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Nathan Goodyear

Association between endogenous sex steroid hormones and inflammatory biomarkers in US men - 0 views

www.ncbi.nlm.nih.gov/...PMC3812341

low Testosterone Estrogen Estradiol low T Testosterone hormone hormones CRP inflammation SHBG WBC men male

shared by Nathan Goodyear on 28 Apr 15 - No Cached
  • modest statistically significant inverse associations for total and calculated free testosterone, and modest positive associations for total and calculated free estradiol with CRP concentration
  • Estradiol concentrations were also weakly positively associated with WBC count
  • SHBG was weakly inversely associated with WBC
  • ...21 more annotations...
  • An association between testosterone and WBC count was not observed
  • These findings are consistent with the hypothesis that in men higher androgen concentration is anti-inflammatory, and higher estrogen concentration is pro-inflammatory.
  • the probability of elevated CRP concentrations (≥ 3 mg/L) decreased with higher total and calculated free testosterone concentrations, while the probability increased with higher total and calculated free estradiol concentrations
  • there is ample evidence supporting the immunosuppressive effect of androgens
  • The incidence of autoimmune diseases is higher in androgen-deficient men
  • Studies have shown that the induction of hypogonadism in older men is followed by a significant increase in IL-6 concentrations (Khosla et al. 2002), a potent stimulator of inflammation, and that activation of the androgen receptor exerts a direct anti-inflammatory effect
  • It has been suggested that the mechanisms for the immunosuppressive effect of androgens could be either a direct effect on the expression of inflammatory genes (Bellido et al. 1995; Asirvatham et al. 2006), or an indirect effect through inhibition of nuclear factor-kB activation
  • Estradiol is the major biologically active estrogen, and about 80% is formed in adult men from the aromatization of testosterone primarily in the adipose tissue
  • estrogen can stimulate the transcription factor C/EBP-β, which is involved in CRP transcription
  • Most prior cross-sectional studies have observed inverse associations between androgen concentrations and inflammatory biomarkers
  • A recent study in Chinese men showed that lower concentrations of total and calculated free testosterone were associated with higher CRP concentration
  • Data from the Boston Area Community Health Survey also reported inverse associations between testosterone and CRP concentrations
  • Total testosterone was inversely associated with WBC count (Tang et al. 2007; Schneider et al. 2009; Brand et al. 2012), but calculated free testosterone was not associated with WBC
  • The first trial found a decrease in CRP, interleukin-1β (IL-1β), and tumor necrosis factor-α (TNFα) but no changes in IL-6 and IL-10 concentrations between the active treatment and placebo arms
  • the majority of studies in the literature have not observed statistically significant associations between estradiol and inflammatory biomarkers in men, although several of them observed point estimates in the positive direction
  • total testosterone and estradiol compete for binding to SHBG, and seem to have opposite effects on the concentration of inflammatory biomarkers
  • A small randomized controlled trial of estrogen replacement therapy in prostate cancer patients showed an increase in CRP in the active treatment group versus the comparator group
  • Obese men are known to have lower androgen concentrations compared to their normal-weight counterparts
  • The strongest suggestion of an interaction was the inverse association between androstanediol glucuronide and CRP concentrations in obese participants, while the association was positive in the non-obese
  • A recent Chinese cross-sectional study observed stronger inverse associations between total testosterone and CRP concentrations in individuals with a BMI of 27.5 kg/m2 or greater
  • our results suggest that total and calculated free testosterone are modestly inversely associated with CRP concentrations, and that total and calculated free estradiol are modestly positively associated with CRP and WBC
  • Nathan Goodyear on 28 Apr 15
     
    Study results suggest that higher Testosterone and lower Estrogen levels provide anti-inflammatory effects in men.  The inflammatory biomarker assessed here was CRP.  Low total and calculated free Testosterone was associated with an increase in CRP.  In contrast, total and free Estrogen was associated with an increase in CRP.  Estradiol increased WBC count and SHBG was inversely related to WBC count in this study.
Nathan Goodyear

Small Differences in Thyroid Function May Be Important for Body Mass Index and the Occurrence of Obesity in the Population -- Knudsen et al. 90 (7): 4019 -- Journal of Clinical Endocrinology & Metabolism - 0 views

jcem.endojournals.org/...4019

TSH thyroid weight obesity BMI

shared by Nathan Goodyear on 02 Feb 11 - No Cached
  • Nathan Goodyear on 02 Feb 11
     
