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The role of adipocytokines in breast cancer. 義大醫院醫研部暨婦產部 義守大學生物科技系 袁行修. Overview of breast cancer. - PowerPoint PPT Presentation
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The role of adipocytokines in breast cancer
義大醫院醫研部暨婦產部義守大學生物科技系
袁行修
2
Overview of breast cancer
Breast cancer is a malignant tumor which severely impairs the woman health. According to the statistics of Department of Health from 1995 to 2007, breast cancer has jumped to the first place in the incidence of women-specific malignancies in Taiwan, and growing at a surprising rapidity.
Known breast cancer risk factors include age, family or personal history of breast cancer, high breast tissue density, atypical hyperplasia, a history of chest radiation, early menarche, recent use of oral contraceptive drugs, age of birth of first child over 30, obesity after menopause (Willett et al., 2004; Viswanathan et al., 2009). It is a critical issue to explore the underlying mechanisms for female breast cancer in Taiwan and to discover the prognostic factors and therapeutic targets for Taiwanese breast cancer.
3
The etiology of breast cancer is still poorly understood, but several risk factors are well confirmed, including increasing age, geographic location (USA and western countries), familial history of breast cancer, genetic mutations (BRCA1, BRCA2, p53, ATM NBS1, LKB1), ionizing radiation exposure, history of benign breast disease, increased mammographic density, early menarche and late menopause, nulliparity and old age at first delivery, exogenous hormone usage, lifestyle (alcohol, diet, obesity and physical activity), high IGF-1 and prolactin levels, etc. (Collaborative Group on
Hormonal Factors in Breast Cancer, 2001; Dumitrescu and Cotarla, 2005).
4
Adipocytokines
Adipose tissue is no longer considered to be an inert tissue functioning solely as an energy store, but is emerging as an important factor in the regulation of many pathological processes. Various products of adipose tissue have been characterized, and some of the soluble factors produced by this tissue are known as adipocytokines (Calle and Kaaks 2004).
The term adipocytokine is used to describe certain cytokines that are mainly produced by adipose tissue, although it is important to note that they are not all exclusively derived from this tissue (Wellen
and Hotamisligil 2005).
5
Adiponectin, leptin, resistin and visfatin are adipocytokines and are thought to provide an important link between obesity, insulin resistance and related inflammatory disorders (Herbert Tilg and Alexander R.
Moschen, 2006).
The incidence of obesity and its associated disorders are increasing markedly worldwide. Obesity predisposes individuals to an increased risk of developing many diseases, including atherosclerosis, diabetes, nonalcoholic fatty liver disease, certain cancers and some immune-mediated disorders (Mannino, Mott et al. 2006).
Resistin (also known asFIZZ3), which is a 114-amino-acid polypeptide, wasoriginally shown to induce insulin resistance in mice80.It belongs to a family of cysteine-rich proteins, alsoknown as resistin-like molecules (RELMs), that havebeen implicated in the regulation of inflammatoryprocesses79. Resistin was shown to circulate in two distinctforms: a more prevalent high-molecular-weighthexamer and a substantially more bioactive, but lessprevalent, low-molecular-weight complex82.
Fig.1 Adipose tissue: cellular components and molecules synthesized. (Herbert Tilg and Alexander R. Moschen, 2006)
7
(Marra and Bertolani 2009)
8 (Herbert Tilg and Alexander R. Moschen, 2006)
9
Adipocytokines function as hormones to influence energy homeostasis and to regulate neuroendocrine function. As cytokines, they affect immune functions and inflammatory processes throughout the body. The field of adipocytokines has attracted tremendous interest recently and the knowledge that has accumulated might lead to the development of new therapeutics (Herbert Tilg and Alexander R. Moschen, 2006).
10
Obesity is a serious health problem in the industrialized world. Also, similar trends have been observed in many developing countries (Shetty
and Schmidhuber 2006). Obesity is associated with a number of disorders including cardiovascular disease, hypertension, Type 2 diabetes, dyslipidemia and cancer (Hanif and Kumar 2002).
