Effect of using a kinetic wedge during the hallux dorsiflexion resistance test in asymptomatic individuals.

BACKGROUND: The hallux dorsiflexion resistance test is a frequently employed clinical maneuver for assessing the initiation of the windlass mechanism This maneuver involves dorsiflexion of the phalanx of the hallux, thereby evaluating plantarflexion of the first metatarsal, elevation of the medial longitudinal arch, and supination of the rearfoot. The windlass mechanism plays a crucial role in gait, and orthopedic devices, such as a kinetic wedge, which aims to facilitate its activation by increasing the hallux dorsiflexion. Although it is believed that facilitating the windlass mechanism with the kinetic wedge should be directly correlated with a decrease in hallux dorsiflexion resistance, its effects have yet to be characterized. Thus, this study aimed to determine the influence of a kinetic wedge on hallux dorsiflexion resistance in asymptomatic individuals. METHODS: The sample comprised thirty participants (14 women and 16 men). A digital force gauge measured the force required to perform the hallux dorsiflexion resistance test during two conditions: barefoot and with a kinetic wedge. The Wilcoxon signed-rank test was used to compare the hallux dorsiflexion resistance between conditions. RESULTS: A statistically significant reduction in force (10.54 ± 3.16N vs. 19.62 ± 5.18N, p < 0.001) was observed when using the kinetic wedge compared to the barefoot condition during the hallux dorsiflexion resistance test. CONCLUSION: The use of a kinetic wedge reduces the required force for performing the passive hallux dorsiflexion resistance test in asymptomatic individuals. Future studies should determine to what extent the kinetic wedge can attenuate the required force to dorsiflex the hallux in individuals with musculoskeletal disorders such as plantar fasciopathy and functional hallux limitus.

Childhood obesity and its impact on the characteristics of gait stance phases: a cross-sectional study.

This study aimed to investigate the variations in foot type, laxity, dynamic characteristics of gait, and the characteristics of the stance phase of gait, in relation to body mass index (BMI) and groups of children of different ages. Additionally, it aimed to explore the correlations between BMI and these variables across children groups of different ages. A cross-sectional study was conducted involving 196 infants aged between 5 and 10 years old. The variables assessed included BMI, foot type, laxity, dynamic variables, and characteristics of the stance phase of gait. Significant variations were observed in foot type, laxity, certain dynamic variables, and characteristics of the stance phase of gait between normoweight (NW) and overweight/obese (OW/OB) groups among children aged between 5 and 10 years old (p ranged between 0.019 and 0.050). Moreover, BMI was also positively associated with the initial forefoot contact, heel off, total duration of the step, and forefoot contact phase of children 7 to 10 years of age (p ranged between < 0.010 and 0.040).   Conclusion: Children who are OW/OB had alterations at different stages of gait. Being OW/OB is related to alterations of the phases of gait mainly from 7 to 10 years of age, and spending more time in each of the phases of walking. This could indicate that children who are OW/OB, in addition to walking slower, overload the musculoskeletal system, subjecting their joints and muscles to greater stress. What is Known: • Children who are overweight (OW) and obese (OB) can experience changes in their musculoskeletal systems, posture, and gait due to increased body mass index. • OW and OB children experience additional stress on their musculoskeletal systems, impacting posture, biomechanics, mobility, physical activity, and daily tasks. Excessive plantar loading is linked to foot pain in adults. What is New: • Body mass index was positively associated with initial forefoot contact, heel off, total duration of the step, and forefoot contact phase in children aged 7 to 10 years old. OW/OB children aged 5-6 exhibited less ankle dorsiflexion and smaller relaxed calcaneal stance position (RCSP) as compared to normal-weight children. • Obese children aged 5-6 showed less pronation excursion, suggesting altered frontal plane movement due to RCSP differences. Children aged 7-8 who are OW/OB spent more time in certain gait phases, particularly in the forefoot contact phase. Being OW/OB is linked to altered gait parameters such as initial forefoot, heel off, total step duration, and forefoot contact phase. Being OW/OB was associated with a longer forefoot contact phase, particularly in the right foot.

