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
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
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
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
we wanted to investigate if other molecular targets and pathways may be used by SARS-CoV-2. We investigated the possibility of the spike 1 S protein and its receptor-binding domain (RBD) to target the epidermal growth factor receptor (EGFR) and its downstream signaling pathway in vitro using the lung cancer cell line (A549 cells). Protein expression and phosphorylation were examined upon cell treatment with the recombinant full spike 1 S protein or RBD. We demonstrate for the first time the activation of EGFR by the Spike 1 protein associated with the phosphorylation of the canonical Extracellular signal-regulated kinase1/2 (ERK1/2) and AKT kinases and an increase in survivin expression controlling the survival pathway.
Cisplatin and 5-FU or CAP (cisplatin, doxorubicin, and cyclophosphamide) regimens can be used for combination chemotherapy
patients with advanced salivary gland malignancy treated with the CAP regimen achieved partial response (PR) or stable disease (SD) rates of 67% (8 out of 12 patients)
Agents commonly given as monotherapy for treating ACC are cisplatin, mitoxantrone, epirubicin, vinorelbine, paclitaxel, and gemcitabine. However, few of these agents have shown efficacy
single agent mitoxantrone or vinorelbine were recommended as reasonable choices
ACC is subdivided into 3 histological groups based on solid components of the tumor including cribriform, tubular, and solid
Cribriform and tubular ACCs usually exhibit a more indolent course, whereas the solid subtype is associated with worse prognosis
ACC consists of two different cell types: inner luminal epithelial cells and outer myoepithelial cells
epithelial cells express c-kit, cox-2 and Bcl-2
myoepithelial cells express EGFR and MYB
a balanced translocation of the v-myb avian myeloblastosis viral oncogene homolog-nuclear factor I/B (MYB-NFIB) is considered to be a signature molecular event of ACC oncogenesis
As a transcription factor, MYB is known to modulate multiple genetic downstream targets involved in oncogenesis, such as cox-2, c-kit, Bcl-2 and BclX
Various signaling cascades are essential for cancer cells to survive and grow. The PI3K/Akt/mTOR pathway is one of them
This pathway regulates cell survival and growth and is upregulated in many cancers
Mutations in genes associated with DNA repair are frequently found in familial cancer syndromes, such as hereditary breast-ovarian cancer syndrome (HBOC), hereditary non-polyposis colorectal cancer (HNPCC, also called Lynch syndrome) and Li-Fraumeni syndrome [30, 31]. These mutations were also reported in non-hereditary cancers
70% of ACC samples (58 of 84) were found to have genetic alterations in the MYB/MYC pathway, indicating that changes in this pathway are crucial in ACC pathogenesis
The second most frequently mutated pathway was involved in chromatin remodeling (epigenetic modification), a pathway that includes multiple histone related proteins, and was altered in 44% of samples
C-kit
VEGF, iNOS and NF-κB were noted to be highly expressed in ACC cells as compared to normal salivary gland cells
members of the SOX family, such as SOX 4 and SOX10, are overexpressed in ACC
FABP7 (Fatty acid binding protein 7) and AQP1 (Aquaporin 1) tend to be overexpressed in ACC cell lines
considerable variability in HER2 overexpression ranging from 0–58% in patients with ACC
the study with cetuximab and concurrent chemoradiation or chemotherapy showed the highest ORR (total 43%, 9.5% CR and 33% PR), but this regimen was only given to the EGFR positive patients
Cancer immunotherapy can be classified into 3 major groups. Active immunization using anti-tumor vaccines to induce and recruit T cells, passive immunization based on monoclonal antibodies, and adoptive cell transfer to expand tumor-reactive autologous T cells ex vivo and then reintroduce these cells into the same individual
LAK cells showed cytotoxicity against ACC cells
cytokine-induced cell apoptosis and the cytotoxic effect of the LAK cells contributed to tumor regression