    TSH doesn't have to be above normal for your weight to be negatively affected
Nathan Goodyear

Associations of body mass index with meniscal tears - 0 views

www.ajpm-online.net/...abstract

weight BMI sports injuries obesity

shared by Nathan Goodyear on 07 Mar 11 - No Cached
  • Nathan Goodyear on 07 Mar 11
     
    weight related to sports injuries
Nathan Goodyear

Prevalence of cardiovascular disease risk factors ... [JAMA. 2009] - PubMed result - 0 views

www.ncbi.nlm.nih.gov/...19470988

cardiovascular prevalence disease NFL players

shared by Nathan Goodyear on 14 May 11 - No Cached
  • NFL players had a lower prevalence of impaired fasting glucose, less reported smoking, a similar prevalence of dyslipidemia, and a higher prevalence of hypertension. Increased size measured by BMI was associated with increased CVD risk factors in this combined population.
  • Nathan Goodyear on 14 May 11
     
    higher disease risk in NFL players
Nathan Goodyear

ENDOGENOUS SEX HORMONES, BLOOD PRESSURE CHANGE, AND RISK OF HYPERTENSION IN POSTMENOPAUSAL WOMEN: THE MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS - 0 views

www.ncbi.nlm.nih.gov/...PMC3428144

hormone hormones Testosterone Estradiol Estrogen women CVD cardiovascular disease female SHBG hypertension post-menopause blood pressure

shared by Nathan Goodyear on 02 Feb 15 - No Cached
  • Among postmenopausal women, serum T was elevated in hypertensive participants [9, 11, 12], and total T, free T, and DHEA were positively correlated with SBP
  • T and DHEA were attenuated by adjustment for BMI, reflecting either a confounding or a mediating effect of obesity
  • SHBG concentration was inversely associated with risk of hypertension and longitudinal rise of BP over time
  • ...8 more annotations...
  • SHBG has been postulated as a marker for insulin resistance
  • In vitro studies showed that insulin inhibits SHBG production from hepatoma cells
  • In intervention studies, successful weight loss and weight maintenance increased SHBG in men with obesity
  • E2 may also induce insulin resistance and thereafter tend to raise BP.
  • strong association between E2 and measures of insulin resistance in postmenopausal women, independent of adiposity
  • In postmenopausal women that received hormone replacement therapy, estrogen therapy increased mononuclear cell secretion of tumor necrosis factor alpha (TNF-α)
  • estrone levels were positively associated with inflammatory markers in postmenopausal women
  • higher baseline concentrations of endogenous E2, total and bioavailable T, and DHEA and lower concentration of SHBG were associated with a higher incidence of hypertension and a greater increase in BP during follow-up
  • Nathan Goodyear on 02 Feb 15
     
    Data from MESA study finds that increasing endogenous Estradiol, Total and free Testosterone, DHEA, and lower SHBG were associated with hypertension in postmenopausal women.
Nathan Goodyear

Testosterone and metabolic syndrome Cunningham GR - Asian J Androl - 0 views

www.ajandrology.com/article.asp

Testosterone metabolic syndrome MetS TT total Testosterone SHBG men male hormone hormones Estradiol insulin resistance

