Serum leptin, adiponectin, and resistin concentration in colorectal ...

Int J Colorectal Dis (2009) 24:275–281 DOI 10.1007/s00384-008-0605-y

ORIGINAL ARTICLE

Serum leptin, adiponectin, and resistin concentration in colorectal adenoma and carcinoma (CC) patients Anna Kumor & Piotr Daniel & Mirosława Pietruczuk & Ewa Małecka-Panas

Accepted: 15 October 2008 / Published online: 1 November 2008 # Springer-Verlag 2008

Abstract Introduction Leptin, adiponectin, and resistin are the proteins secreted by adipocytes, which affects the metabolism. While the role of leptin in colon carcinogenesis is documented, the effect of adiponectin and resistin remains unclear. It has been indicated that while leptin may potentiate the cancer cells growth, adiponectin and resistin may act oppositely. Aim The aim of this study is to determine the concentration of leptin, adiponectin, and resistin in patients with adenomatous polyps and colorectal cancer. Methods The serum concentration investigated adipohormones had been measured with ELISA in 37 patients with colorectal adenomas, 36 with colorectal cancer (CC) and in 25 controls with no colorectal pathology. Endoscopically removed polyps and CC biopsies had been evaluated with histopathology. Mean BMI value was calculated for all patients. Results Among 37 adenomas, 25 revealed high-grade dysplasia (HGD) and 12 low-grade dysplasia (LGD). All cases of CC were adenocarcinomas. No difference in the level of investigated adipohormones in serum between patients with HGD and LGD polyps was observed. The serum concentration of leptin and adiponectin in CC patients was lower than in patients with adenomas (p0.05; Table 3). There were also no significant differences in serum concentration of leptin depending on polyp localization (p>0.05). On the other hand, the serum leptin concentration in CC was 4.12± 1.98 ng/ml which was significantly lower than in colorectal polyps (7.59±3.94 ng/ml) and in control group (10.21± 3.1 ng/ml; p0.05). The concentration of adiponectin in control group (17.8± 7.8 μg/ml) was only slightly higher than in colorectal adenomas (15.4±7.6 μg/ml; p>0.05) and significantly higher than in CC (12.0±4.9 μg/ml; p0.05; p>0.05, respectively). There were also no significant differences in serum concentration of adiponectin between A+B vs. C+D CC stage (12.3±3.9 μg/ml vs. 11.4± Table 3 Mean serum leptin concentration and p value in examined groups Group of patients Control group LGD colorectal adenoma HGD colorectal adenoma Adenocarcinoma, Dukes’ A+B Adenocarcinoma, Dukes’ C+D a

Serum leptin concentration (ng/ml) 10.21±3.1 6.72±2.04a 6.07±2.84b 3.88±2.01c 4.02±2.29d

p0.05 compared to LGD adenoma c p0.05 compared to adenocarcinoma, Dukes’ A+B b

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Int J Colorectal Dis (2009) 24:275–281 LEPTIN vs. ADIPONEC

Table 4 Mean serum adiponectin concentration and p value in examined groups

Control group LGD adenoma HGD adenoma Adenocarcinoma, Dukes’ A+B Adenocarcinoma, Dukes’ C+D

Serum adiponectin concentration (μg/ml) 17.8±7.8 14.7±6.2a 15.9±8.0b 12.3±3.9c 11.4±3.2d

a

p>0.05 compared to control group p>0.05 compared to LGD adenoma c p0.05 compared to adenocarcinoma, Dukes’ A+B b

3.2 μg/ml; p>0.05) as well as depending on tumor localization (p>0.05). The serum concentration of resistin in CC patients (6.79± 2.41 ng/ml) as well as in colorectal adenomas (5.29± 2.44 ng/ml) was significantly higher than in the control group (3.6±1.08 ng/ml; p0.05. No differences depending on polyp localization in resistin values have been found (p>0.05). Similarly, no differences considering resistin level between patients with tubulous (5.46± 3.03 ng/ml) and tubulovillous polyps (5.11±1.79 ng/ml) have been detected (p>0.05). There were also no significant differences in serum concentration of resistin between A+B vs. C+D CC stage (5.86±3.1 ng/ml vs. 6.76±4.2 ng/ml; p>0.05) as well as its localization (p>0.05). Among all examined patients with CC and adenomas, the correlation between adiponectin and leptin serum concentration (r=0,61) has been observed (Fig. 1). Table 5 Mean serum resistin concentration and p value in examined groups Group of patients

Serum resistin concentration (ng/ml)

Control group LGD adenoma HGD adenoma Adenocarcinoma, Dukes’ A+B Adenocarcinoma, Dukes’ C+D

3.6±1.08 4.89±2.15a 5.7±2.89b 5.86±3.1c

a

6.79±2.41d

p0.05 compared to LGD adenoma c p>0.05 compared to HGD adenoma d p>0.05 compared to adenocarcinoma, Dukes’ A+B b

