COMPARISON OF BLOOD SPOT, SALIVARY AND SERUM PROGESTERONE ASSAYS IN THE NORMAL MENSTRUAL CYCLE
1More
Tricycle Manufacturers - 0 views
www.wheelchairindia.com/...TRICYCLE
Comfortable Ergonomics For Wheelchair Users lightweight frames and seats Tricycle Manufacturers increase strength and coordination durability and safety Karman Ergonomic Wheelchair upper body strength
shared by wheelchairindia9 on 13 May 15
- No Cached
-
Tricycles make cycling accessible to all, whatever personal challenges. There are a wide range of disability cycles that suit people with a variety of learning and physical disabilities, as well as health issues. Tricycles have 3 wheels, which means that the rider does not need to be able to balance. This is particularly useful for people with learning disabilities, such as Dyspraxia, and those recovering from illnesses. Tricycles can be fitted with foot plates to make it easier for riders to rotate the pedals and they come in upright or recumbent (horizontal sitting position). For adults and children with balance issues, stabilisers can also be fitted to standard bikes, which makes them more like tricycles. Tricycles come in a variety of accessible styles for people of all abilities including many persons with spinal cord injury disabilities. Tricycles is a great upper body workout and can provide a great sense of freedom for persons with disabilities. While the high cost prevents many from enjoying Tricycles they are steadily growing in popularity. Tricycle Deluxe Double Hand Drive: Frame : Made by E.R.W. Tubes 38.0 mm-16 G. 25.4 mm & 22.22 mm- 18 G. Seat & Back: M S, C.R.C. Sheet. Seat Size 18"x 16" Wheel Size: Wheel Diameter 24"x 1 1/2" Tyre and Tube Standard Company. Parts: Standard Quality. Color: Black Painted. Brake: Front Wheel liver System Drive: Rear Wheel Right Side. Hand powered cycles work along the same principle as standard cycles. The pedals are replaced with handles that also steer, and riders use their arms to push the handles around to drive the chain and wheels. Most hand cycles have 3 wheels, although some have 4 wheels. 4-wheel cycles may have power assistance instead of the rider turning handles,or they may be built for going down hill, in which case gravity powers the bike. As with tricycles, hand cycles can have upright seats or low down recumbent seats. Specialist 'clip on' cycles are also available that can be attached
1More
Tricycle For Disabled Children - 0 views
www.wheelchairindia.com/...Handicapped-Child-Tricycle
Tricycle For Adults And Children With Special Needs shape of a conventional bicycle leg calibers various seating and bar adjustment reduced power height adjustable backrests control poles steering restrictors
shared by wheelchairindia9 on 17 Apr 15
- No Cached
-
The tricycles are individually designed to meet the needs of each disabled child and help provide physiotherapy, build muscle tone and promote play. Italso help benefit growth and development in children with disabilities, enabling them to keep active and retain their independence. Disabled children get huge physical and emotional benefits from having the specially tricycles, which are each custom made to suit the individual child's needs. Riding a tricycle provides both fun and fitness, and is a therapeutic activity that allows children to exercise their lower extremities. As the muscles move through cycling motions, they are flexed, extended and stretched. This range of motion is crucial for children with disabilities, because muscles are incapable of keeping up with bone growth unless fully extended. Tricycles are provided to severely disabled children and adults and come in two sizes, 20 inch and 24 inch models. These trikes are grant funded and to qualify for one of these, an individual must suffer from a condition such as, but not limited to, Cerebral Palsy, Down Syndrome, Traumatic Brain Injury or Autism. Trunk support system is ideal for riders who have trouble remaining upright while seated. An optional headrest is available. A headrest can be purchased with either a flat or contoured headpiece, and adjusts both horizontally and vertically for optimum positioning. The Front Pulley System maintains a level pedal position for children whose extreme tone forces the front of the pedal downward. Turn the oval knob to raise and lower the handlebar. A handbrake for the conventional handlebar will arrive installed on Large tricycle. Open access combined with a low transfer step makes it easy to get on and off trikes. Tricycle Deluxe Double Hand Drive: Frame : Made by E.R.W. Tubes 38.0 mm-16 G. 25.4 mm & 22.22 mm- 18 G. Seat & Back : M S, C.R.C. Sheet. Seat Size 18"x 16" Wheel Size : Wheel Diameter 24"x 1 1/2" Tyre and Tube Standard Company. Pa
1More
Estrogen receptor related beta is expressed in human endometrium throughout the normal ... - 0 views
humrep.oxfordjournals.org/...2782.full
ER-alpha ER-beta estrogen receptor estrogen receptors estrogen receptor alpha estrogen receptor beta estrogen receptor alpha beta endometrium menstrual cycle human
shared by Nathan Goodyear on 07 Dec 12
- No Cached
-
ER-beta found throughout both the proliferative and secretory phases of the menstrual cycle. ER-beta expression was higher in the proliferative versus the secretory phases, though not statistically significant. This makes since as estrogen stimulation dominates the proliferative phase. Additionally, ER-beta expression was found throughout all levels of the endometrium and the myometrium.