The resting calcaneal stance position (RCSP): an old dog, with new tricks.

The objective of this study was to establish the accuracy of the resting calcaneal stance position (RCSP) for the assessment of flat foot (FF) in children, aligned to the validity of the foot posture index (FPI). The RCSP cut-off point was explored, in context of both FF prevalence and the relationship between FF and body weight. A total of 205 healthy children, aged 5 to 10 years, participated in a cross-sectional study. Correlation was performed between RCSP and FPI. ROC curve technique was calculated to assess differentiation between groups. A score equal to or greater than 7 on the FPI was used as the 'gold standard' for analysis. The correlation between FPI and RCSP was significant (r = 0.63; p < 0.01). The discrimination score on the ROC curve (6 points/degrees) shows that the model can be used to identify FF through RCSP, with a sensitivity of 67% and specificity of 85% returned.  Conclusion: The results of this study indicate the role of RCSP for simple, accessible and quick screening of paediatric FF. This is especially pertinent for non-podiatric healthcare professional without specialised paediatric foot knowledge. What is Known: • Most children develop a normal arch quickly, and flat feet usually resolve on their own between 2 and 6 years of age. • The measurement used to diagnose flat foot in children must be accurate, consistent, and valid to characterize the standard foot position. The Resting Calcaneal Stance Position (RCSP) is another widely used measure to evaluate the position of the flat foot in children. What is New: • The RCSP cut-off point 6 shows a sensitivity of 67% and a specificity of 85% thanks to the FPI as the Gold standard. • The RCSP is useful for health professionals who are not specialised in pediatric foot health. The RCSP is useful to detect flat foot in children.

Effects of Low-Dye Tape on Arch Height and Its Impact on the Medial Gastrocnemius Electromyographic Activity in Structurally Differentiable Foot Types: A Cross-Sectional Observational Study.

BACKGROUND: Low-Dye tape (LDT) is a short-term treatment for plantar fasciitis, where external stabilization by means of the tape improves kinetics, kinematics, pain level, and electromyography (EMG). PURPOSE: The purpose of this study was to compare the EMG of the medial gastrocnemius (MG) and changes in arch height (AH) based on the type of foot. METHODS: A total of 30 subjects participated in this study; they walked on a treadmill barefoot and when taped, where the average activity and changes in AH were measured over a 30 s period. The statistical intraclass correlation coefficient (ICC) to test for reliability was calculated, and the Wilcoxon test was determined for measures of EMG and AH. RESULTS: The reliability of the values of EMG was almost perfect. The data show that there was an increase in height in the comparison of the moment pre-baseline walking and post-taped walking on neutral feet (5.61 ± 0.46 vs. 5.77 ± 0.39 cm, p < 0.05), on pronated feet (5.67 ± 0.57 vs. 6.01 ± 0.53 cm, p < 0.001) and on supinated feet (5.97 ± 0.36 vs. 6.28 ± 0.27 cm, p < 0.05). In the MG, EMG activity decreased significantly in the taped condition compared to the baseline condition in neutral subjects (0.0081 ± 0.016 vs. 0.076 ± 0.016 mV, p < 0.05) and in pronated subjects (0.081 ± 0.022 vs. 0.068 ± 0.025 mV, p < 0.05). CONCLUSIONS: It was demonstrated that with the use of LDT, there was an improvement in the average activity in the MG in pronated and neutral feet. All foot types improved in arch height with the use of tape.

Overweight and Obesity: Its Impact on Foot Type, Flexibility, Foot Strength, Plantar Pressure and Stability in Children from 5 to 10 Years of Age: Descriptive Observational Study.

