癌症、高血壓、肥胖與血管：新生流行病學及藥物學觀點

(1)

700 78

1 2,3 3

1 2

3

VEGF, bFGF, TNF-

( Cancer )

( Hypertension ) ( Obesity )

( Hyperinsulinemia ) ( Angiogenesis )

( Antihypertensives )

1

2

( endothelial cells ) ( migration ) ( proliferation ) ( tube formation )

( angiogenesis or neovascularization )

(2)

2 mm

³

3

( metastasis )

( tumor suppressor gene )

( modifier gene )

⁴

( oncogene )

( angiogenic switch ) ( angiogenic activators )

( angiogenic inhibitors ) ( )

5 - 7

( ) 1. /

( proan- giogenic signal )

( vascular endothelial growth factor,

VEGF) ( basic fibrob-

last growth factor, bFGF ) 2.

( extracellular protease ) (extracellular matrix, ECM )

( matrix metalloproteinases, MMP )

( basal lamina ) type IV collagen ( degradation )

( r e m o d e l i n g ) -

( urokinase-type plasminogen activator, uPA )

( MMP uPA )

3. ( integrin-

v 3, v 5 ) MMPs uPA

( sprout ) 4. ( stromal cells)

( angiopoeitins, Ang, Ang-1, Ang-2 ) ( tyrosine protein ki- nase ) Tie ( Tie-1, Tie-2 )

⁸

( apoptosis )

( platelet derived growth factor, PDGF )

VEGF

( vascular permeability factor, VPF ) ( Flt-1 Flt-1/K- DR or Flk-1 )

VEGF

9 - 11

V E G F f l k - 1

( in-

(3)

ducible nitric oxide synthase, iNOS )

N O ( C O X )

PGE

1

PGE

2

PGF

2

COX-2

VEGF PDGF

Bcl-2 VEGF

p53 COX-2

PGE2 VEGF

COX-2

12

( hypoxia-inducible transcription factor,

HIF ) ( interleukin )

IL-6 IL-8 ( tumor necrosis fac-

tor- , TNF- )

H I F

VEGF Ang-2 Tie-1/ Tie-2 NOS bFGF

bFGF

VEGF bFGF

aFGF / bFGF Angiogenin

Angiopoietin-1/ Angiopoietin-2 Angiotensin-II

Bradykinin COX-2 Del-1 Estrogen Follistatin

Granulocyte colony-stimulating factor (G-CSF) Hepatocyte growth factor (HGF) /scatter factor (SF) Interleukins (IL-4, IL-6, IL-8, IL-13)

Integrin v 3/ Integrin v 5 IGF-1

Leptin Midkine

MMPs (MMP-1, MMP-2, MMP-9) NO

Pleiotrophin (PTN) Progranulin Proliferin

Platelet-derived endothelial cell growth factor (PD-ECGF) Platelet-derived growth factor-BB (PDGF-BB)

Placental growth factor PGE

1

, PGE

2

Transforming growth factor- (TGF- ) Tunica internal endothelial cell kinase (Tie-2) TNF-

Vascular endothelial growth factor (VEGF) reference 1, 5, 6, 14, 15, 48, 58.

Angioarrestin

Angiostatin (plasminogen fragment) Antiangiogenic antithrombin III Cartilage-derived inhibitor (CDI) CD59 complement fragment Endostatin (collagen XVIII fragment) Fibronectin fragment

Gro-betaHeparinases

Heparin hexasaccharide fragment Human chorionic gonadotropin (hCG) Interferon / /

Interferon inducible protein (IP-10) Interleukins (IL-10, IL-12) Kringle 5 (plasminogen fragment) Metalloproteinase inhibitors (TIMPs) 2-Methoxyestradiol

Placental ribonuclease inhibitor Plasminogen activator inhibitor Platelet factor-4 (PF4) Prolactin 16kD fragment Proliferin-related protein (PRP) Retinoids

Suramin Thalidomide

Thrombospondins (TSP-1, TSP-2) Transforming growth factor- (TGF-b) Tetrahydrocortisol-S

Vasculostatin

Vasostatin (calreticulin fragment)

(4)

1971

¹³

Dr. Judah Folkman

( dormancy )

14

1. ( )

2.