1More
Presence of Estrogen Receptor β in the Human Endometrium through the Cycle: E... - 0 views
jcem.endojournals.org/...1379.long
ER-alpha ER-beta estrogen receptor alpha estrogen receptor beta estrogen receptor alpha beta endometrium menstrual cycle
shared by Nathan Goodyear on 07 Dec 12
- No Cached
1More
Estrogen receptor related beta is expressed in human endometrium throughout the normal ... - 0 views
1More
Fluctuation of Peripheral Blood T, B, and NK Cells during a Menstrual Cycle of Normal H... - 0 views
www.jimmunol.org/...756.full
NK cells menstrual cycle women pregnancy fertility progesterone estrogen
shared by Nathan Goodyear on 20 Apr 12
- No Cached
1More
A Randomized Pilot Study of Monthly Cycled Testosterone Replacement or Continuous Testo... - 0 views
1More
Does experimental pain response vary across the menstrual cycle? A methodological revie... - 0 views
3More
COMPARISON OF BLOOD SPOT, SALIVARY AND SERUM PROGESTERONE ASSAYS IN THE NORMAL MENSTRUA... - 0 views
-
We conclude that blood spot and saliva Po levels both correlate well with Po levels in serum, but that blood spot Po levels are more reliable.
91More
Press-pulse: a novel therapeutic strategy for the metabolic management of cancer | Nutr... - 0 views
nutritionandmetabolism.biomedcentral.com/...s12986-017-0178-2
ketogenic diet ketogenic press-pulse hyperbaric oxygen therapy HBOTnutrition diet cancer HBOT IVC IV vitamin C DCA dichloracetic acid cancer therapy cancer treatment alternative cancer treatment
shared by Nathan Goodyear on 09 Jul 17
- No Cached
mamdouh_hfz liked it
-
A “press” disturbance was considered a chronic environmental stress on all organisms in an ecological community
-
“pulse” disturbances were considered acute events that disrupted biological communities to produce high mortality
- ...84 more annotations...
-
Data from the American Cancer Society show that the rate of increase in cancer deaths/year (3.4%) was two-fold greater than the rate of increase in new cases/year (1.7%) from 2013 to 2017
-
glucose is first split into two molecules of pyruvate through the Embden–Meyerhof–Parnas glycolytic pathway in the cytosol
-
Aerobic fermentation, on the other hand, involves the production of lactic acid under normoxic conditions
-
persistent lactic acid production in the presence of adequate oxygen is indicative of abnormal respiration
-
The Crabtree effect is an artifact of the in vitro environment and involves the glucose-induced suppression of respiration with a corresponding elevation of lactic acid production even under hyperoxic (pO2 = 120–160 mmHg) conditions associated with cell culture
-
the Warburg theory of insufficient aerobic respiration remains as the most credible explanation for the origin of tumor cells [2, 37, 51, 52, 53, 54, 55, 56, 57].