Probably, a large number of cancers are linked with obesity such as cancers of the colon, breast (postmenopausal), endometrium, kidney, esophagus and gastric cardia (adenocarcinoma), gall bladder, liver, pancreas, prostate (advanced malignancy), ovary and hematopoietic tissues like non-Hodgkin's lymphoma (NHL), multiple myeloma and leukemia (Calle 2007).
11
Furthermore, it is worthy to mention that obesity may influence prognosis through various mechanisms, including co-morbidities and endocrine factors (McTiernan 2005). In addition to serve as an energy depot, adipose tissue or fat mass releases several hormone-like chemicals or adipokines, which perhaps provide a link among cancer, insulin resistance, inflammation and oxidative stress (Ruan and
Lodish 2004).
Here, we provide an overview of recent advances in our view of the role of adipocytokines in breast cancers.
12 Figure 1: Effects of obesity on the pathological processes that favor carcinogenesis (Murthy, Mukherjee et al. 2009)
13
14
Increased resistin and its association with positive ER status in breast cancer is
associated with a poor overall survival
15
Resistin
Resistin, a 12.5 kDa protein and named for resistance to insulin, is a signaling molecule secreted from adipocytes. It is expressed in adipocytes, muscle, pancreatic cells, and mRNA displays an even wide range, having been found in white fat, spleen, hypothalamus, adrenal gland, skeletal muscle, gastrointestinal tract, and pancreas (Wozniak et al., 2009).
Resistin serves as a hormone (Steppan et al., 2001), that could decrease the sensitivities of insulin in the adipose cells so that insulin resistance is formed (Steppan and Lazar, 2004).
16
Circulating resistin levels are decreased by the anti-diabetic drug, increased in diet-induced and genetic forms of obesity. Insulin-stimulated glucose uptake by adipocytes is enhanced by neutralization of resistin and is reduced by resistin treatment (Kang et
al., 2006).
In cancer studies, human serum resistin levels are significantly increased in breast cancer patients as compared to controls, especially after menopause, and correlated with the size of tumor. In addition, resistin concentration in lymph node metastasis group is higher than that in the group without lymph node metastasis, suggest that resistin may promote metastasis of breast cancer cells (Hou et al., 2007).
17
Fig.3 Effects of various adipocytokines on the monocyte–macrophage system. c | The receptor for resistin is unknown, but this adipocytokine induces the activation of p38, ERK and phosphatidylinositol 3-kinase (PI3K). Resistin increases the production of TNF, IL-1β, IL-6 and IL-12. Its effect on monocyte and macrophage functions is not known. Whereas adiponectin can be considered an anti-inflammatory strategy of the ‘adipose organ’, leptin and resistin have dominant pro-inflammatory features (Herbert Tilg and Alexander R. Moschen, 2006).
18
To determine the expression profiles of resistin in breast cancer and their correlation with prognosis and other clinico-pathological parameters.
Positive > 30%
19
Table 1. Correlation of resistin expression in the serum of breast cancer and non breast cancer.
Resistin (Mean±SD) 30.78 ±8.59 ng/ml 26.91±5.00 ng/ml 0.001
Breast cancer (n=81) Non breast cancer (n=81) P value *
*The P value was calculated by the t-test.
20
Table 2. Clinicopathological characteristics in breast cancer.
Characteristics patients with breast cancer % of patients (n=81)Stage I 39 48.1 II 31 38.3 III 11 13.6
Grade
I 9 11.1 II 54 66.7 III 18 22.2
Age
≦50 39 48.1 > 50 42 51.9
LN Metastasis
Negative 56 69.1 Positive 25 30.9
ER
Negative 29 35.8 Positive 52 64.2
PR
Negative 40 49.4 Positive 41 50.6
Her2/Neu
Negative 50 61.7 Positive 31 38.3
21
Table 3. Correlation of resistin expression with clinicopathological characteristics in breast cancer.
resistin
Characteristics ≦27 ng/ml (%) > 27 ng/ml (%) P value* Stage
I 11 (28.2) 28 (71.8) 0.413
II 7 (22.6) 24 (77.4)
III 1 (9.1) 10 (90.9)
Grade
I 1 (11.1) 8 (88.9) 0.618
II 14 (25.9) 40 (74.1)
III 4 (22.2) 14 (77.8)
Age
≦50 8 (20.5) 31 (79.5) 0.547
> 50 11 (26.2) 31 (73.8)
LN Metastasis
Negative 17 (30.4) 39 (69.6) 0.028
Positive 2 (8.0) 23 (92.0)
ER
Negative 11 (37.9) 18 (62.1) 0.022
Positive 8 (15.4) 44 (84.6)
PR
Negative 13 (32.5) 27 (67.5) 0.058
Positive 6 (14.6) 35 (85.4)
Her2/Neu
Negative 14 (28.0) 36 (72.0) 0.220
Positive 5 (16.1) 26 (83.9)
*The P value was calculated by the chi-square test.