molecular finding of the MYB-NFIB fusion gene has the greatest potential to target what appears to be a fundamental event in disease pathogenesis
of the approximately 108 cannabinoids produced by C. sativa, Δ9-tetrahydrocannabinol (thc) is the most relevant because of its high potency and abundance in plant preparations
Tetrahydrocannabinol exerts a wide variety of biologic effects by mimicking endogenous substances—the endocannabinoids anandamide3 and 2-arachidonoylglycerol4,5—that engage specific cell-surface cannabinoid receptors
two major cannabinoid-specific receptors—cb1 and cb2
transient receptor potential cation channel subfamily V, member 1
orphan G protein–coupled receptor 55
Most of the effects produced by cannabinoids in the nervous system and in non-neural tissues rely on cb1 receptor activation
the cb2 receptor was initially described to be present in the immune system6, but was more recently shown to also be expressed in cells from other origins
cardiovascular tone, energy metabolism, immunity, and reproduction
cannabinoids are well known to exert palliative effects in cancer patients
best-established use is the inhibition of chemotherapy-induced nausea and vomiting
thc and other cannabinoids exhibit antitumour effects in a wide array of animal models of cancer
cannabinoid receptors and their endogenous ligands are both generally upregulated in tumour tissue compared with non-tumour tissue
cb2 promotes her2 (human epidermal growth factor receptor 2) pro-oncogenic signalling in breast cancer
pharmacologic activation of cannabinoid receptors decreases tumour growth
endocannabinoid signalling can also have a tumour-suppressive role
pharmacologic stimulation of cb receptors is, in most cases, antitumourigenic. Nonetheless, a few reports have proposed a tumour-promoting effect of cannabinoids
most prevalent effect is the induction of cancer cell death by apoptosis and the inhibition of cancer cell proliferation
impair tumour angiogenesis and block invasion and metastasis
thc and other cannabinoids induce the apoptotic death of glioma cells by cb1- and cb2-dependent stimulation
Autophagy is primarily a cytoprotective mechanism, although its activation can also lead to cell death
autophagy is important for cannabinoid antineoplastic activity
autophagy is upstream of apoptosis in the mechanism of cannabinoid-induced cell death
the effect of cannabinoids in hormone- dependent tumours might rely, at least in part, on the ability to interfere with the activation of growth factor receptors
glioma cells), pharmacologic blockade of either cb1 or cb2 prevents cannabinoid-induced cell death with similar efficacy
other types of cancer cells (pancreatic48, breast24, or hepatic43 carcinoma cells, for example), antagonists of cb2 but not of cb1 inhibit cannabinoid antitumour actions
thc promotes cancer cell death in a cb1- or cb2-dependent manner (or both) at lower concentrations
cannabidiol (cbd), a phytocannabinoid with a low affinity for cannabinoid receptors15, and other marijuana-derived cannabinoids57 have also been proposed to promote the apoptotic death of cancer cells acting independently of the cb1 and cb2 receptors
In cancer cells, cannabinoids block the activation of the vascular endothelial growth factor (vegf) pathway, an inducer of angiogenesi
In vascular endothelial cells, cannabinoid receptor activation inhibits proliferation and migration, and induces apoptosis
cb1 or cb2 receptor agonists (or both) reduce the formation of distant tumour masses in animal models of both induced and spontaneous metastasis, and inhibit adhesion, migration, and invasiveness of glioma64, breast65,66, lung67,68, and cervical68 cancer cells in culture
the ceramide/p8–regulated pathway plays a general role in the antitumour activity of cannabinoids targeting cb1 and cb2
cbd, by acting independently of the cb1 and cb2 receptors, produces a remarkable anti-tumour effect—including reduction of invasiveness and metastasis
cannabinoids can also enhance immune system–mediated tumour surveillance in some contexts
ability of thc to reduce inflammation75,76, an effect that might prevent certain types of cancer