-
The main points of Warburg’s theory are; 1) insufficient respiration is the predisposing initiator of tumorigenesis and ultimately cancer, 2) energy through glycolysis gradually compensates for insufficient energy through respiration, 3) cancer cells continue to produce lactic acid in the presence of oxygen, and 4) respiratory insufficiency eventually becomes irreversible
-
Efraim Racker coined the term “Warburg effect”, which refers to the aerobic glycolysis that occurs in cancer cells
-
Warburg clearly demonstrated that aerobic fermentation (aerobic glycolysis) is an effect, and not the cause, of insufficient respiration
-
all tumor cells that have been examined to date contain abnormalities in the content or composition of cardiolipin
-
The evidence supporting Warburg’s original theory comes from a broad range of cancers and is now overwhelming
-
respiratory insufficiency, arising from any number mitochondrial defects, can contribute to the fermentation metabolism seen in tumor cells.
-
data from the nuclear and mitochondrial transfer experiments suggest that oncogene changes are effects, rather than causes, of tumorigenesis
-
Normal mitochondria can suppress tumorigenesis, whereas abnormal mitochondria can enhance tumorigenesis
-
Glutamine is anapleurotic and can be rapidly metabolized to glutamate and then to α-ketoglutarate for entry into the TCA cycle
-
Amino acid fermentation can generate energy through TCA cycle substrate level phosphorylation under hypoxic conditions
-
Although Warburg’s hypothesis on the origin of cancer has created confusion and controversy [37, 38, 39, 40], his hypothesis has never been disproved
-
Warburg referred to the phenomenon of enhanced glycolysis in cancer cells as “aerobic fermentation” to highlight the abnormal production of lactic acid in the presence of oxygen
-
Emerging evidence indicates that macrophages, or their fusion hybridization with neoplastic stem cells, are the origin of metastatic cancer cells
-
Radiation therapy can enhance fusion hybridization that could increase risk for invasive and metastatic tumor cells
-
Kamphorst et al. in showing that pancreatic ductal adenocarcinoma cells could obtain glutamine under nutrient poor conditions through lysosomal digestion of extracellular proteins
-
It will therefore become necessary to also target lysosomal digestion, under reduced glucose and glutamine conditions, to effectively manage those invasive and metastatic cancers that express cannibalism and phagocytosis.
-
Previous studies in yeast and mammalian cells show that disruption of aerobic respiration can cause mutations (loss of heterozygosity, chromosome instability, and epigenetic modifications etc.) in the nuclear genome
-
The somatic mutations and genomic instability seen in tumor cells thus arise from a protracted reliance on fermentation energy metabolism and a disruption of redox balance through excess oxidative stress.
-
According to the mitochondrial metabolic theory of cancer, the large genomic heterogeneity seen in tumor cells arises as a consequence, rather than as a cause, of mitochondrial dysfunction
-
A therapeutic strategy targeting the metabolic abnormality common to most tumor cells should therefore be more effective in managing cancer than would a strategy targeting genetic mutations that vary widely between tumors of the same histological grade and even within the same tumor
-
Tumor cells are more fit than normal cells to survive in the hypoxic niche of the tumor microenvironment
-
Hypoxic adaptation of tumor cells allows for them to avoid apoptosis due to their metabolic reprograming following a gradual loss of respiratory function
-
The high rates of tumor cell glycolysis and glutaminolysis will also make them resistant to apoptosis, ROS, and chemotherapy drugs
-
Despite having high levels of ROS, glutamate-derived from glutamine contributes to glutathione production that can protect tumor cells from ROS
-
It is clear that adaptability to environmental stress is greater in normal cells than in tumor cells, as normal cells can transition from the metabolism of glucose to the metabolism of ketone bodies when glucose becomes limiting
-
Mitochondrial respiratory chain defects will prevent tumor cells from using ketone bodies for energy
-
glycolysis-dependent tumor cells are less adaptable to metabolic stress than are the normal cells. This vulnerability can be exploited for targeting tumor cell energy metabolism
-
In contrast to dietary energy reduction, radiation and toxic drugs can damage the microenvironment and transform normal cells into tumor cells while also creating tumor cells that become highly resistant to drugs and radiation
-
Drug-resistant tumor cells arise in large part from the damage to respiration in bystander pre-cancerous cells
-
Because energy generated through substrate level phosphorylation is greater in tumor cells than in normal cells, tumor cells are more dependent than normal cells on the availability of fermentable fuels (glucose and glutamine)
-