shared by Nathan Goodyear on 02 Mar 15 - No Cached
  • The relationship of low testosterone to MetS often is considered to be bidirectional; however, the relationships probably are not direct
  • Many of the components of the MetS are recognized risk factors for the development of cardiovascular disease (CVD)
  • Multiple cross-sectional studies have found low TT and low sex hormone binding globulin (SHBG) levels in Caucasian and African-American men with the MetS, irrespective of age
  • ...20 more annotations...
  • Low TT and SHBG levels also are prevalent in Chinese [7],[8] and Korean [9] men with the MetS
  • Normally 40%-50% of TT is bound to SHBG, so reducing SHBG levels will decrease TT.
  • Hyperinsulinism suppresses SHBG synthesis and secretion by the liver
  • significant increase in SHBG levels occurred after acutely lowering insulin levels in obese men
  • Estradiol levels are increased in men with the MetS, and they are positively correlated with the number of abnormal components of the MetS.
  • Although it is known that estrogen will increase SHBG levels, apparently the hyperinsulinism associated with obesity has a greater effect on SHBG levels
  • Estradiol also can inhibit luteinizing hormone (LH) secretion
  • Inflammatory cytokines are thought to have a direct effect on the pituitary to reduce LH secretion [15] and also a direct effect on Leydig cell secretion of testosterone
  • Low TT Levels have been shown to predict development of the MetS in men with normal BMI
  • Men in the lowest quartiles of serum TT, calculated free testosterone (cFT) and SHBG at baseline had the highest odds ratios for developing the MetS or DM during the 11 years follow-up
  • More recently, investigators conducting population-based studies have reported that only SHBG is associated with future development of the MetS
  • Additional evidence that low TT increases the risk of MetS comes from androgen deprivation treatment of prostate cancer
  • Low TT and low bioavailable testosterone (bT) were each significantly associated with elevated 20 years risk of CVD mortality in an older population in which cause-specific mortality was age, adiposity, and lifestyle-adjusted.
  • combination of low bT and ATP III-defined MetS is associated with increased cardiovascular mortality in men aged 40 years and above
  • in elderly men, testosterone may weakly protect against CVD. Alternatively, low TT may indicate poor general health
  • Muraleedharan and Jones [27] concluded that there is convincing evidence that low T is a biomarker for disease severity and mortality.
  • The evidence that TRT improves insulin sensitivity and glucose control is conflicted
  • It is widely recognized that testosterone treatment can reduce fat mass and increase lean body mass; however, until recently most reports have not been associated with much weight loss
  • Changes in body composition and weight loss are considered potential mechanisms by which testosterone treatment improves insulin sensitivity and glucose control in patients with diabetes. Effects on inflammatory cytokines [38] and changes in oxidative metabolism [39] also have been reported to improve glucose metabolism.
  • Testosterone replacement therapy has been reported to improve some or all of the components of the MetS.
  • Nathan Goodyear on 02 Mar 15
     
    To be read article on Testosterone and Metabolic Syndrome.
Nathan Goodyear

Estradiol and Metabolic Syndrome in Older Italian Men: the InCHIANTI Study - 0 views

www.ncbi.nlm.nih.gov/...PMC2842460

Men hormone hormones estradiol estrogen metabolic syndrome MetS InCHIANTI study

shared by Nathan Goodyear on 30 Apr 13 - No Cached
  • Nathan Goodyear on 30 Apr 13
     
    Men with metabolic syndrome found to be associated with higher Estradiol levels.  Thus, Estradiol in "older men", >65 in this study, is associated with metabolic syndrome.
Nathan Goodyear

Menopausal Complaints Are Associated With Cardiovascular Risk Factors - 0 views

hyper.ahajournals.org/...1492.full

cardiovascular disease CVD heart health hot flashes night sweats vasomotor symptoms women female menopausal symptoms

shared by Nathan Goodyear on 11 Mar 15 - No Cached
  • women with complaints of flushing or night sweats have an unfavorable cardiovascular risk profile compared with women without vasomotor complaints and with increased cholesterol levels, systolic and diastolic blood pressures, and BMI.
  • Nathan Goodyear on 11 Mar 15
     
    Women with hot flashes and night sweats have increased cardiovascular risk compared to women that do not.
Nathan Goodyear

Testosterone and benign prostatic hyperplasia Jarvis TR, Chughtai B, Kaplan SA, - Asian J Androl - 0 views

www.ajandrology.com/preprintarticle.asp

Testosterone BPH low T low Testosterone prostate cancer men male hormone hormones

