16. Cancer Flashcards Preview

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Flashcards in 16. Cancer Deck (36):
1

3 most common cancers

1. prostate and breast (men vs women)
2. lung
3. colorectal

2

what is cancer

abnormal cell growth
- mass of tissue

3

types of tumors

benign
- non-cancerous
- rarely threatening
- dont spread

malignant
- cancerous

4

spread of cancer cells

metastasis
- development of secondary tumors
- into blood/lymph system

5

cancer process

1. initiation
- DNA damage (ROS)
- irreversible changes to cells
- genomic instability -> hyperplasia

2. promotion
- evade immune system
- promote cell survival (proliferation)
- angiogenesis
- time of rapid growth

3. progression
- metastasis
- growth, invades surrounding tissue
- affects normal function

6

hyperplasia of cancer

1. increase cell proliferation
2. decrease/block apoptosis

*** 2 seperate processes

7

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

8

obestity promote cancer cell survival

adipocytes
- decrease adiponectin
- increase leptin

macrophages
- increase IL-6, IL-1beta
- increase TNFalpha

9

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)

10

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

11

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

12

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

13

insulin and cancer

hyperinsulinemia
- increase insulin and free IGF-1
- increase cell growth and proliferation
- decrease apoptosis
- stim VEGF expression and promote angiogenesis

14

VEGF

vascular endtholial growth factor

15

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

16

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

17

cachexia metabolic change associations

- insulin resistance
- increase glucose production in liver
- increased lipolysis

18

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

19

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

20

survival rate

about 1/2 with cachexia weight loss

21

adverse outcomes of cachexia

more complication and death
decrease treatment response
increased therapy toxicity
increased hospotal stal

22

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

23

mediators of cancer cachexia

proinflammatory cytokines
- TNFa and IL-6

Eicosanoids
- prostoglandins

Tumor derived products
- PIF LMF

24

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

25

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

26

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)

27

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

28

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

29

tumor -derived products

proteolysis inducing factor (PIF)
lipid mobalizing factor (LMF)

30

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

31

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)

32

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

33

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

34

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

35

sarcopenia

severe muscle loss

36

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