Although some tumor cells might appear to oxidize ketone bodies by the presence of ketolytic enzymes [181], it is not clear if ketone bodies and fats can provide sufficient energy for cell viability in the absence of glucose and glutamine
-
A calorie restricted ketogenic diet or dietary energy reduction creates chronic metabolic stress in the body
-
The KD can more effectively reduce glucose and elevate blood ketone bodies than can CR alone making the KD potentially more therapeutic against tumors than CR
-
Campbell showed that tumor growth in rats is greater under high protein (>20%) than under low protein content (<10%) in the diet
-
Calorie restriction, fasting, and restricted KDs are anti-angiogenic, anti-inflammatory, and pro-apoptotic and thus can target and eliminate tumor cells through multiple mechanisms
-
Ketogenic diets can also spare muscle protein, enhance immunity, and delay cancer cachexia, which is a major problem in managing metastatic cancer
-
The GKI can therefore serve as a biomarker to assess the therapeutic efficacy of various diets in a broad range of cancers.
-
It is important to remember that insulin drives glycolysis through stimulation of the pyruvate dehydrogenase complex
-
The water-soluble ketone bodies (D-β-hydroxybutyrate and acetoacetate) are produced largely in the liver from adipocyte-derived fatty acids and ketogenic dietary fat. Ketone bodies bypass glycolysis and directly enter the mitochondria for metabolism to acetyl-CoA
-
Due to mitochondrial defects, tumor cells cannot exploit the therapeutic benefits of burning ketone bodies as normal cells would
-
Therapeutic ketosis with racemic ketone esters can also make it feasible to safely sustain hypoglycemia for inducing metabolic stress on cancer cells
-
ketone bodies can inhibit histone deacetylases (HDAC) [229]. HDAC inhibitors play a role in targeting the cancer epigenome
-
Therapeutic ketosis reduces circulating inflammatory markers, and ketones directly inhibit the NLRP3 inflammasome, an important pro-inflammatory pathway linked to carcinogenesis and an important target for cancer treatment response
-
Chronic psychological stress is known to promote tumorigenesis through elevations of blood glucose, glucocorticoids, catecholamines, and insulin-like growth factor (IGF-1)
-
In addition to calorie-restricted ketogenic diets, psychological stress management involving exercise, yoga, music etc. also act as press disturbances that can help reduce fatigue, depression, and anxiety in cancer patients and in animal models
-
This physiological state also enhances the efficacy of chemotherapy and radiation therapy, while reducing the side effects
-
lower dosages of chemotherapeutic drugs can be used when administered together with calorie restriction or restricted ketogenic diets (KD-R)
-
Besides 2-DG, a range of other glycolysis inhibitors might also produce similar therapeutic effects when combined with the KD-R including 3-bromopyruvate, oxaloacetate, and lonidamine
-
It is important to recognize, however, that the radiotherapy used in glioma patients can damage the respiration of normal cells and increase availability of glutamine in the microenvironment, which can increase risk of tumor recurrence especially when used together with the steroid drug dexamethasone
-
Poff and colleagues demonstrated that hyperbaric oxygen therapy (HBOT) enhanced the ability of the KD to reduce tumor growth and metastasis
-
The effects of the KD and HBOT can be enhanced with administration of exogenous ketones, which further suppressed tumor growth and metastasis
-
Besides HBOT, intravenous vitamin C and dichloroacetate (DCA) can also be used with the KD to selectively increase oxidative stress in tumor cells
-
Recent evidence also shows that ketone supplementation may enhance or preserve overall physical and mental health
-
Some tumors use glucose as a prime fuel for growth, whereas other tumors use glutamine as a prime fuel [102, 186, 262, 263, 264]. Glutamine-dependent tumors are generally less detectable than glucose-dependent under FDG-PET imaging, but could be detected under glutamine-based PET imaging
-
Many of the current treatments used for cancer management are based on the view that cancer is a genetic disease
-
Emerging evidence indicates that cancer is a mitochondrial metabolic disease that depends on availability of fermentable fuels for tumor cell growth and survival
-
Glucose and glutamine are the most abundant fermentable fuels present in the circulation and in the tumor microenvironment
-
Low-carbohydrate, high fat-ketogenic diets coupled with glycolysis inhibitors will reduce metabolic flux through the glycolytic and pentose phosphate pathways needed for synthesis of ATP, lipids, glutathione, and nucleotides
13More
microRNA Expression in Ethnic Specific Early Stage Breast Cancer: an Integration and Co... - 0 views
-
dysregulated miRNA could be involved in tumor cell proliferation and growth as well as cell cycle progression
-
The upregulated miR-183 in our samples was predicted to be responsible for the decrease in expression of the BTG1 mRNA whose protein is involved in cell cycle arrest and apoptosis in breast cancer cells18.
