16. Cancer Flashcards
3 most common cancers
- prostate and breast (men vs women)
- lung
- colorectal
what is cancer
abnormal cell growth
- mass of tissue
types of tumors
benign
- non-cancerous
- rarely threatening
- dont spread
malignant
- cancerous
spread of cancer cells
metastasis
- development of secondary tumors
- into blood/lymph system
cancer process
- initiation
- DNA damage (ROS)
- irreversible changes to cells
- genomic instability -> hyperplasia - promotion
- evade immune system
- promote cell survival (proliferation)
- angiogenesis
- time of rapid growth - progression
- metastasis
- growth, invades surrounding tissue
- affects normal function
hyperplasia of cancer
- increase cell proliferation
- decrease/block apoptosis
*** 2 seperate processes
abdominal obesity metabolic abnormalities that increase risk
Metabolic
- insulin resistance and hyperinsulinemia
- hyperglycemia and hyperlipidemia
Altered metabolic hormones
- increase insulin-like growth factor (IGF-1) (colon)
- estrogen (breast)
Abnormal adipokine production
- metabolic signals
- insulin resistance and high insulin -> risk of some cancers
obestity promote cancer cell survival
adipocytes
- decrease adiponectin
- increase leptin
macrophages
- increase IL-6, IL-1beta
- increase TNFalpha
obesity promote cell proliferation
hormones
- estradiole increase (in blood and tumor)
insulin resistance
- increase insulin and IGF-1
- adipocytes (adiponectin decrease and leptin increase promote insulin resistance)
obesity promote angiogenesis
hormones
- increase estradiol bioavailability
insulin resistance
- increase insulin and IGF-1
- adipocytes (adiponectin decrease and leptin increase promote insulin resistance)
adipocytes
- leptin increase
- adiponectin decrease
- directly influence
leptin in caner
Promote tumor initiation and Cancel cell proliferation, survival and migration
increase NFkB and STAT3 activation
- increase inflammatory cytokine (TNFa and IL-6 respectively)
promote cell proliferation and cell survival
attract neutrophils and other immune cells
- into tumor microenvironment (CHEMOTACTIC)
- increase ROS production -> DNA damage
- secrete pro-inflam cytokines -> IL-1B, IL-6. IL-8, TNFa
antagonizes anti-inflam mechanisms
- adiponectin
- IL-10
adiponectin and cancer
reduce cell proliferation and survival
- inhibits signal pathways
- reduce cell growth and proliferation
pro-apoptotic
- activates caspases
- stims cytochrome C release from mitochondria
anti-inflammatory
- stim PPARgamma -> block NFkB activation and cytokine production (TNFa)
- increase IL-10
activates APPL1
- binds adiponectin receptor
- reduces ROS production
*** reduced levels in obesity
insulin and cancer
hyperinsulinemia
- increase insulin and free IGF-1
- increase cell growth and proliferation
- decrease apoptosis
- stim VEGF expression and promote angiogenesis
VEGF
vascular endtholial growth factor
inflammatory cytokines / transcription factors and cancer
IL-6 increases STAT 3 activation
- active >50% of tumors
- anti apoptotic (reduce gene expression)
- promote cell proliferation
- stim VEGF -> pro angiogetic
- prolonged NFkB activation
NFkB increases TNFa
- increase proliferation and angiogenesis
- increase cIAP (cellular inhibitor of apoptosis)**
- inhibits caspase activity**
- promotes cell invasion and metastasis via MMP activation
cancer cachexia
body weight loss
- both skeletal muscle and adipose
- adequate nutrition
30-80% of cancer patients
- severe in 15% (10% loss initial body weight)
- pancreatic, gastric and SI cancers
- death at 25-30% weight loss
cachexia metabolic change associations
- insulin resistance
- increase glucose production in liver
- increased lipolysis
causes of cachexia
tumor by-products - inflam cytokines (TNFa, IL-6), and leptin dysphagia - difficulty swallowing gastrointestinal disturbances - obstruction/constipation malabsorption treatment toxicities - nausea and vomiting uncontrolled symptoms - pain, dyspnea (diff bretahing) Xerostomia - dry mouth
depletion in muscle mass
hypoanabolism
- hormone change
- lack amino acids
hypercatabolism
- proteolytic enzymes
- proinflam cytokines (TNFa and IL-6)