BACKGROUND: Overweight (OW) and childhood obesity (OB) may cause foot problems and affect one's ability to perform physical activities. The study aimed to analyze the differences in descriptive characteristics, foot type, laxity, foot strength, and baropodometric variables by body mass status and age groups in children and, secondly, to analyze the associations of the BMI with different physical variables by age groups in children. METHODS: A descriptive observational study involving 196 children aged 5-10 years was conducted. The variables used were: type of foot, flexibility, foot strength and baropodometric analysis of plantar pressures, and stability by pressure platform. RESULTS: Most of the foot strength variables showed significant differences between the normal weight (NW), OW and OB groups in children aged between 5 and 8. The OW and OB groups showed the highest level of foot strength. In addition, the linear regression analyses showed, in children aged 5 to 8 years, a positive association between BMI and foot strength (the higher the BMI, the greater the strength) and negative association between BMI and stability (lower BMI, greater instability). CONCLUSIONS: Children from 5 to 8 years of age with OW and OB show greater levels of foot strength, and OW and OB children from 7 to 8 years are more stable in terms of static stabilometrics. Furthermore, between 5 and 8 years, having OW and OB implies having more strength and static stability.

Microbiota-derived genotoxin tilimycin generates colonic stem cell mutations.

The DNA-alkylating metabolite tilimycin is a microbial genotoxin. Intestinal accumulation of tilimycin in individuals carrying til+ Klebsiella spp. causes apoptotic erosion of the epithelium and colitis. Renewal of the intestinal lining and response to injury requires the activities of stem cells located at the base of intestinal crypts. This study interrogates the consequences of tilimycin-induced DNA damage to cycling stem cells. We charted the spatial distribution and luminal quantities of til metabolites in Klebsiella-colonized mice in the context of a complex microbial community. Loss of marker gene G6pd function indicates genetic aberrations in colorectal stem cells that became stabilized in monoclonal mutant crypts. Mice colonized with tilimycin-producing Klebsiella displayed both higher frequencies of somatic mutation and more mutations per affected individual than animals carrying a non-producing mutant. Our findings imply that genotoxic til+ Klebsiella may drive somatic genetic change in the colon and increase disease susceptibility in human hosts.

Changes in the Kinematics of Midfoot and Rearfoot Joints with the Use of Lateral Wedge Insoles.

The lateral wedge insole (LWI) is a typical orthopedic treatment for medial knee osteoarthritis pain, chronic ankle instability, and peroneal tendon disorders. It is still unknown what the effects are in the most important joints of the foot when using LWIs as a treatment for knee and ankle pathologies. Objectives: The aim of this study was to determine the influence of LWIs on the position of the midfoot and rearfoot joints by measuring the changes using a tracking device. Methods: The study was carried out with a total of 69 subjects. Movement measurements for the midfoot were made on the navicular bone, and for the rearfoot on the calcaneus bone. The Polhemus system was used, with two motion sensors fixed to each bone. Subjects were compared by having them use LWIs versus being barefoot. Results: There were statistically significant differences in the varus movement when wearing a 4 mm LWI (1.23 ± 2.08°, p < 0.001) versus the barefoot condition (0.35 ± 0.95°), and in the plantarflexion movement when wearing a 4 mm LWI (3.02 ± 4.58°, p < 0.001) versus the barefoot condition (0.68 ± 1.34°), in the midfoot. There were also statistically significant differences in the valgus movement when wearing a 7 mm LWI (1.74 ± 2.61°, p < 0.001) versus the barefoot condition (0.40 ± 0.90°), and in the plantar flexion movement when wearing a 4 mm LWI (2.88 ± 4.31°, p < 0.001) versus the barefoot condition (0.35 ± 0.90°), in the rearfoot. Conclusions: In the navicular bone, a varus, an abduction, and plantar flexion movements were generated. In the calcaneus, a valgus, an adduction, and plantar flexion movements were generated with the use of LWIs.

Management of post-surgical infection of onychocryptosis with topical application of hyaluronic acid versus antibacterial ointments.