- ...9 more annotations...
-
nother molecule related to cell proliferation that was over-expressed in our data and suggested as a target of downregulated miR-376c is AURKA
-
the over-expression of miR-183 and miR-21 in Lebanese breast cancer tissues is consistent with downregulation of two important tumor suppressor predicted targets: AKAP12 whose protein regulates cellular adhesion dynamics by controlling cytoskeletal architecture, cell migration, and mitogenic signaling20; and LATS2 whose protein causes cell cycle arrest
-
dysregulation in cancer particularly in breast cancer highlights their importance in tumor development
-
mRNA-miRNA integration analysis of early breast cancer revealed a potential role of miRNA in increasing cellular proliferation and progression, and decreasing invasion and migration
-
most of the miRNA dysregulated in Lebanese breast cancer patients are similar to those dysregulated in American patients, differences in miRNA expression exist and could be attributed either to the patients’ age at diagnosis or to ethnic variation in miRNA epigenetic regulation and sequence variation of pre-miRNA
-
microRNA (miRNA) are small non-coding 18–25 nucleotide RNA molecules currently being studied as potential diagnostic, prognostic and therapeutic biomarkers for cancer and other diseases
-
Extensive research on these post-transcriptional modulators has proven that they are deregulated in breast cancerous tissues and even in biological fluids from breast cancer patients
1More
ScienceDirect.com - The Journal of Steroid Biochemistry and Molecular Biology - Differe... - 0 views
5More
An adaptive response to uncertainty can lead to weight gain during dieting attempts - 0 views
-
dieting attempts cause weight gain via providing (misleading) information about the environment to the subconscious systems that control body mass
-
Our model predicts that energy reserves should respond to repeated attempts to diet by weight cycling and becoming greater from one cycle to the next
-
the very conditions that cause weight gain initially—a glut of food—causes further weight gain once cyclical dieting begins
- ...1 more annotation...
-
There is evidence that among weight cycling, people those who switch between dieting and binge-eating more frequently gain more weight
1More
Omega-3 fatty acids supplementation improves endothelial function and maximal oxygen up... - 0 views
www.tandfonline.com/...17461391.2014.949310
fish oil omega 3 omega-3 n-3 cycling athletes NO endurance sports endurance athletes endurance exercise
shared by Nathan Goodyear on 06 Jul 16
- No Cached
1More
Access : Sulforaphane Inhibits Mitotic Clonal Expansion During Adipogenesis Through Cel... - 0 views
www.nature.com/...oby2011388a.html
sulphoraphane obesity overweight weight-loss PPAR-gamma C_EBP-alpha
shared by Nathan Goodyear on 31 Jan 12
- No Cached
6More
Estrogenic regulation of skeletal muscle proteome: a study of premenopausal women and p... - 0 views
-
Female aging is characterized by menopausal change in sex steroid hormones concomitant to increase in aging-related decrements in skeletal muscle performance that can be attenuated by HRT use
-
The major canonical pathways found to be differentially regulated included mitochondrial dysfunction, oxidative phosphorylation, glycolysis, and TCA-cycle, strong indicators for affected energy metabolism
- ...2 more annotations...