22
Fig. 2 The average tumor size (cm in diameter) for breast patients with low and high
resistin expression. The average tumor size was 2.71±0.27 cm for low resistin expression
(n=19) and 2.86±0.18 cm for high resistin expression (n=62) in breast cancer, P=0.689.
Values were expressed as Mean±SEM determined by independent-samples t test.
23
P=0.033
Fig. 3 Kaplan–Meier survival curves are shown for the low and high resistin expression groups in breast cancer.
Low( 27 ng/ml)≦High( > 27 ng/ml)
24
Fig. 4 Kaplan–Meier survival curves are shown for the low and high resistin expression groups combined with
positive and negative ER status in breast cancer.
P =0.108
High( > 27 ng/ml) resistin expression and ER positive
Low ( 27 ng/ml) resistin expression and ER negative≦Low ( 27 ng/ml) resistin expression and ER positive≦High( > 27 ng/ml) resistin expression and ER negative
25
Table 5. Cox regression multivariate analysis of overall survival for breast cancer.
Variables Odds ratio (95% CI) P value
Tumor stage (I/II/III) 3.203 (1.386-7.403) 0.006
Tumor grade (I/II/III) 2.088 (0.713-6.115) 0.179
Age ( > 50 years) 0.676 (0.229-1.993) 0.478
ER status (Negative/Positive) 2.420 (0.788-7.433) 0.123
PR status (Negative/Positive) 1.345 (0.377-4.803) 0.648
Her2/Neu status (Negative/Positive) 1.139 (0.864-1.500) 0.356
Resistin expression (Low/High) 15.373 (1.629-145.098) 0.017
26
Fig. 1 Immunohistochemistry showing high (A) and low (B) expression of resistin in breast cancer tissue. (C) normal breast tissue, (D) negative control. Original magnification was X100.
A B
C D
27
33 (89.2%) <0.001
4 (10.8%)
18 (48.6%)
19 (51.4%)
Low-expression
High-expression
Resistin
Breast cancer tissue (n=37) Adjacent normal breast tissue (n=37) P value *
*The P value was calculated by the chi-square test.
Table 1. Immunohistochemistry of resistin expressions in breast cancer and adjacent normal breast tissue.
28
Table 2. Clinicopathological characteristics in breast cancer.
Characteristics patients with breast cancer % of patients (n=108)
Stage
I 55 50.9 II 40 37.0 III 13 12.0
Grade
I 12 11.1 II 71 65.7 III 25 23.1
Age
≦50 53 49.1 > 50 55 50.9
LN Metastasis
Negative 76 71.4 Positive 32 29.6
ER
Negative 40 37.0 Positive 68 63.0
PR
Negative 52 48.1 Positive 56 51.9
Her2/Neu
Negative 67 62.0 Positive 41 38.0
29
Table 3. Correlation of resistin expression with clinicopathological characteristics in breast cancer.
resistin
Characteristics Low (%) High (%) P value*
Stage
I 23 (41.8) 32 (58.2) 0.061
II 8 (20.0) 32 (80.0)
III 3 (23.1) 10 (76.9)
Grade
I 4 (33.3) 8 (66.7) 0.277
II 19 (26.8) 52 (73.2)
III 11 (44.0) 14 (56.0)
Age
≦50 22 (41.5) 31 (58.5) 0.028
> 50 12 (21.8) 43 (78.2)
LN Metastasis
Negative 28 (36.8) 48 (63.2) 0.065
Positive 6 (18.8) 26 (81.2)
ER
Negative 18 (45.0) 22 (55.0) 0.020
Positive 16 (23.5) 52 (76.5)
PR
Negative 20 (38.5) 32 (61.5) 0.132
Positive 14 (25.0) 42 (75.0)
Her2/Neu
Negative 20 (29.9) 47 (70.1) 0.641
Positive 14 (34.1) 27 (65.9)
*The P value was calculated by the chi-square test.