Introduction: The prevention and cure of postoperative infections has been a source of study over the years and is currently being studied. In this bibliographic review, a comparison between the different products used for the prevention and treatment of postsurgical infections has been procured, likewise, being able to determine which would be the best option for the treatment of post-surgical infections. In this bibliographic review we focus on Onychocryptosis because it is an emerging problem today. Many surgeries are performed to fix this condition, which increases the risk of infections. Material: databases, including PubMed and Cochrane Library, as well as websites of international organizations, were searched up to January 2021. The search included studies and trials in humans on the use of hyaluronic acid and antibacterial ointments in various conditions or diseases. Results: 18 articles were analyzed individually, which included randomized studies of Hyaluronic Acid, various antibiotics and honey, and variables used topically. 3 articles were also selected to explain onychocryptosis and postoperative infections. Conclusion: Despite being able to determine which antibiotic would be the best, and whether hyaluronic acid can be used for the prevention and/or cure of post-surgical infections, this review emphasizes that there is still a need for more specific studies on its use of these variables, both in post-surgical infections in general and in post-surgical onychocryptosis infections.

Evaluation of the Relationship between Lower Limb Hypermobility and Ankle Muscle Strength in a Paediatric Population: Protocol for a Cross Sectional Study.

The methodological heterogeneity in paediatric foot studies does not entail a stable foundation on which to focus the diagnosis and treatment of the various childhood foot problems. For this reason, the use of highly reliable tests is essential to find relationships and to establish a basis to guide the following studies. The main objective proposed in this cross-sectional observational study protocol is to examine the relationship between hypermobility (Lower Limb Assessment Score and Beighton score) and ankle muscle strength in different types of feet. The second objective is to describe the relationship between physical activity tests in children, and to compare with foot type and ankle muscle strength. The Strengthening Reporting of Observational Studies in Epidemiology (STROBE) criteria will be followed. The hypermobility, posture, strength and physical condition tests will be analyzed through three stations, each one directed by a single specialist in paediatric podiatry. The study has been approved by the Ethics Committee of the Universidad Católica San Antonio de Murcia CE112104. The results will be disseminated regardless of the magnitude or direction of effect. Intra-examiner and inter-examiner reliability will be analyzed.

Innovative Medial Cushioning Orthoses Affect Peroneus Longus Electromyographic Activity during Running.

Background: Over-supination processes of the foot and ankle involving peroneus longus (PL) damage during running sports have been treated conservatively with passive control tools, such as tapes, braces, or external ankle supports, but the effect of orthoses with typical lateral wedging orthoses (TLWO) on the muscular activity of PL during running remains unclear. Here we investigate the effects of innovative medial cushioning orthoses (IMCO) on PL activity during the full running gait cycle. In addition, we wished to ascertain the effects of innovative medial cushioning orthoses (IMCO) on PL activity during running. Methods: Thirty-one healthy recreational runners (mean age 34.5 ± 3.33) with neutral foot posture index scores, were selected to participate in the present study. They ran on a treadmill at 9 km/h wearing seven different orthoses (NRS, IMCO 3 mm, IMCO 6 mm, IMCO 9 mm, TLWO 3 mm, TLWO 6 mm and TLWO 9 mm), randomly performed on the same day while electromyographic activity of the PL muscle was recorded. Statistical intraclass correlation coefficient (ICC) to test reliability was carried out and the Wilcoxon test with Bonferroni's correction was developed to analyze the differences between the conditions. Results: the reliability of all assessments showed data higher than 0.81, that is, "almost perfect reliability"; all EMG PL values wearing either TLWO or IMCO showed a statistically significant reduction versus NRS during the fully analyzed running gait cycle; the highest difference was set on NRS 23.08 ± 6.67 to TLWO 9 mm 17.77 ± 4.794 (p < 0.001). Conclusions: Muscular EMG activity of the PL during the full running gait cycle decreases when wearing either TLWO or IMCO relative to NRS; therefore, these orthoses could be prescribed to treat the strain and overload pathologies of PL. In addition, IMCO­as it less thick, compared with TLWO­can be used when aiming to achieve better running economy.