recent observations suggest that the combined administration of cannabinoids with other anticancer drugs acts synergistically to reduce tumour growth
combined administration of gemcitabine (the benchmark agent for the treatment of pancreatic cancer) and various cannabinoid agonists synergistically reduced the viability of pancreatic cancer cells
Other reports indicated that anandamide and HU-210 might also enhance the anticancer activity of paclitaxel89 and 5-fluorouracil90 respectively
Combined administration of thc and cbd enhances the anticancer activity of thc and reduces the dose of thc needed to induce its tumour growth-inhibiting activity
Preclinical animal models have yielded data indicating that systemic (oral or intraperitoneal) administration of cannabinoids effectively decreases tumour growth
Combinations of cannabinoids with classical chemotherapeutic drugs such as the alkylating agent temozolomide (the benchmark agent for the management of glioblastoma80,84) have been shown to produce a strong anticancer action in animal models
pharmacologic inhibition of egfr, erk83, or akt enhances the cell-death-promoting action of thc in glioma cultures (unpublished observations by the authors), which suggests that targeting egfr and the akt and erk pathways could enhance the antitumour effect of cannabinoids
Androgen receptors may be associated with bladder cancer progression. This study finds AR up regulates Epidermal growth factor in bladder cancer cells.
We now recognize that human cancers evolve in an environment of metabolic stress. Rapidly proliferating tumor cells deprived of adequate oxygen, nutrients, hormones and growth factors up-regulate pathways that address these deficiencies to overcome hypoxia (HIF), vascular insufficiency (VEGF), growth factor deprivation (EGFR, HER2) and the loss of hormonal support (ER, PR, AR) all to enhance survival and proliferation
RAS, PI3K, TP53 and MYC
The results suggest that breast cancer could be preceded by systemic subclinical disturbances in glucose-insulin homeostasis characterized by mild, likely asymptomatic, IEM-like biochemical changes
The process would include variable periods of hyperinsulinemia with the consequent systemic MYC activation of glycolysis, glutaminolysis, structural lipidogenesis and further exacerbation of hypoglycemia, the result of MYC's known role as an inhibitor of liver gluconeogenesis
The metabolic changes we describe in breast cancer arise in concert with IEM-like changes in oxidative phosphorylation as detected by increased values of the ratio lactate/pyruvate (Supplementary Table 2A, 2B) characteristic of Ox/Phos deficiency [25]. In our study, 76% (70/92) of the European breast cancer patients had lactate/pyruvate ratios values higher than the normal value of 25.8
four-fold higher frequency of cancer (including breast) in patients with energy metabolism disorders
growing recognition that cancer cells differ from their normal counterparts in their use of nutrients, synthesis of biomolecules and generation of energy
glutamine concentrations in the cancer patients were reduced to nearly 1/8 of the levels observed in the normal population
blood concentrations of aspartate (p = 1.7e-67, FDR = 8.3e-67) (Figure (Figure1E)1E) and glutamate (p = 6.4e-96, FDR = 6.2e-95) (Figure (Figure1F)1F) were nearly 10 fold higher than the normal ranges of 0–5 μM/L and 40 μM/L, respectively
glutamine consumption associated with parallel increases in glutamate and aspartate (Figure (Figure1A1A red arrows) is considered a hallmark of MYC-driven “glutaminolysis”
Gln/Glu ratio inversely correlates with i- late stage metabolic syndrome and with ii- increased chance of death
changes in glutamine consumption, reflected by the Gln/Glu ratio could provide a metabolic link between breast cancer initiation and diabetes, reflective of a systemic metabolic reprogramming from glucose to glutamine as the preferred source of precursors for biosynthetic reactions and cellular energy
lower Gln/Glu ratios inversely correlated with insulin resistance and the risk of diabetes
the metabolic dependencies of cancer characterized by excessive glycolysis, glutaminolysis and malignant lipidogenesis, previously considered a consequence of local tumor DNA aberration [23] could, instead, represent a systemic biochemical aberration that predates and very likely promotes tumorigenesis