30
Fig. 2 The average tumor size (cm in diameter) for breast patients with low and high resistin expression. The average
tumor size was 1.79±0.15 cm for low resistin expression (n=34) and 2.29±0.14 cm for high resistin expression (n=74)
in immunohistochemistry analysis groups, *P=0.017. Values were expressed as Mean±SEM determined by
independent-samples t test.
*
31
P=0.003
Low
High
Fig. 3 Kaplan–Meier survival curves are shown for the low and high resistin expression groups, determined by
immunohistochemistry analysis.
32
Fig. 4 Kaplan–Meier survival curves are shown for the low and high resistin expression groups combined with positive
and negative ER, determined by immunohistochemistry analysis.
P=0.004
High resistin expression and ER positive
Low resistin expression and ER negative
Low resistin expression and ER positive
High resistin expression and ER negative
33
Table 4. Cox regression multivariate analysis of overall survival for breast cancer.
Variables Odds ratio (95% CI) P value
Tumor stage (I/II/III) 2.791 (1.291-6.036) 0.009
Tumor grade (I/II/III) 4.448 (1.400-14.129) 0.011
Age ( > 50 years) 0.285 (0.073-1.111) 0.071
ER status (Negative/Positive) 1.282 (0.877-1.873) 0.199
PR status (Negative/Positive) 1.174 (0.839-1.643) 0.349
Her2/Neu status (Negative/Positive) 1.192 (0.943-1.507) 0.142
Resistin expression (Low/High) 11.250 (1.216-104.077) 0.033
34
Conclusion
Altered resistin expression may be involved in the pathogenesis of breast cancer in an ER-dependent manner.
Adipocytokines could be attractive candidates as the missing link between obesity and cancer.
35
Altered visfatin expression in breast cancer tissue is associated with a poor
overall survival
36
Visfatin
Visfatin, a 52 kDa protein and produced by lymphocytes (Fukuhara et al.,
2005), has nicotinamide adenine dinucleotide (NAD) biosynthetic activity, which is essential for B-cell maturation and function (Samal et
al., 1994; 2003; Revollo et al., 2007).
Recently, visfatin has been identified as an adipocytokine hormone that could make adipose cells to increase the sensitivity of insulin (Fukuhara et al., 2005) and associated with obesity, type II diabetes and rheumatoid arthritis (Brentano et al., 2007).
37
In human studies, a positive correlation between visfatin gene expression in visceral adipose tissue and body mass index (BMI) is noted, along with negative correlation between BMI and subcutaneous fat visfatin (Berndt et
al., 2005), suggesting that visfatin regulation in these different depots is different, and adipose depot ratios are highly dependent on the obesity of the subjects.
In breast cancer studies, visfatin is reported to be expressed in doxorubicin-responsive breast cancer (Folgueira et al., 2005), and have demonstrated that visfation mRNA and protein expressed in MCF-7 breast cancer cells. Furthermore, visfatin is present in bovine mammary epithelial cells, lactating mammary gland and milk (Yonezawa et al., 2006). These studies suggest that visfatin may be plays some important role in the mammary epithelial cells and mammary gland.
38
(Hausenloy 2009)
39
To determine the expression profiles of visfatin in breast cancer and their correlation with prognosis and other clinico-pathological parameters.
Positive > 30%
40
Table 1. Correlation of visfatin expression in the serum of breast cancer and non breast cancer.
Breast cancer (n=68) Non breast cancer (n=68) p value *
Visfatin (Mean±SD) 39.98 ±22.09 ng/ml 31.92±19.90 ng/ml 0.007
*The P value was calculated by the T-test.
41
Table 2. Clinicopathological characteristics in breast cancer.
