Based on NHANES cycles from 1999–2014, we find that SO and sarcopenia are significantly associated with increased mortality while obesity is a protective factor in cancer patients. Furthermore, this study answers the question of what factors may lead to the occurrence of SO. Even though several previous systematic reviews have speculated the potential factors of SO, to date there is still no clearly evidence to substantiate these speculations. We confirm that individuals with IR or HTG are respectively 2.63 and 1.40 times more likely to have SO than those without.
4.1 Molecular mechanisms of interaction between SO, IR and HTG in cancer settings
For purpose of figuring out factors associated with SO, our study found cancer participants with IR or HTG are more likely to have SO which may cast a shadow on their life expectancy.
Cancer and lifestyle-related diseases such as SO tend to have a complex interplay with hereditary factors, environmental influences and molecular mechanisms at cellular, tissue and systemic levels22–25, just like a huge, interconnected network. The interaction between cancer-related and SO-related mechanisms are barely known and there are few studies available specifically investigated molecular signaling pathways of SO in the context of cancer, more basic researches could be carried out to identify biomarkers or specific regulatory factors.
Emerging evidence and signaling pathways analysis in relevant studies may conduce to explicit the mechanism of how SO develop under circumstance of malignant tumor.
Fatigue, weakness, cachexia, inactivity, malnourishment and senescence of cancer patients accounts, in part, for reduced resting metabolic rates, decreased energy efficiency at mitochondrial level and accelerated skeletal muscle mitochondrial damage, especially in the context of obesity. These can lead to slow oxidative capacity of skeletal muscle mass, releasing caspase mediated apoptosis, and over time, resulting in diminished muscle mass and function26. Excessive fatty acid, as the result of all above, on one hand, are raw materials for synthesis of triglycerides which leads to HTG, dyslipidemia, and obesity27; on the other hand may cause ectopic fat infiltration in skeletal muscles and other organs28,1, as an emerging factor associated with both systemic and muscular metabolic disarrangement, which can in turn induce mitochondrial dysfunction26. The existence of intermuscular adipose tissue block glucose transporter type 4 (GLUT4) translocation from the inside of the cell to the membrane through PI3K-AKT and MAPK pathways and the function loss of which can result in decreased glucose uptake and utilization29; 30, decreased synthesis of muscle mitochondrial proteins, disturbed fatty acid β-oxidation in the mitochondria, increased reactive oxygen species (ROS) formation and IR27; 28; 31; 32, factors known to create a lipid toxic environment and eventually, development of sarcopenia33.
Additionally, intermuscular adipose tissue also has its endocrine functions. It secretes myokines such as myostatin, cytokines and other hormones, modulating both skeletal muscle and adipose metabolism34; 35. In the context of adiposity and metabolic disorders, increase in pro-inflammatory cytokines and persistent inflammation play important roles in sarcopenia, can both promote protein degradation and reduce synthesis36, induce IR and skeletal muscle loss by suppressing PI3K-AKT signaling pathway leading to activation of caspase-3 and ubiquitin-proteasome proteolytic pathway37.
Furthermore, the increase in fat mass can mask the muscle loss, making the symptoms more insidious4.
IR is commonly identified as the decrease in sensitivity to normal levels of insulin, resulting in abnormal glucose utilization and uptake, often leading to hyperinsulinemia. It is the basis of a variety of pathophysiological states such as obesity, type 2 diabetes, metabolic syndrome, hypertension, lipid metabolism disorders, sarcopenia, etc38.
The vast majority of people with IR are obese or overweight with fat organ dysfunction and altered fat metabolic processes. Evidence was observed that IR leads to dyslipidemic triad of high serum triglycerides, low levels of high-density lipoprotein, and increase in low-density lipoproteins39. Also, adipose tissue macrophage-derived exosomal miRNAs can modulate insulin sensitivity, in turn accelerate the development of IR40.
4.2 Obesity in cancer
Conclusions derived from previous systemic reviews and observations consistently convinced that excess body weight is an established risk factor and have adverse influences on survival rates and progression in multiple types of cancer41. Nonetheless, the opposite conclusions were drawn in some findings that being obese is linked to better mortality overall in cancer patients which is in conformity with our findings42.
This paradox is observed more common in overweight and moderate obese groups while less seen in severe or even morbidly obese groups43, which is possibly caused by individuals with malignant tumor classified as normal weight or even underweight have less energy reserve against chronic consumptive in the advanced stages and poorer prognosis.
The reason why we did not investigate the chronic inflammation is because inflammatory markers in NHANES were found to be temporal which was uncapable to reflect the dynamitic and long-term evolution process.
4.3 Reasons for selecting RFM instead of BMI
Orison O. Woolcott and Richard N. Bergman identified a new estimator named as the relative fat mass (RFM) to estimate adiposity percentage of the whole body by using the cross-sectional data from NHANES. RFM, of which the equation based on height, waist circumference, and sex has already been proved superior, more accurate and easier to be calculated than the traditionally obese definition-BMI. We used this simple and liner equation with diagnosis cutoff to define obesity as an alternative of BMI15–17.
4.4 Treatment for SO
Although limited evidence is available currently and there have been no interventional studies or randomized controlled trial so far, hypothesis proposed nutritional supplement, aerobic exercise and resistance training are the key points to restore health2; 44. In our result, lifestyle intervention (encompassing doing muscle strengthening activities, increasing physical activity, sufficient protein and Vitamin D intake) are protective factors that could substantially reduce all-cause mortality in cancer settings which is consistent with the hypothesis.
However, among cancer population with SO, these manners of lifestyle have no significant effect on improving prognosis. The discrepancy between theory and our result may be due to the feebleness or fasting state caused by cachexia, cancer-related pain or complications of advanced cancer.
4.5 Novelty and Limitations
About novelty, in the first place, of the available studies on SO in cancer populations, the majority were conducted in the context of a single type of cancer and had limited sample sizes. Pan-cancer and large sample studies are scarce. Besides, aims mostly are to explore the impact of SO on prognosis or on postoperative complications, causing the research methods and conclusions monotonous. To cover the blank of current research status, this study utilized the public NHANES database to obtain sufficient sample population with various cancer types, long follow-up period and complete examination results.
Next then, generalized conjectures have been proposed regarding factors associated with the occurrence of SO in cancer patients in available reviews, however, no findings so far have provided clarity and verification. Our cross-sectional study figures out the exact predictors which provides ideas for future laboratory research.
Lastly, oncologists tend to lack awareness and popularization of SO in clinical work. This paper intents to provide clinical practitioners with a better understanding of SO and to implement early prevention, diagnosis and treatment of this insidious disease.
Moving to limitations, firstly, our study is a cross-sectional study with lower proof strength than a randomized controlled studies or cohort studies. More studies are needed for further analysis.
Secondly, DXA data obtained from NHANES data source is multiple imputed which is impracticable to compare it with other body composition measurement indicators in R software.
Thirdly, the mechanism is still unclear and biological markers or molecular signals remain missing, it is necessary for basic researches to further explore the specific molecular pathways of SO in the cancer setting.
Finally, the awareness of SO in clinical work is still not enough45. There is neither consensus on the definition of SO nor uniform guidelines for cancer clinicians to deliver optimal treatment and nutrition care.