A non-dividing cell population with high pyruvate dehydrogenase kinase activity regulates metabolic heterogeneity and tumorigenesis in the intestine.

Although reprogramming of cellular metabolism is a hallmark of cancer, little is known about how metabolic reprogramming contributes to early stages of transformation. Here, we show that the histone deacetylase SIRT6 regulates tumor initiation during intestinal cancer by controlling glucose metabolism. Loss of SIRT6 results in an increase in the number of intestinal stem cells (ISCs), which translates into enhanced tumor initiating potential in APCmin mice. By tracking down the connection between glucose metabolism and tumor initiation, we find a metabolic compartmentalization within the intestinal epithelium and adenomas, where a rare population of cells exhibit features of Warburg-like metabolism characterized by high pyruvate dehydrogenase kinase (PDK) activity. Our results show that these cells are quiescent cells expressing +4 ISCs and enteroendocrine markers. Active glycolysis in these cells suppresses ROS accumulation and enhances their stem cell and tumorigenic potential. Our studies reveal that aerobic glycolysis represents a heterogeneous feature of cancer, and indicate that this metabolic adaptation can occur in non-dividing cells, suggesting a role for the Warburg effect beyond biomass production in tumors.

GM-CSF Protects Macrophages from DNA Damage by Inducing Differentiation.

At inflammatory loci, pro-inflammatory activation of macrophages produces large amounts of reactive oxygen species (ROS) that induce DNA breaks and apoptosis. Given that M-CSF and GM-CSF induce two different pathways in macrophages, one for proliferation and the other for survival, in this study we wanted to determine if these growth factors are able to protect against the DNA damage produced during macrophage activation. In macrophages treated with DNA-damaging agents we found that GM-CSF protects better against DNA damage than M-CSF. Treatment with GM-CSF resulted in faster recovery of DNA damage than treatment with M-CSF. The number of apoptotic cells induced after DNA damage was higher in the presence of M-CSF. Protection against DNA damage by GM-CSF is not related to its higher capacity to induce proliferation. GM-CSF induces differentiation markers such as CD11c and MHCII, as well as the pro-survival Bcl-2A1 protein, which make macrophages more resistant to DNA damage.

Kinematic Effect on the Navicular Bone with the Use of Rearfoot Varus Wedge.

BACKGROUND: The rearfoot varus wedge (RVW) is a common treatment for foot pain and valgus deformity. There is research on its effects in the calcaneus, but there is little research on the navicular. More research is needed with the use of RVW due to the relationship that exists between the position of the navicular and the risk of suffering an injury. OBJECTIVES: this study sought to understand how RVW can influence the kinematics of the navicular bone, measuring their movement with the 6 SpaceFastrak system. METHODS: a total of 60 subjects participated in the study. Two sensors were used to measure the movement of the calcaneus and navicular using RVWs as compared in the barefoot position in a static way. RESULTS: there were statistically significant differences, the use of RVWs caused changes in the navicular bone, with subjects reaching the maximum varus movement with the use of RVW 7 mm of 1.35 ± 2.41° (p < 0.001), the maximum plantar movement flexion with the use of RVW 10 mm of 3.93 ± 4.44° (p < 0.001). CONCLUSIONS: when RVWs were placed under the calcaneus bone, the navicular bone response was in varus movement too; thus, the use of rearfoot varus wedge can influence the movement of the navicular bone.

Assessment of a New Lateral Cushioned Casting Orthosis: Effects on Peroneus Longus Muscle Electromyographic Activity During Running.