Characteristics patients with breast cancer % of patients (n=68)Stage I 37 54.4 II 23 33.8 III 8 11.8
Grade
I 6 8.8 II 45 66.2 III 17 25.0
Age
≦50 36 52.9 > 50 32 47.1
LN Metastasis
Negative 49 72.1
Positive 1927.9
ER
Negative 25 36.8 Positive 43 63.2
PR
Negative 30 44.1 Positive 38 55.9
Her2/Neu
Negative 44 64.7 Positive 24 35.3
42
Table 3. Correlation of resistin expression with clinicopathological characteristics in breast cancer.
visfatin
Characteristics ≦32 ng/ml (%) > 32 ng/ml (%) P value* Stage
I 20 (54.1) 17 (45.9) 0.084
II 9 (39.1) 14 (60.9)
III 1 (12.5) 7 (87.5)
Grade
I 4 (66.7) 2 (33.3) 0.285
II 17 (37.8) 28 (62.2)
III 9 (52.9) 8 (47.1)
Age
≦50 18 (50.0) 18 (50.0) 0.300
> 50 12 (37.5) 20 (62.5)
LN Metastasis
Negative 26 (53.1) 23 (46.9) 0.017
Positive 4 (21.1) 15 (78.9)
ER
Negative 7 (28.0) 18 (72.0) 0.041
Positive 23 (53.5) 20 (46.5)
PR
Negative 9 (30.0) 21 (70.0) 0.037
Positive 21 (55.3) 17 (44.7)
Her2/Neu
Negative 22 (50.0) 22 (50.0) 0.186
Positive 8 (33.3) 16 (66.7)
*The P value was calculated by the chi-square test.
43
Fig. 1 The average tumor size (cm in diameter) for breast patients with low and high
resistin expression. The average tumor size was 2.61±0.17 cm for low resistin expression
(n=30) and 2.88±0.20 cm for high resistin expression (n=38) in serum analysis groups,
P=0.341. Values were expressed as Mean±SEM determined by independent-samples t test.
44
Fig. 2 Kaplan–Meier survival curves generated by the low and high visfatin expression groups.
Low expression ( 32 ng/ml)≦High expression ( > 32 ng/ml)
P=0.021
45
High expression( > 32 ng/ml) and ER negative
Low expression( 32 ng/ml) and ER positive≦High expression( > 32 ng/ml) and ER positive
Low expression( 32 ng/ml) and ER negative≦
P=0.002
Fig. 3 Kaplan–Meier survival curves generated by the low and high visfatin expression groups combined with
positive and negative ER status.
46
High expression( > 32 ng/ml) and PR negative
Low expression( 32 ng/ml) and PR positive≦High expression( > 32 ng/ml) and PR positive
Low expression( 32 ng/ml) and PR negative≦
P=0.004
Fig. 4 Kaplan–Meier survival curves generated by the low and high visfatin expression groups combined with
positive and negative PR status.
47
Variables Odds ratio (95% CI) P Value
Tumor stage (I/II/III)
Tumor grade (I/II/III)
Age (>50 years)
ER status (negative/positive)
PR status (negative/positive)
Her2/Neu status (negative/positive)
Visfatin expression (High/Low)
12.38 (3.14-48.93)
7.34 (1.10-49.16)
0.07 (0.01-0.77)
8.37 (0.84-83.68)
1.31 (0.63-2.75)
1.21 (0.58-2.49)
29.47 (2.72-319.96)
<0.001
0.040
0.029
0.070
0.472
0.613
0.005
Table 4. Cox regression multivariate analysis of overall survival for breast cancer
48
Fig. 1 Immunohistochemistry showing high (A) and low (B) expression of visfatin in breast cancer tissue. (C) normal breast tissue, (D) negative control. Original magnification was X100.
A B
C D
49
Breast cancer tissue (%) Adjacent normal breast tissue (%) P value *
Visfatin
Low-expression
High-expression
29 (64.4%)
16 (35.6%)
41 (91.1%) 0.002
4 (8.9%) *The P value was calculated by the chi-square test.
Table 1. Immunohistochemistry of visfatin expressions in breast cancer and adjacent normal breast tissue (n=45).
50
Table 2. Clinicopathological characteristics in breast cancer.