these metabolic disturbances would be expected to remain extant after therapeutic interventions
accumulation of very long chain acylcarnitines such as C14:1-OH (p = 0.0, FDR = 0.0), C16 (p = 0.0, FDR = 0.0), C18 (p = 0.0, FDR = 0.0) and C18:1 (p = 1.73e-322, FDR = 1.16-321) and lipids containing VLCFA (lysoPC a C28:0) (p = 1.14-e95, FDR = 1.65e-95) in the blood of breast and colon cancer patients
Among the most powerful metabolic equations for MYC-activation is that which links the widely used MYC-driven desaturation marker ratio of SFA/MUFA to the MYC glutaminolysis-associated ratio of (Asp/Gln)
liver dysfunction shares many features with both IEM and cancer suggesting a role for hepatic dysfunction in carcinogenesis
cancer “conscripts” the human genome to meet its needs under conditions of systemic metabolic stress
The switch may also involve down-regulation of endogenous inhibitors of angiogenesis such as endostatin, angiostatin or thrombospondin (reviewed in [5]) and has thus been regarded as the result of tipping the net balance between positive and negative regulators
There is a complex interrelationship between tumor hypoxia and tumor angiogenesis
Environmental stress as a result of low oxygen and proper nutrient deprivation, such as glucose deprivation, are capable of inducing VEGF mRNA stabilization resulting in increased levels of the secreted ligand and angiogenic growth
HIFalpha subunits accumulate in the cytoplasm where they bind HIFbeta to form a heterodimer that subsequently translocates to the nucleus to activate transcription of target genes, including genes important for various processes such as metabolism (glucose transporter (GLUT)-1, hexokinase (HK)-1), cell growth (cyclin (CCN)-D1 [23]) and also angiogenesis, such as erythropoietin, VEGF and PDGF [24] (summarized in Fig. 1)
When oxygen levels are low (hypoxia; red arrow) PHDs cannot hydroxylate HIFalphas thereby allowing them to escape pVHL-mediated degradation. HIFalpha subunits accumulate and bind to their heterodimeric partner, HIFbeta, translocate into the nucleus and activate a cascade of hypoxic signaling first by the transcription of various target genes including microRNAs that are important for tumor promoting pathways
c-Src is also capable of activating HIFs by indirectly inhibiting PHD activity via the NADPH oxidase/Rac pathway.
mTOR can also promote stabilization and HIF transcriptional activity
hypoxia inducible factors (HIFs), heterodimeric transcription factors composed from alpha and beta subunits, which can be rapidly stabilized to fluidly adapt to and overcome the effects of a hypoxic environment
Curcumin inhibits the expression of epidermal growth factor receptor (EGFR), VEGFR-1, VEGFR-2 and VEGFR-3, and the kinase activity of Src and FAK, which are responsible for the induction of angiogenic genes as well as endothelial cell polarity and migration
Curcumin also reduces the MMP-2 and MMP-9 expression, along with the suppression of growth and invasion potential of tumor cells in culture and xenograft experiments
The expression of angiogenic biomarkers COX-2 and serum levels of VEGF were significantly reduced in the curcumin-treated group
Resveratrol inhibits capillary endothelial cell growth and new blood vessel growth in animals
[155] and impeding angiogenesis by suppressing VEGF expression through down-regulation of HIF-1alpha
resveratrol was reported to inhibit cell proliferation of human ovarian cancer cells and human osteosarcoma cells by attenuating HIF-1alpha
prevents cytokine-induced vascular leakage and tumor metastasis
The underlying molecular mechanisms include: blocking VEGF- and FGF-receptor-mediated MAPK activation, inhibiting Akt- and MAPK-driven HIF-1alpha basal expression and its induction by IGF-1, stimulating the proteasomal degradation of HIF-1alpha, inhibiting phosphatidyl inositol (PI)-3K/Akt and Ras/mitogen/extracellular signal-regulated kinase (MEK)/ERK pathways, and activation of forkhead box (FOX)O transcription factors