BACKGROUND: Classical medial wedge (CMW) orthoses have been prescribed to treat overpronation foot pathologies in runners. The effects of a novel supination orthosis (NSO) on the surface electromyography (EMG) activity of the peroneus longus (PL) muscle during a complete cycle of running have yet to be tested. PURPOSE/HYPOTHESIS: The purpose of this study was to compare the EMG activity of the PL in participants wearing CMW orthoses and NSOs versus neutral running shoes (NRS) during a full cycle of running gait. It was hypothesized that the PL muscle activity would be lower for the NSO compared with CMW or NRS. STUDY DESIGN: Controlled laboratory study. METHODS: Included were 31 healthy recreational runners of both sexes (14 male and 17 female; mean age, 38.58 ± 4.02 years) with a neutral Foot Posture Index and standard rearfoot-strike pattern. Participants ran on a treadmill at 9 km/h while wearing NSO (3-, 6-, and 9-mm thicknesses), CMW (3-, 6-, and 9-mm thicknesses), and NRS, for a total of 7 different conditions randomly selected, while the EMG signal activity of the PL was recorded for 30 seconds. Each trial was recorded 3 times, and the intraclass correlation coefficient (ICC) to test reliability of the measurements was calculated. The Wilcoxon pair to pair nonparametric test with Bonferroni correction was performed to analyze differences among the conditions. RESULTS: The reliability of all assessments was almost perfect (ICC, >0.81). For both the CMW and NSO, regardless of thickness, the PL activity was statistically significantly lower compared with the NRS (P < .05 for all). For all CMW thicknesses, the PL activity was lower compared with the respective NSO thicknesses, with the 3-mm thickness having the largest difference (CMW3mm, 18.63 ± 4.64 vs NSO3mm, 20.78 ± 4.99 mV; P < .001). CONCLUSION: Both CMW and NSO produced reduced EMG activity of the PL muscle; therefore, they can be prescribed to treat overpronation pathologies without associated PL strain concerns. In addition, the NSO saved the enhancement material placed on the medial-rear side of CMW, making it easier to wear sports shoes. CLINICAL RELEVANCE: Knowing the safety of CMW and NSO will aid in understanding treatments for overpronation pathologies.

Sirtuins as Metabolic Regulators of Immune Cells Phenotype and Function.

Beyond its role on the conversion of nutrients into energy and biomass, cellular metabolism is actively involved in the control of many physiological processes. Among these, it is becoming increasingly evident that specific metabolic pathways are associated with the phenotype of several immune cell types and, importantly, are crucial in controlling their differentiation, proliferation, and effector functions, thus shaping the immune response against pathogens and tumors. In this context, data generated over the last decade have uncovered mammalian sirtuins as important regulators of cellular metabolism, immune cell function, and cancer. Here, we summarize our current knowledge on the roles of this family of protein deacylases on the metabolic control of immune cells and their implications on immune-related diseases and cancer.

A unique subset of glycolytic tumour-propagating cells drives squamous cell carcinoma.

Head and neck squamous cell carcinoma (SCC) remains among the most aggressive human cancers. Tumour progression and aggressiveness in SCC are largely driven by tumour-propagating cells (TPCs). Aerobic glycolysis, also known as the Warburg effect, is a characteristic of many cancers; however, whether this adaptation is functionally important in SCC, and at which stage, remains poorly understood. Here, we show that the NAD+-dependent histone deacetylase sirtuin 6 is a robust tumour suppressor in SCC, acting as a modulator of glycolysis in these tumours. Remarkably, rather than a late adaptation, we find enhanced glycolysis specifically in TPCs. More importantly, using single-cell RNA sequencing of TPCs, we identify a subset of TPCs with higher glycolysis and enhanced pentose phosphate pathway and glutathione metabolism, characteristics that are strongly associated with a better antioxidant response. Together, our studies uncover enhanced glycolysis as a main driver in SCC, and, more importantly, identify a subset of TPCs as the cell of origin for the Warburg effect, defining metabolism as a key feature of intra-tumour heterogeneity.

Thyroid hormone inhibits hepatocellular carcinoma progression via induction of differentiation and metabolic reprogramming.