shared by Nathan Goodyear on 01 Dec 14 - No Cached
  • The prevalence of hypogonadism (often defined as serum testosterone < 300 ng dl−1 ) ranges from 6% [10] to as high as 38%
  • The process of BPH, however, continues as men age and despite the fact their serum testosterone decreases
  • Liu et al. [12] demonstrated that in a group of older males (mean age 59.8 years) that there was not a significant correlation of serum testosterone levels (total, free or bioavailable) with either prostate volume or International Prostate Symptom Score (IPSS)
  • ...11 more annotations...
  • in eugonadal men, studies have demonstrated that the prostate can increase in volume by approximately 12%
  • There seems to be little doubt that the treatment with testosterone of a young hypogonadal male leads to significant growth of the prostate
  • Behre et al. [22] demonstrated increased prostate volume and prostate-specific antigen (PSA) levels in hypogonadal men
  • Most studies, however, have shown no effect of exogenous androgens on PSA or prostate volume for older hypogonadal males
  • saturation model
  • They argue that the prostate is relatively insensitive to changes in androgen concentration at normal levels or in mild hypogonadism because the AR is saturated by androgens and therefore maximal androgen-AR binding is achieved. Conversely, the prostate is very sensitive to changes in androgen levels when testosterone is low
  • visceral obesity (one of the most significant components of metabolic syndrome) is associated with prostate volume and influences prostate growth during TRT.
  • This hypothesis of inflammation induced LUTS is also argued to be a mechanism for improvement of LUTS with PDE5I
  • The concept, therefore, that treatment with TRT of hypogonadal males with metabolic syndrome might lead to improvement/stabilization of their LUTS, appears to be confirmed in recent work by Francomano et al.
  • There was also an improvement in components of the patient's metabolic syndrome (such as BMI, waist circumference, hemoglobin A1c [HbA1c], insulin sensitivity, and lipid profile) as well as inflammatory markers and C-reactive protein.
  • They concluded that TRT was safe in this group of men, and hypothesize that TRT mitigates the pro-inflammatory factors associated with metabolic syndrome.
  • Nathan Goodyear on 01 Dec 14
     
    Authors review the literature behind Testosterone and BPH.  The authors highlight the 4 proposed theories behind BPH: Testosterone, Estrogen, inflammation, and metabolic.   The conclusion is mixed: pointing out that no high level of evidence exists on either side of the debate of Testosterone and BPH.
Nathan Goodyear

Testosterone levels improve in obese men following a common weight-loss operation: Sleeve gastrectomy procedure is beneficial in lowering BMI, raising testosterone levels in obese men, leading to other health benefits -- ScienceDaily - 0 views

www.sciencedaily.com/...151005151204.htm

low Testosterone low T Testosterone men hormones bariatric surgery

shared by Nathan Goodyear on 11 Nov 15 - No Cached
  • Nathan Goodyear on 11 Nov 15
     
    The ignorance of this authors statements is unmeasurable.  Numerous other studies have shown weight loss in men with obesity is associated with increased Testosterone production.  My book highlights the mechanism by which adipose tissue decreased Testosterone production.  The author was quoted as pointed to no Testosterone replacement (even if levels are low????) despite the evidence that Testosterone will improve glucose metabolism, build muscle (reverse sarcopenia obesity), improve cholesterol metabolism,  and significantly aid Diabetes control just to name a few; yet the author says, give surgery instead.  I am sure the author is a surgeon and thus bias might, just might, be present.
Nathan Goodyear

International Journal of Obesity - Identification of skeletal muscle mass depletion across age and BMI groups in health and disease[mdash]there is need for a unified definition - 0 views

www.nature.com/...ijo2014161a.html

Muscle mass fat free mass lead dry mass fat obesity body composition muscle muscle loss sarcopenic obesity sarcopenia

shared by Nathan Goodyear on 18 Nov 15 - No Cached
  • Nathan Goodyear on 18 Nov 15
     
    good article to review the components of body composition.
Nathan Goodyear

Nutrients | Free Full-Text | Vitamin C Status Correlates with Markers of Metabolic and Cognitive Health in 50-Year-Olds: Findings of the CHALICE Cohort Study | HTML - 0 views