-
After menopause, when ovarian E2 production is ceased, the prevalence of cardio-metabolic diseases increases. Our result that different trajectories of the energy pathways in the skeletal muscle may be regulated by E2 provides candidate molecules as key targets for future interventions to prevent or treat postmenopausal metabolic dysregulation
-
Study finds Estradiol regulates human skeletal muscle cell signaling (mitochondrial function, oxidative phosphorylation, glycolysis, and TCA cycle) in study of pre/post menopause women through proteome analysis. This study would have been complete if they had carried to search beyond that of protein to epigenetics.
1More
Effects of low dose quercetin: Cancer cell-specific inhibition of cell cycle progression - 0 views
1More
Metabolic profiles characterizing different phenotypes of polycystic ovary syndrome: pl... - 0 views
bmcmedicine.biomedcentral.com/...1741-7015-10-153
PCOS polycystic ovary syndrome glycolysis kreb's cycle TCA gluconeogenesis
shared by Nathan Goodyear on 11 Dec 17
- No Cached
128More
Induction of metastasis, cancer stem cell phenotype, and oncogenic metabolism in cancer... - 0 views
www.ncbi.nlm.nih.gov/...PMC5282724
EMT TME metastasis cancer stem cells cancer MMP2 Notch MMP-9 MMP-2 radioresistance Hedgehog CSC MMP9 Snail HIF-1alpha tumor microenvironment epithelial to mesenchymal transition TGF-beta radiation
shared by Nathan Goodyear on 09 Feb 21
- No Cached
-
Nuclear DNA is the primary target of IR; it causes DNA damage (genotoxic stress) by direct DNA ionization
- ...121 more annotations...
-
EMT, stemness, and oncogenic metabolism are known to be associated with resistance to radiotherapy and chemotherapy
-
Hanahan and Weinberg proposed ten hallmarks of cancer that alter cell physiology to enhance malignant growth: 1) sustained proliferation, 2) evasion of growth suppression, 3) cell death resistance, 4) replicative immortality, 5) evasion of immune destruction, 6) tumour-promoting inflammation, 7) activation of invasion and metastasis, 8) induction of angiogenesis, 9) genome instability, and 10) alteration of metabolism
-
EMT is a developmental process that plays critical roles in embryogenesis, wound healing, and organ fibrosis
-
transforming growth factor-β [TGF-β], epidermal growth factor [EGF]) and their associated signalling proteins (Wnt, Notch, Hedgehog, nuclear-factor kappa B [NF-κB], extracellular signal-regulated kinase [ERK], and phosphatidylinositol 3-kinase [PI3K]/Akt
-
activate EMT-inducing transcription factors, including Snail/Slug, ZEB1/δEF1, ZEB2/SIP1, Twist1/2, and E12/E47
-
IR has been shown to induce EMT to enhance the motility and invasiveness of several cancer cells, including those of breast, lung, and liver cancer, and glioma cells
-
IR may increase metastasis in both the primary tumour site and in normal tissues under some circumstance
-
sublethal doses of IR have been shown to enhance the migratory and invasive behaviours of glioma cells
-
High levels of ROS trigger cell death by causing irreversible damage to cellular components such as proteins, nucleic acids, and lipids, whereas low levels of ROS have been shown to promote tumour progression—including tumour growth, invasion, and metastasis
-
Treatment with the N-acetylcysteine (NAC), a general ROS scavenger, prevents IR-induced EMT, adhesive affinity, and invasion of breast cancer cells
-
IR activates the p38 MAPK pathway, which contributes to the induction of Snail expression to promote EMT and invasion
-
HIF-1 is a heterodimer composed of an oxygen-sensitive α subunit and a constitutively expressed β subunit.
