Metabolic Complications in Childhood

Cancer Survivors

Inflammation and Infection Research – School of Medical Sciences

Dr David Simar,

Inflammation and Infection Research

School of medical Sciences, UNSW d.simar@unsw.edu.au

Eslami S, Cohn RJ, Johnston K, Barres R, Simar D

Childhood cancer in Australia

1 in 600 children diagnosed each year with cancer

Improved treatment survival rate exceeding 85%

More than 65% of survivors develop long term complications,

including metabolic disorders (insulin resistance, T2D) that

contribute to the risk of life threatening cardiac complications.

Risk factors have been identified

Risk factors for insulin resistance in CCS

N=78 Odds ratio 95% CI p value

Age 1.08 0.99-1.18 0.07

Gender 1.58 0.51-4.91 0.43

Overweight (BMI>25kg/m2) 4.13 1.20-14.17 0.02*

Abdominal adiposity (W/H>0.5) 4.06 1.21-13.54 0.02*

Age at diagnosis 1.01 0.91-1.13 0.79

Treatment duration 1.07 0.81-1.43 0.62

Surgery 0.86 0.27-2.72 0.80

Acute Lymphoblastic Leukemia 0.80 0.25-2.59 0.71

HSCT (n=20) vs others (n=58) 3.65 1.10-12.04 0.03*

Total body irradiation 10.71 2.58-44.50 <0.01*

Abdominal irradiation 2.09 0.64-6.83 0.22

Irradiation to other areas 1.14 0.32-4.17 0.84

BMI: body mass index, W/H: waist to height ratio, HSCT: hematopoietic stem

cells transplant

Total body irradiation

(N=14)

Non Irradiated

(N=27)

Age (yr) 24.6 (16-44) 22.8 (17-34)

Gender (M/F) 5/9 14/13

BMI (kg/m2) 23.9±6.8 25.6±5.8

Waist to height ratio 0.51±0.11 0.50±0.08

Triglycerides (mmol/l) 1.93±1.74* 0.96±0.46

Cholesterol (mmol/l) 5.28±0.97* 4.78±0.77

HDL-C (mmol/l) 1.28±0.41 1.58±0.72

LDL-C (mmol/l) 3.09±0.97 2.84±0.51

Insulin (mU/l) 9.24±8.02 5.62±4.61

Glucose (mmol/l) 5.87±3.40* 4.77±0.47

Insulin resistant (%) 7 (50%)* 2 (7.4%)

*: p<0.05, TBI vs. non irradiated, BMI: body mass index, HDL-C: high-density

lipoprotein cholesterol, insulin resistance: HOMA-IR score above 1.8.

Radiotherapy and insulin resistance in CCS

Inflammation Van Gaal et al., Nature, 2006

Visceral adipose tissue

Obesity and metabolic disorders

Childhood Cancer Survivors treated with total body irradiation

are not characterised by impaired body composition:

Role of inflammation?

Dr David Simar 2014

Obesity and metabolic disorders

Osborne and Olefsky, Nat Med Rev, 2012

Pro-inflammatory cytokines in CCS?