Characteristics patients with breast cancer % of patients (n=98)
Stage
I 53 54.1 II 34 34.7 III 11 11.2
Grade
I 7 7.1 II 65 66.3 III 26 26.5
Age
≦50 51 52.0 > 50 47 48.0
LN Metastasis
Negative 72 73.5 Positive 26 26.5
ER
Negative 37 37.8 Positive 61 62.2
PR
Negative 42 42.9 Positive 56 57.1
Her2/Neu
Negative 64 65.3 Positive 34 34.7
51
Table 3. Correlation of resistin expression with clinicopathological characteristics in breast cancer.
visfatin
Characteristics Low (%) High (%) P value*
Stage
I 31 (58.5) 12 (41.5) 0.284
II 14 (41.2) 20 (58.8)
III 6 (54.5) 5 (45.5)
Grade
I 3 (42.9) 4 (51.7) 0.641
II 36 (55.4) 29 (44.6)
III 12 (46.2) 14 (53.8)
Age
≦50 31 (60.8) 20 (39.2) 0.071
> 50 20 (42.6) 27 (57.4)
LN Metastasis
Negative 41 (56.9) 31 (43.1) 0.106
Positive 10 (38.5) 16 (61.5)
ER
Negative 13 (35.1) 24 (64.9) 0.009
Positive 38 (62.3) 23 (37.7)
PR
Negative 16 (38.1) 26 (61.9) 0.017
Positive 35 (62.5) 21 (37.5)
Her2/Neu
Negative 30 (46.9) 34 (53.1) 0.160
Positive 21 (61.8) 13 (38.2)
*The P value was calculated by the chi-square test.
52
Fig. 2 The average tumor size (cm in diameter) for breast patients with low and high visfatin expression. The average
tumor size was 1.97±0.14 cm for low visfatin expression (n=51) and 2.63±0.25 cm for high visfatin expression (n=47),
*P=0.024. Values were expressed as Mean±SEM determined by independent-samples t test.
*
53
Fig. 3 Kaplan–Meier survival curves generated by the low and high visfatin expression groups.
Low expression
High expression
P=0.005
54
High visfatin expression and ER negative
Low visfatin expression and ER positive
High visfatin expression and ER positive
Low visfatin expression and ER negative
P=0.001
Fig. 4 Kaplan–Meier survival curves generated by the low and high visfatin expression groups combined with
positive and negative ER status.
55
High visfatin expression and PR negative
Low visfatin expression and PR positive
High visfatin expression and PR positive
Low visfatin expression and PR negative
P=0.005
Fig. 5 Kaplan–Meier survival curves generated by the low and high visfatin expression groups combined with
positive and negative PR status.
56
Variables Odds ratio (95% CI) P Value
Tumor stage (I/II/III)
Tumor grade (I/II/III)
Age (>50 years)
ER status (negative/positive)
PR status (negative/positive)
Her2/Neu status (negative/positive)
Visfatin expression (High/Low)
14.49 (2.65-79.19)
1.90 (0.57-6.39)
1.22 (0.20-7.41)
5.60 (0.34-92.57)
1.70 (0.07-39.45)
1.24 (0.78-1.99)
14.40 (1.33-155.90)
0.002
0.298
0.827
0.228
0.742
0.367
0.028
Table 4. Cox regression multivariate analysis of overall survival for breast cancer
57
Conclusion
The elevated expression of visfatin may play a role in the carcinogenesis of breast cancer and the visfatin may serve as an independent prognostic factor for breast cancer.
Further investigations are required to better understand the detailed mechanisms of visfatin signaling in breast cancer development.
58
Acknowledgements
National Yang-Ming University
Department of Biomedical Imaging and Radiological Science, Hsin-Ell Wang.
National Chiao-Tung University
Department of Biological Science and Technology, Yun-Ming Wang and Jinn-Moon Yang.
Kaohsiung Medical University
Graduate Institute of Nature Products, Yang-Chag Wu. General Surgery and Cancer Center, Ming-Feng Hou.
E-DA Hospital
Chest Surgery, Yu-Jen Cheng and Kun-Chou Hsin.
General Surgery, Chao-Ming Hung and Liu Xian .
Colorectal Surgery, Shin-Pao Chen .
Medical Research, Ya-jing XIE .
Chang Gung University
Graduate Institute of Nature Products, Pei-Wen Hsieh.
I-Shou University
Department of Medical Nutrition, Jer-Yiing Houng .
59
60
Thank you for your attention