-
Under normoxia, HIF-1α is rapidly degraded, whereas hypoxia induces stabilisation and accumulation of HIF-1α
-
levels of HIF-1α mRNA are enhanced by activation of the PI3K/Akt/mammalian target of rapamycin (mTOR)
-
IR is known to increase stabilisation and nuclear accumulation of HIF-1α, since hypoxia is a major condition for HIF-1 activation
-
IR causes the reoxygenation of hypoxic cancer cells to increase ROS production, which leads to the stabilisation and nuclear accumulation of HIF-1
-
IR increases glucose availability under reoxygenated conditions that promote HIF-1α translation by activating the Akt/mTOR pathway
-
The stabilised HIF-1α then translocates to the nucleus, dimerizes with HIF-1β, and increases gene expression— including the expression of essential EMT regulators such as Snail—to induce EMT, migration, and invasion
-
PAI-1 signalling is also implicated in IR-induced Akt activation that increases Snail levels to induce EMT
-
EGFR activation is known to be associated with IR-induced EMT, cell migration, and invasion by activating two downstream pathways: PI3K/Akt and Raf/MEK/ERK
-
IR has been shown to induce Akt activation through several signalling pathways (EGFR, C-X-C chemokine receptor type 4 [CXCR4]/C-X-C motif chemokine 12 [CXCL12], plasminogen activator inhibitor 1 [PAI-1]) and upstream regulators (Bmi1, PTEN) that promote EMT and invasion
-
CSCs possess a capacity for self-renewal, and they can persistently proliferate to initiate tumours upon serial transplantation, thus enabling them to maintain the whole tumour
-
Conventional cancer treatments kill most cancer cells, but CSCs survive due to their resistance to therapy, eventually leading to tumour relapse and metastasis
-
identification of CSCs, three types of markers are utilised: cell surface molecules, transcription factors, and signalling pathway molecules
-
CSCs express distinct and specific surface markers; commonly used ones are CD24, CD34, CD38, CD44, CD90, CD133, and ALDH
-
signalling pathways, including those of TGF-β, Wnt, Hedgehog, Notch, platelet-derived growth factor receptor (PDGFR), and JAK/STAT
-
EMT-inducing transcription factors, such as Snail, ZEB1, and Twist1, are known to confer CSC properties
-
Signalling pathways involved in EMT, including those of TGF-β, Wnt, and Notch, have been shown to play important roles in inducing the CSC phenotype
-
TGF-β1 not only increases EMT markers (Slug, Twist1, β-catenin, N-cadherin), but also upregulates CSC markers (Oct4, Sox2, Nanog, Klf4) in breast and lung cancer cells
-
IR has been shown to induce the CSC phenotype in many cancers, including breast, lung, and prostate cancers, as well as melanoma
-
Genotoxic stress due to IR or chemotherapy promotes a CSC-like phenotype by increasing ROS production
-
In prostate cancer patients, radiotherapy increases the CD44+ cell population that exhibit CSC properties
-
IR also induces the re-expression of stem cell regulators, such as Sox2, Oct4, Nanog, and Klf4, to promote stemness in cancer cells
-
EMT-inducing transcription factors and signalling pathways, including Snail, STAT3, Notch signalling, the PI3K/Akt pathway, and the MAPK cascade, have been shown to play important roles in IR-induced CSC properties
-
STAT3 directly binds to the Snail promoter and increases Snail transcription, which induces the EMT and CSC phenotypes, in cisplatin-selected resistant cells
-
Other oncogenic metabolic pathways, including glutamine metabolism, the pentose phosphate pathway (PPP), and synthesis of fatty acids and cholesterol, are also enhanced in many cancers
-
cancer cells depend on mitochondrial metabolism and increase mitochondrial production of ROS that cause pseudo-hypoxia
-
CAFs have defective mitochondria that lead to the cells exhibiting the Warburg effect; the cells take up glucose, and then secrete lactate to 'feed' adjacent cancer cells
-
Epithelial cancer cells express MCT1, while CAFs express MCT4. MCT4-positive, hypoxic CAFs secrete lactate by aerobic glycolysis, and MCT1-expressing epithelial cancer cells then uptake and use that lactate as a substrate for the tricarboxylic acid (TCA) cycle