Lean Obese

Dr David Simar 2014

Radiotherapy and inflammation in CCS

CCS treated with

irradiation have

increased systemic

inflammation associated

with insulin resistance

Source of pro-inflammatory cytokines

Osborne and Olefsky, Nat Med Rev, 2012

Dr David Simar 2014

Radiotherapy and inflammation in CCS

CCS treated with total body irradiation

Are characterized by Tcell polarisation towards Th1

Dr David Simar 2014

Res

t

Stim

ulate

dRes

t

Stim

ulate

d0

20

40

60

p-p

38 M

FI in

CD

4+

cells

p = 0.02

* *

TBI Non-IRR

Rest

Stimula ted

Rest

Stimula ted

0

100

200

300

2000

4000

6000

pS6K

1 MF

I in C

D4+ c

ells

p = 0.04

* *

TBI Non-IRR

Res

t

Stim

ulate

dRes

t

Stim

ulate

d0

100

200

300

pA

kt

Ser4

73 M

FI in

CD

4+

cells

* *

TBI Non-IRR

Res

t

Stim

ulate

dRes

t

Stim

ulate

d0

20

40

60

80

p-J

NK

MF

I in

CD

4+

cells

TBI Non-IRR

Res

t

Stim

ulate

dRes

t

Stim

ulate

d0

100

200

300

2000

4000

6000p

S6K

1 M

FI in

CD

4+

cells

p = 0.04

* *

TBI Non-IRR

Radiotherapy and inflammation in CCS

p38/JNK

ERK

TBI

Non-IRR

Rest

Rest

PMA

PMA

* : significant difference between rest and stimulated condition

Jurkat cells exposed to radiation

Direct irradiation does not directly impact on the activation

of the intracellular signaling pathways

responsible for Th1 polarisation in T cells

Tcell signaling in CCS

Activation of p38 and mTORC1 signaling in T cells in response to radiation:

a direct or indirect effect?

0

25

50

75

100

1day 14days 28days

p-p

38 M

FI in

Ju

rkat

cells

0Gy 1Gy 3Gy 6Gy

0

250

500

750

1000

1day 14days 28daysp

S6K

1 M

FI in

Ju

rkat

cells

0Gy 1Gy 3Gy 6Gy

Dr David Simar 2014

RPMI 0Gy 1Gy 3Gy 6Gy0

10

20

30

40

p-p

38 M

FI in

CD

4+

cells

p = 0.04

p < 0.01 p < 0.01

RPMI 0Gy 1Gy 3Gy 6Gy0

20

40

60

80

100

pS

6K

1 M

FI in

CD

4+

cells p = 0.05

p < 0.01

p = 0.01 p < 0.01

T cells signaling in CCS

Activation of p38 and mTORC1 signaling in T cells in response to radiation:

a direct or indirect effect?T cells exposed to conditioned media from irradiated adipocytes

Activation of those 2 signaling pathways

is achieved through a bystander but not a direct effect

How to explain the long-term memory effect?

Dr David Simar 2014

Mechanisms for long-term memory of irradiation?

Epigenetic modifications:

heritable gene alterations without changes to DNA sequence

CH3 CH3

CH3

TRANSCRIPTION MACHINERY

x

GENE EXPRESSION

MEMORY

3- Small RNA expression

1- HISTONE modification

2- DNA methylation

Changes in DNA methylation in response to irradiationKalinish et al., Radiat Res, 1989

Metabolic disorders associated with epigenetic changesBarres et al, Cell Metab, 2009

Simar et al., Metabolism, 2014

Dr David Simar 2014

TBI non-IRR0

5

10

15

MeC

5 L

ym

ph

ocyte

s (

MF

I)

p > 0.05

TBI non-IRR0

5

10

15

MeC

5 C

D4

cells (

MF

I) p = 0.05

TBI non-IRR0

20

40

60

MeC

5 M

on

ocyte

s (

MF

I) p > 0.05

TBI non-IRR0

5

10

15

MeC

5 C

D8 c

ells (

MF

I) p = 0.07

IRR non-IRR0

2

4

6

8

MeC

5 B

cells (

MF

I)

p > 0.05

Epigenetic changes in PBMCs in CCS

T cells from childhood cancer survivors treated with radiation

characterised by unique epigenetic signature

Role in long-term memory of treatment?

Dr David Simar 2014

Metabolic complications in childhood cancer survivors

CCS: - increased risk of metabolic diseases

- irradiation is a major risk factorNeville et al., J Clin Endo Metab, 2006

Survivors treated with total body irradiation:

- increased insulin resistance

- increased levels of pro-inflammatory cytokines

Systemic inflammation in CCS:

- increased T cells polarised activation towards Th1

- increased intracellular signaling due to a bystander effect

- linked to unique epigenetic signature

Immune alterations in childhood cancer survivors:

to monitor and facilitate early detection of survivors at risk

Dr David Simar 2014

UNSW

IIR: Dr Saghar Eslami

SCH: APr Richard J Cohn, Karen Johnston

Adult Cancer Program: Dr Luc Hesson, Dr Jia Liu

Novo Nordisk Foundation

Centre for Basic Metabolic Research

AProf Romain Barres, Vibe Nylander,

Dr Soetkin Verstyhe, Ida Donkin, Dr Anna Fossum

Support