steroid hormones typically interact with their cognate receptor in the cytoplasm for AR, glucocorticoid receptor (GR) and PR, but may also bind receptor in the nucleus as appears to often be the case for ERα and ERβ
This ligand binding results in a conformational change in the cytoplasmic NRs that leads to the dissociation of HSPs, translocation of the ligand-bound receptor to the nucleus
In the nucleus, the ligand-bound receptor dimerizes and then binds to DNA at specific HREs to regulate gene transcription
some steroid hormone-induced nuclear events can occur in minutes
the genomic effects of steroid hormones take longer, with changes in gene expression occurring on the timescale of hours
Classical steroid hormone signaling occurs when hormone binds nuclear receptors (NR) in the cytoplasm, setting off a chain of genomic events that results in, among other changes, dimerization and translocation to the nucleus where the ligand-bound receptor forms a complex with coregulators to modulate gene transcription through direct interactions with a hormone response element (HRE)
NRs have been found at the plasma membrane of cells, where they can propagate signal transduction often through kinase pathways
Membrane-localized ER, PR and AR have been reported to modulate the activity of MAPK/ERK, phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), nitric oxide (NO), PKC, calcium flux and increase inositol triphosphate (IP3) levels to promote cell processes including autophagy, proliferation, apoptosis, survival, differentiation, and vasodilation
ERα36, a 36kDa truncated form of ERα that lacks the transcriptional activation domains of the full-length protein. Membrane-localized ERα36 can activate pathways including protein kinase C (PKC) and/or mitogen activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) to promote the progression of various cancers
G protein-coupled receptor 30 (GPR30), also referred to as G protein-coupled estrogen receptor (GPER), is a membrane-localized receptor that has been observed to respond to estrogen to activate rapid signaling
hormone-responsive G protein coupled receptor is Zip9, which androgens can activate
GPRC6A is another G protein-coupled membrane receptor that is responsive to androgen
androgen-mediated non-genomic signaling through this GPCR can modulate male fertility, hormone secretion and prostate cancer progression
non-NR proteins located at the cell surface can bind to steroid hormones and respond by eliciting rapid signaling events
Estrogens have been shown to induce rapid (i.e. seconds) calcium flux via membrane-localized ER (mER)
ER-calcium dynamics lead to activation of kinase pathways such as MAPK/ERK which can result in cellular effects like migration and proliferation
17β-estradiol (E2) has been reported to promote angiogenesis through the activation of GPER
Membrane NRs may also mediate rapid signaling through crosstalk with growth factor receptors (GFR)
A similar crosstalk occurs between the receptor tyrosine kinase insulin-related growth factor-1 receptor (IGF-IR) and ERα. Not only does IGF-IR activate ERα, but inhibition of IGF-IR downregulates estrogen-mediated ERα activity, suggesting that IGF-IR is essential for maximal ERα signaling
This is a bombshell that shatters the current right brain approach to ER. It completely shatters the concept of eat sugar, whatever you want, with cancer treatment in ER+ or hormonally responsive cancer!
Further, ER activates IGF-IR pathways including MAPK
GPER is involved in the transactivation of the EGFR independent of classical ER
tight interconnection between genomic and non-genomic effects of NRs.
non-genomic pathways can also lead to genomic effects
androgen-bound AR associates with the kinase Src at the plasma membrane, activating Src which then leads to a signaling cascade through MAPK/ERK
However, Src can also increase the expression of AR target genes by the ligand-independent transactivation of AR
extranuclear steroid hormone actions can potentially reprogram nuclear NR events
estrogen modulated the expression of several genes including endothelial nitric oxide synthase (eNOS) via rapid signaling pathways
epigenetic changes can then mediate genomic events in uterine tissue and breast cancer cells