www.mdpi.com/...htm

vitamin C health cognition

shared by Nathan Goodyear on 28 Feb 18 - No Cached
  • vitamin C deficiency is the fourth most prevalent nutrient deficiency reported in the United States
  • Hypovitaminosis C (defined as a plasma concentration ≤23 µmol/L)
  • The CHALICE (Canterbury Health, Ageing and Lifecourse) study is a unique New Zealand study comprising a comprehensive database of determinants of health
  • ...17 more annotations...
  • The CHALICE cohort of 404 individuals aged 50 years had an average vitamin C intake of ~110 mg/day, which should provide adequate plasma concentrations [14]. Despite this, a significant proportion of the participants had inadequate plasma vitamin C status
  • inadequate plasma vitamin C concentrations (i.e., <50 µmol/L)
  • adequate plasma levels (i.e., >50 µmol/L)
  • Higher plasma vitamin C status was associated with lower weight, BMI and waist circumference
  • plasma vitamin C was negatively associated with blood triglycerides, HbA1c and insulin, and positively associated with HDL levels.
  • No correlation was found between plasma vitamin C and the two indicators of heart health; blood pressure and cardiovascular risk score.
  • 2.4% of 50-year-olds were deficient in vitamin C (i.e., <11 µmol/L)
  • hypovitaminosis C (i.e., <23 µmol/L)
  • A high proportion (63%) of our participants had inadequate plasma vitamin C concentrations (i.e., <50 µmol/L)
  • The association of low vitamin C with obesity in this study replicates results in the literature [35,40,41,42,43,44], and it is apparent that individuals with higher weight require higher intakes of vitamin C to reach adequate vitamin C status
  • higher plasma vitamin C status is associated with lower circulating levels of blood triglycerides, insulin and HbA1c
  • A role for vitamin C in the prevention or management of diabetes and/or metabolic syndrome has been suggested
  • In this study, we also demonstrate lower levels of mild cognitive impairment in those with high vitamin C status
  • The odds of mild cognitive impairment were twice as high for those below 23 μmol/L plasma vitamin C concentration.
  • Vitamin C is present at very high concentrations in the brain
  • animal models have shown that the brain is the last organ to be depleted of the vitamin during prolonged deficiency
  • A recent animal study has shown that moderate vitamin C deficiency may play a role in accelerating amyloid plaque accumulation in Alzheimer’s disease
  • Nathan Goodyear on 28 Feb 18
     
    New study: vitamin C levels correlate with cognitive and metabolic health. What is your vitamin C level? Despite the adequate levels of vitamin C intake, a large % of the individuals had inadequate vitamin C levels which points to a demand issue.  Higher oxidative stress, chronic inflammation... would drive demand for vitamin C higher. Lower vitamin C levels were associated with more metabolic disease, ie. DM, and more cognitive decline.
Nathan Goodyear

Thyroid disorders and polycystic ovary syndrome: An emerging relationship - 0 views

www.ncbi.nlm.nih.gov/...PMC4287775

PCOS polycystic ovarian syndrome thyroid hypothryoidism obesity BMI insulin resistance IR leptin inflammation

shared by Nathan Goodyear on 13 Sep 17 - No Cached
  • Nathan Goodyear on 13 Sep 17
     
    good read on the association and common finding of hypothyroid and PCOS--no causation link.
Nathan Goodyear

Induction of metastasis, cancer stem cell phenotype, and oncogenic metabolism in cancer cells by ionizing radiation - 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
  • More than half of cancer patients are treated with IR at some point during their treatment
  • fractionation schedule is the delivery of 1.8–2.0 Gy per day, five days per week
  • Nuclear DNA is the primary target of IR; it causes DNA damage (genotoxic stress) by direct DNA ionization
  • ...121 more annotations...
  • IR also indirectly induces DNA damage by stimulating reactive oxygen species (ROS) production
  • IR is known to induce EMT in vitro
  • p53 is activated in response to IR-induced DNA damage
  • IR paradoxically also promotes tumour recurrence and metastasis
  • DNA double-strand breaks (DSBs)
  • cancer cells undergoing EMT acquire invasive and metastatic properties
  • changes in the tumour microenvironment (TME)
  • IR seems to induce EMT and CSC phenotypes by regulating cellular metabolism
  • 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
  • IR is known to induce stemness and metabolic alterations in cancer cells
  • 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
  • Loss of E-cadherin is considered a hallmark of EMT
  • 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
  • ROS are known to play an important role in IR-induced EMT
  • 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
  • hypoxia-inducible factor-1 (HIF-1) is involved in IR-induced EMT
  • Treatment with the N-acetylcysteine (NAC), a general ROS scavenger, prevents IR-induced EMT, adhesive affinity, and invasion of breast cancer cells
    • Nathan Goodyear
      Nathan Goodyear on 09 Feb 21
       