- tumor derived catabolic factors
**key distinction for treatment
survival rate
about 1/2 with cachexia weight loss
adverse outcomes of cachexia
more complication and death
decrease treatment response
increased therapy toxicity
increased hospotal stal
primary cachexia vs secondary
primary - cancer mediated
- metabolic abnormalities
- extreme muscle tissue loss
- suffiecient kcal
secondary - not enough kcal
- anorexia
- due to treatments
- dysphagia - swallowing
- poor oral hygeine
- gastrointestinal obstruction
mediators of cancer cachexia
proinflammatory cytokines
- TNFa and IL-6
Eicosanoids
- prostoglandins
Tumor derived products
- PIF LMF
TNFa and cancer cachexia
muscle protein degredation
- activates NFkB
- induces ROS
stim lipolysis in adipose
- upregulate MAPK and JNK
- activate PPAR gamma
- activate NFkB
Insulin resistance
IL-6 and cancer cachexia
muscle protein degredation
- activates non-lysosomal (proteosome) pathway
- activate lysomal (cathepsin) pathway
- works with TNFa
directly induce acute phase protein respinse to trigger tissue catabolism
upregulate stat3
eiconsanoids
prostoglandin
PGE2 in colon cancer biopsies
inflam mediators (activate NFkB)
induce peripheral tissue loss
- direct and indirect via acute phase tissue response
produced by tumors
derived from
- n6 arachidonic acid (proinflammatory)
- n3 EPA (anti inflammatory)
PGE2
prostoglandin E2
inhibit apoptosis - decrease Bcl2 expression promote proliferation and survival - activate B-catenin signal pathway promote angiogenesis - VEGF (vascular endothelial growth factor helps metastasis - induce MMP - degrades ECM pro inflammatory
- one type of prostoglandin -> others not as potenet
- derived from arachidonic acid N6
- n3 derived are anti-inflam
PIF
proteolysis inducing factor (PIF)
- skeletal muscle and liver
- in urine of weight loss patients (bio marker)
- depress prot syn 50%
- promote prot degredation 50%
activates NFkB -> ROS production
induces IL-6
tumor -derived products
proteolysis inducing factor (PIF)
lipid mobalizing factor (LMF)
LMF
tumor derived product
- lipid mobilizing factor
- found in urine
identical to - zinc alpha 2 glycoprotein (ZAG) in mice
induce lypolysis (increase lypolytic enzyme expression)
- UPC-1 and UPC-3 in BAT (brown adipose tissue)
- increase substrate utilization
- adipose tissue TAG (ATAG) lipase
- hormone sensative lipase (HSL)
secreted by adipose and tumor
treatment of cachexia
1) appetite stimulants (CNS)
- megesterol acetate
2) muscle anabolics
- steroids (oxandrolone, nandrolone)
- AA or protein supplements
- creatine
- exercise**
3) anti- catabolic and anti inflammatory therapies
- NSAIDs
- n3 (EPA)
4) nutritional supplements
- palliative (end of life care)
Physical acitivity and cachexia
improve cancer related symptoms
- skel muscle loss, improve blood flow, reduce nausea fatigue, quality of life
increase metabolites that reduce inflammation
- IL-10, soluble TNF receptors (binds in blood to deactivate)
increase glut4 synthesis
- glucose transport
increase PI-3-K expression
- insulin sensitivity
- glucose transport
- protein synthesis
types of physical activity
moderate aerobic
- 60-75% VO2
- reduced systemic inflammation
- increase IL-10 and soluble TNF receptors
strength
- decrease muscle loss
- protein syn and reduce degredation
n3 and cachexia
decrease proinflammatory cytokines
- impairs PIF
- tumor associated proteolysis
may improve muscle sensitivity to insulin
- chemotherapy reduces n3 in blood
- supplement treats this
- 69% maintained / gained muscle with treatment
- only 29% with normal care (other treatments)
- greatest increases = greatest increases in muscle gain
EPA -> relationship not yet proven
sarcopenia
severe muscle loss
carnatine in cachexia
facilitates transfer of activated long chain FA from cytoplasm to mitochondria
- 75% diet derived / 25% liver and kidneys
- from lysine and methionine
- skel muscle and myocardium are dependent (rq FA ox)
deficient in cachexia
- treatments lower absorption, synthesis and secretion
supplement
- L-carnitine
- improves liver lipid metabolism
- reduced inflam cytokine levels