3.

4.

15

1. ( interferon ) bFGF 2.

suramin (

/ ) bFGF PDGF 3.

a n g i o s t a t i n e n d o s t a t i n thrombospondin 4.

MMP -marimastat prinomastat neovastat 5.

COX-2 fu-

magillin integrin

16-17

( heterogeneity )

( heterogeneity in vascu-

(5)

( combination antiangiogenic agents therapy )

18

( coex-

istence ) ( coincidental )

19-23

/

24-25

( WHO )

²⁶

2000

13% 1

1/4

50%

V E G F

bFGF TNF-

^5,8,19,24

( eNOS ) ( home-

ostasis )

²⁷

( bradykinin )

NO NO

VEGF bFGF TNF- NO

NO VEGF bFGF T-

NF-

IL-6 IL-8 TNF-

( neutrophil ) ( monocyte )

2 8

/

( primary pulmonary hypertension )

NO eNOS -

( renin- angiotensin system )

( a n -

giotensinogen ) ( ACE )

a n g i o t e n s i n - I I a n -

giotensin-II 1 ( angiotensin

type-1, AT1 )

( LDL-C )

^29-31

( up-

regulate ) ( rostral ventro-

lateral medulla, RVLM ) AT1

32-33

angiotensin-II AT1

Angiotensin-II VEGF VEGF

AT 1

V E G F

ACEI angiotensin-

c-myc c-fos

bradykinin

1

34-35

lisinopril

37-38

atenolol diltiazem enalapril

captopril perindopril

perindopril VEGF

perindopril indapamide quinaprilat ( quinapril )

39-40

prazosin amlodipine

(6)

thiazide

( potassium-sparing ) reserpine

4 4

A C E I

( American Cancer Society )

45

20% 14%

( BMI ) 9 ( B M I > 4 0 )

( BMI=18.5-24.9 ) 62%

5 2 %

2004 WHO

46-47

1/4 1/3

11% 9 11%

4 8 - 5 0

( leptin )

( insulin-like growth factor, IGF )

-Y ( Neuropeptide Y, NP-Y )

3

-adrenergic

( )

VEGF

55-56

b F G F V E G F

IGF

57-58

IGF -3 ( IGFBP-3 ) IGF

59-60

-

(KCPS)

⁶¹

62-64

B M I

6 5 - 6 6

m e t -

formin leptin MMP-2

PPAR-

67-69

rosiglitazone pioglitazone

VEGF cytokin COX-2

70

2 sulfonylureas ( exogenous )

metformin

(7)

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www.pslgroup.com/dg/24e366.htm.

Cancer, Hypertension, Obesity and Angiogenesis Epidemiological

and Pharmacological Aspects

Kuo Chieh

¹

, Chang-Chen Tang

^2,3

, and Shih-Yuan Hsu

³

Cancer and hypertension are two leading diseases in Taiwan for years. Often they coexist with some common predisposing factors in patients e.g., obesity and ageing. The common biologic mechanisms involved among cancer, hypertension and obesity are angiogenesis, leptin, insulin, insulin-like growth factor and steroid hormones.

An abnormal angiogenesis is a common pathological feature, which may be induced by proangiogenic factors e.g., bFGF, VEGF, TNF- and few interleukins. A number of epidemiological studies have found that the use of antihypertensives, antidiabetics may associate with risk of cancer, and they also have showed some proangiogenic activity on certain antihypertensives and insulin secretagogues. However, a better understanding of common cell biology and the relationship among hyperinsulinemia, hypertension and malignancy may be helpful in elucidating more preventive and therapeutic avenues to manage obesity, hypertension and cancer. ( J Intern Med Taiwan 2005; 16: 260-268 )

1

Cardiology,

²

Pharmacy, Sin-Lau Christian Hospital, Tainan city, Taiwan

3