      NAC for all patients receiving radiation therapy
  • Snail has been shown to play a crucial role in IR-induced EMT, migration, and invasion
  • IR activates the p38 MAPK pathway, which contributes to the induction of Snail expression to promote EMT and invasion
  • NF-κB signalling that promotes cell migration
  • ROS promote EMT to allow cancer cells to avoid hostile environments
  • 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 induces vascular damage that causes hypoxia
  • ROS is implicated in IR-induced 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
  • TGF-β signalling has been shown to play a crucial role in IR-induced EMT
  • AP-1 transcription factor is involved in IR-induced TGF-β1 expression
  • Wnt/β-catenin signalling is also implicated in IR-induced EMT
  • Notch signalling is known to be involved in IR-induced EMT
  • IR also increases Notch-1 expression [99]. Notch-1 is known to induce EMT by upregulating Snail
  • 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
  • ROS and RNS are also implicated in IR-induced EGFR activation
  • IR has also been shown to activate Hedgehog (Hh) signalling to induce EMT
  • 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
  • Transcription factors, including Oct4, Sox2, Nanog, c-Myc, and Klf4,
  • signalling pathways, including those of TGF-β, Wnt, Hedgehog, Notch, platelet-derived growth factor receptor (PDGFR), and JAK/STAT
  • microRNAs (miRNAs), including let-7, miR-22, miR-34a, miR-128, the miR-200 family, and miR-451
  • Non-CSCs can be reprogrammed to become CSCs by epigenetic and genetic changes
  • 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
  • some CSC subpopulations arise independently of EMT
  • 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
  • IR has been shown to induce reprogramming of differentiated cancer cells into CSCs
  • 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
  • metabolic reprogramming
  • HIF-1α, p53, and c-Myc, are known to contribute to oncogenic metabolism
  • metabolic reprogramming
  • tumour cells exhibit high mitochondrial metabolism as well as aerobic glycolysis
  • occurring within the same tumour
  • CSCs can be highly glycolytic-dependent or oxidative phosphorylation (OXPHOS)-dependen
  • mitochondrial function is crucial for maintaining CSC functionality
  • cancer cells depend on mitochondrial metabolism and increase mitochondrial production of ROS that cause pseudo-hypoxia
  • HIF-1 then enhances glycolysis
  • 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
  • lactate transporter, monocarboxylate transporter (MCT)
  • nutrient microenvironment
  • 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
  • HIF-1α, p53, and c-Myc, are known to contribute to oncogenic metabolism
  • 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
  • STAT3 has been implicated in EMT-induced metabolic changes as well
  • TGF-β and Wnt play important roles in the metabolic alteration of cancer cells
  • Akt is also implicated in the glycolytic switch and in promoting cancer cell invasiveness
  • EMT, invasion, metastasis, and stemness
  • pyruvate kinase M2 (PKM2), LDH, and pyruvate carboxylase (PC), are implicated in the induction of the EMT and CSC phenotypes
  • decreased activity of PKM2 is known to promote an overall shift in metabolism to aerobic glycolysis
  • LDH catalyses the bidirectional conversion of lactate to pyruvate
  • High levels of LDHA are positively correlated with the expression of EMT and CSC markers
  • IR has been shown to induce metabolic changes in cancer cells
  • 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 can activate latent TGF-
  • 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)
  • intrinsic immunogenicity or induce tolerance
  • cancer immunoediting’
  • three phases: 1) elimination, 2) equilibrium, and 3) escape.
  • 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
    • Nathan Goodyear
      Nathan Goodyear on 09 Feb 21
       
      And now the receipts
  • MMPs degrade ECM that facilitates angiogenesis, tumour cell invasion, and metastasis
    • Nathan Goodyear
      Nathan Goodyear on 09 Feb 21
       
      Receipts and mechanisms
  • IR also promotes MMP-2/9 activation in cancer cells to promote EMT, invasion, and metastasis
  • IR-induced Snail increases MMP-2 expression to promote EMT
  • Radiotherapy has the paradoxical side-effect of increasing tumour aggressiveness
  • 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
  • Metabolic alterations
  • oncogenic metabolism
  • elicit various changes in the TME
  • Although IR activates an antitumour immune response, this signalling is frequently suppressed by tumour escape mechanisms
  • Nathan Goodyear on 09 Feb 21
     
    Important review article.
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