-
MCT4-positive cancer cells depend on glycolysis and then efflux lactate, while MCT1-positive cells uptake lactate and rely on OXPHOS
-
metabolic heterogeneity induces a lactate shuttle between hypoxic/glycolytic cells and oxidative/aerobic tumour cells
-
bulk tumour cells exhibit a glycolytic phenotype, with increased conversion of glucose to lactate (and enhanced lactate efflux through MCT4), CSC subsets depend on oxidative phosphorylation; most of the glucose entering the cells is converted to pyruvate to fuel the TCA cycle and the electron transport chain (ETC), thereby increasing mitochondrial ROS production
-
the major fraction of glucose is directed into the pentose phosphate pathway, to produce redox power through the generation of NADPH and ROS scavengers
-
regulatory molecules involved in EMT and CSCs, including Snail, Dlx-2, HIF-1, STAT3, TGF-β, Wnt, and Akt, are implicated in the metabolic reprogramming of cancer cells
-
HIF-1 induces the expression of glycolytic enzymes, including the glucose transporter GLUT, hexokinase, lactate dehydrogenase (LDH), and MCT, resulting in the glycolytic switch
-
HIF-1 represses the expression of pyruvate dehydrogenase kinase (PDK), which inhibits pyruvate dehydrogenase (PDH), thereby inhibiting mitochondrial activity
-
pyruvate kinase M2 (PKM2), LDH, and pyruvate carboxylase (PC), are implicated in the induction of the EMT and CSC phenotypes
-
IR enhances glycolysis by upregulating GAPDH (a glycolysis enzyme), and it increases lactate production by activating LDHA, which converts pyruvate to lactate
-
IR enhances glycolysis by upregulating GAPDH (a glycolysis enzyme), and it increases lactate production by activating LDHA, which converts pyruvate to lactate
-
IR also elevates MCT1 expression that exports lactate into the extracellular environment, leading to acidification of the tumour microenvironment
-
IR increases intracellular glucose, glucose 6-phosphate, fructose, and products of pyruvate (lactate and alanine), suggesting a role for IR in the upregulation of cytosolic aerobic glycolysis
-
lactate stimulates cell migration and enhances secretion of hyaluronan from CAF that promote tumour metastasis
-
promote tumour survival, growth, invasion, and metastasis; enhance the stiffness of the ECM; contribute to angiogenesis; and induce inflammation by releasing several growth factors and cytokines (TGF-β, VEGF, hepatocyte growth factor [HGF], PDGF, and stromal cell-derived factor 1 [SDF1]), as well as MMP
-
tumours recruit the host tissue’s blood vessel network to perform four mechanisms: angiogenesis (formation of new vessels), vasculogenesis (de novo formation of blood vessels from endothelial precursor cells), co-option, and modification of existing vessels within tissues.
-
immunosuppressive cells such as tumour-associated macrophages (TAM), MDSCs, and regulatory T cells, and the immunosuppressive cytokines, TGF-β and interleukin-10 (IL-10)
-
immunosuppressive cells such as tumour-associated macrophages (TAM), MDSCs, and regulatory T cells, and the immunosuppressive cytokines, TGF-β and interleukin-10 (IL-10)
-
The third phase, tumour escape, is mediated by antigen loss, immunosuppressive cells (TAM, MDSCs, and regulatory T cells), and immunosuppressive cytokines (TGF-β and IL-10).
-
IR can elicit various changes in the TME, such as CAF activity-mediated ECM remodelling and fibrosis, cycling hypoxia, and an inflammatory response
-
IR activates CAFs to promote the release of growth factors and ECM modulators, including TGF-β and MMP
-
TGF-β directly influences tumour cells and CAFs, promotes tumour immune escape, and activates HIF-1 signalling
-
MMPs degrade ECM that facilitates angiogenesis, tumour cell invasion, and metastasis
-
IR promotes ROS production in cancer cells, which may induce the activation of oncogenes and the inactivation of tumour suppressors, which further promote oncogenic metabolism
-
Although IR activates an antitumour immune response, this signalling is frequently suppressed by tumour escape mechanisms