BACKGROUND & AIMS: Only limited therapeutic options are currently available for hepatocellular carcinoma (HCC), making the development of effective alternatives essential. Based on the recent finding that systemic or local hypothyroidism is associated with HCC development in humans and rodents, we investigated whether the thyroid hormone triiodothyronine (T3) could inhibit the progression of HCCs. METHODS: Different rat and mouse models of hepatocarcinogenesis were investigated. The effect of T3 on tumorigenesis and metabolism/differentiation was evaluated by transcriptomic analysis, quantitative reverse transcription PCR, immunohistochemistry, and enzymatic assay. RESULTS: A short treatment with T3 caused a shift in the global expression profile of the most aggressive preneoplastic nodules towards that of normal liver. This genomic reprogramming preceded the disappearance of nodules and involved reprogramming of metabolic genes, as well as pro-differentiating transcription factors, including Kruppel-like factor 9, a target of the thyroid hormone receptor ß (TRß). Treatment of HCC-bearing rats with T3 strongly reduced the number and burden of HCCs. Reactivation of a local T3/TRß axis, a switch from Warburg to oxidative metabolism and loss of markers of poorly differentiated hepatocytes accompanied the reduced burden of HCC. This effect persisted 1 month after T3 withdrawal, suggesting a long-lasting effect of the hormone. The antitumorigenic effect of T3 was further supported by its inhibitory activity on cell growth and the tumorigenic ability of human HCC cell lines. CONCLUSIONS: Collectively, these findings suggest that reactivation of the T3/TRß axis induces differentiation of neoplastic cells towards a more benign phenotype and that T3 or its analogs, particularly agonists of TRß, could be useful tools in HCC therapy. LAY SUMMARY: Hepatocellular carcinoma (HCC) represents an important challenge for global health. Recent findings showed that systemic or local hypothyroidism is associated with HCC development. In rat models, we showed that administration of the thyroid hormone T3 impaired HCC progression, even when given at late stages. This is relevant from a translational point of view as HCC is often diagnosed at an advanced stage when it is no longer amenable to curative treatments. Thyroid hormones and/or thyromimetics could be useful for the treatment of patients with HCC.

Metabolic pathways regulating colorectal cancer initiation and progression.

Colorectal cancer (CRC) is one of the most common types of cancer worldwide. Despite recent advances in the molecular genetics of CRC, poor treatment outcomes highlight the need for a better understanding of the underlying mechanisms accounting for tumor initiation and progression. Recently, deregulation of cellular metabolism has emerged as a key hallmark of cancer. Reprogramming of core cellular metabolic pathways by cancer cells provides energy, anaplerotic precursors and reducing equivalents required to support tumor growth. Here, we review key findings implicating cancer metabolism as a major contributor of tumor initiation, growth and metastatic dissemination in CRC. We summarize the metabolic pathways governing stem cell fate in the intestine, the metabolic adaptations of proliferating colon cancer cells and their crosstalk with oncogenic signaling, and how they fulfill the energetic demands imposed by the metastatic cascade. Lastly, we discuss how some of these metabolic pathways could represent new vulnerabilities of CRC cells with the potential to be targeted.

SIRT6 Suppresses Cancer Stem-like Capacity in Tumors with PI3K Activation Independently of Its Deacetylase Activity.

Cancer stem cells (CSCs) have high tumorigenic capacity. Here, we show that stem-like traits of specific human cancer cells are reduced by overexpression of the histone deacetylase sirtuin 6 (SIRT6). SIRT6-sensitive cancer cells bear mutations that activate phosphatidylinositol-3-kinase (PI3K) signaling, and overexpression of SIRT6 reduces growth, progression, and grade of breast cancer in a mouse model with PI3K activation. Tumor metabolomic and transcriptomic analyses reveal that SIRT6 overexpression dampens PI3K signaling and stem-like characteristics and causes metabolic rearrangements in this cancer model. Ablation of a PI3K activating mutation in otherwise isogenic cancer cells is sufficient to convert SIRT6-sensitive into SIRT6-insensitive cells. SIRT6 overexpression suppresses PI3K signaling at the transcriptional level and antagonizes tumor sphere formation independent of its histone deacetylase activity. Our data identify SIRT6 as a putative molecular target that hinders stemness of tumors with PI3K activation.