscle dystrophies (MDs), MuSCs fail to properly proliferate, differentiate, or replenish the stem cell compartment, leading to fibrotic deposition. However, besides MuSCs, interstitial nonmyogenic cells and inflammatory cells also play a key role in orchestrating muscle repair. A complete understanding of the complexity of these mechanisms should allow the design of interventions to attenuate MDs pathology without disrupting regenerative processes. In this review we will focus on the contribution of immune cells in the onset and progression of MDs, with particular emphasis on Duchenne muscular dystrophy (DMD). We will briefly summarize the current knowledge and recent advances made in our understanding of the involvement of different innate immune cells in MDs and will move on to critically evaluate the possible role of cell populations within the acquired immune response. Revisiting previous observations in the light of recent evidence will likely change our current view of the onset and progression of the disease.
Pub.: 17 Jul '14, Pinned: 31 Jul '17
Abstract: MicroRNAs (miRs) are small non-coding RNAs that regulate gene (mRNA) expression. Although the pathological role of miRs have been studied in muscle wasting conditions such as myotonic and muscular dystrophy, their roles in cancer cachexia (CC) are still emerging.The objectives are (i) to profile human skeletal muscle expressed miRs; (ii) to identify differentially expressed (DE) miRs between cachectic and non-cachectic cancer patients; (iii) to identify mRNA targets for the DE miRs to gain mechanistic insights; and (iv) to investigate if miRs show potential prognostic and predictive value.Study subjects were classified based on the international consensus diagnostic criteria for CC. Forty-two cancer patients were included, of which 22 were cachectic cases and 20 were non-cachectic cancer controls. Total RNA isolated from muscle biopsies were subjected to next-generation sequencing.A total of 777 miRs were profiled, and 82 miRs with read counts of ≥5 in 80% of samples were retained for analysis. We identified eight DE miRs (up-regulated, fold change of ≥1.4 at P < 0.05). A total of 191 potential mRNA targets were identified for the DE miRs using previously described human skeletal muscle mRNA expression data (n = 90), and a majority of them were also confirmed in an independent mRNA transcriptome dataset. Ingenuity pathway analysis identified pathways related to myogenesis and inflammation. qRT-PCR analysis of representative miRs showed similar direction of effect (P < 0.05), as observed in next-generation sequencing. The identified miRs also showed prognostic and predictive value.In all, we identified eight novel miRs associated with CC.
Pub.: 07 Jan '17, Pinned: 31 Jul '17
Abstract: Dendritic cells (DCs) are antigen-presenting cells that can acquire tumour antigens and initiate cytotoxic T cell reactions. Obesity has been proposed as a cause for tumours escaping immune surveillance, but few studies investigate the impact of other body composition parameters. We examined the relationship of DC phenotype with computer tomography (CT)-defined parameters in patients with colorectal cancer (CRC). DCs were identified within peripheral blood mononuclear cells by flow cytometry as HLA-DR positive and negative for markers of other cell lineages in 21 patients. Analysis of CT scans was used to calculate lumbar skeletal muscle index (LSMI) and mean muscle attenuation (MA). Positive correlation between the LSMI and expression of CD40 in all DCs (r = 0.45; p = 0.04) was demonstrated. The MA was positively correlated with scavenger receptor CD36 [all DCs (r = 0.60; p = 0.01) and myeloid DCs (r = 0.63; p < 0.01)]. However, the MA was negatively correlated with CCR7 expression in all DCs (r = −0.46, p = 0.03.) and with CD83 [all DCs (r = −0.63; p = 0.01) and myeloid DCs (r = −0.75; p < 0.01)]. There were no relationships between the fat indexes and the DC phenotype. These results highlight a direct relationship between muscle depletion and changes in stimulatory, migratory and fatty acid-processing potential of DC in patients with CRC.
Pub.: 10 Mar '16, Pinned: 31 Jul '17