30

ADIPONEC (mcg/ml)

Group of patients

r=0.61

34

26 22 18 14 10 6

0

2

4

6

LEPTIN (ng/ml)

8

10

Fig. 1 Correlation between leptin and adiponectin

Discussion Leptin, adiponectin, and resistin play the physiologic role in the reduction of food intake, energy homeostasis, and regulation of body weight. Simons JP et al. and Wallace AM et al. suggested that low-serum leptin concentration in their studies could be related to decreased body fat mass which is in opposition to our results [24–26]. In the present study, we did not observe a relationship between serum leptin concentration and weight loss in investigated groups. These data are with agreement with the study of Arpaci et al. who also observed decreased serum level of leptin in CC patients without weight loss and anorexia [1]. Based on our observations, we suspect that weight loss is not a causative factor of hypoleptinemia and some unknown mechanisms may be responsible for low-serum leptin level in colorectal adenoma and CC patients. We observed, to our knowledge, for the first time, lower leptin concentration in patients who presented with colorectal adenomas. We also found out that serum concentration of leptin did not differ in patients with colorectal adenomas depending on the grade of dysplasia, histopatology, and localization, what also have not been studied. Hardwick JC et al. observed increased proliferation of human colon cancer cells lines in studies in vitro and in vivo after stimulation with leptin. Based on this, the authors suspect that leptin represents the growth factor for colonic epithelial cells and can stimulate proliferation of the colon mucosa cells [27]. Similarly, Garofalo et al. suggested that leptin not only stimulates cell growth via ERK1/2 pathway in colorectal cancer but also reduces cell apoptosis [28]. However, Aparicio et al. observed that leptin stimulates proliferation only in vitro but did not promote tumor growth in in vivo study. We assume that these observations may be caused due to a much higher leptin concentration used in in vitro study. Tessitore et al. observed increased

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serum leptin concentration in breast cancer patients in comparison to control group [18]. The stimulatory effects of leptin on hormone-dependent tumors growth, such as breast and prostate cancer growth were considered to occur primarily via activation of the estrogen receptor [29, 30]. In our study, we observed significantly lower serum leptin concentration in CC patients than in patients with colorectal adenomas as well as in the control group. We did not observe differences between CC depending on stage (Dukes’ and TNM scale), which is in agreement with the study of Levy et al. The authors did not observe a statistically significant difference in leptin and adiponectin serum concentration between early and metastatic stages of colorectal cancer [31]. Our observations are also in agreement with the study of Bolukbas et al. Those authors observed significantly lower serum leptin concentration in CC patients than in control group. On the other hand, Tessitore L et al. showed that plasma leptin levels in CC were similar to controls [18]. Fukumoto et al. observed in patients with adenoma, slightly lower adiponectin serum concentration than in healthy controls [32]. As far as we are aware, this is the first analysis of the differences in adiponectin serum concentration in colorectal adenoma patients depending on grade of dysplasia, histopatology, and polyp localization. In our study, we also observed higher serum adiponectin concentration in control group than in patients with colorectal adenomas and CC. Our data correspond with the observations of Ishikawa M et al. who found lower adiponectin serum level in patients with gastric cancer in comparison to the control group [33]. Moreover, they observed that adiponectin serum concentration inversely correlated with tumor size and TNM stage. The latter may give support to our data concerning patients with different CC stages. In addition, a prospective study by Wei E et al. has detected an increased risk of CC in patients with low adiponectin concentration [34]. We hypothesized that probably, a low concentration of adiponectin in CC patients may be caused by overexpression of proinflammatory cytokines often observed in carcinogenesis. Wang et al. suspect that low concentration of adiponectin in CC patients serum can be caused by inhibition of this adipohormone not only by TNF alpha but also other cytokines [35]. On the other hand, a relatively low concentration of adiponectin may be caused by elevated expression of adipohormone receptors— AdipoR1 and Adipo R2—which was recently observed in vivo in colorectal cancer tissue and in vitro study [36]. Ogunwobi et al. have shown that adiponectin inhibits leptininduced cell proliferation via adiponectin receptor 1 (Adipo R1) in esophageal cancer tissue. The authors suspect that relative adiponectin deficiency may cause increased proliferation that predispose to malignant transformation [37]. In the present study, we observed that highest resistin serum concentration in CC patients and lowest in control

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group. Resistin is produced mostly by monocytes and macrophages of peripheral blood. Lehrke et al. observed that TNF alpha and IL-6 induced production of resistin mRNA as well as protein secretion by primary human macrophages [38]. These data can explain the highest concentration of resistin in colorectal cancer, which is strongly connected with inflammation [39]. They also found out that insulin sensitizers that have anti-inflammatory properties, including a synthetic PPARγ agonist (rosiglitazone), as well as aspirin, suppress macrophage resistin expression. To our best knowledge, there are no published data on resistin in colorectal adenomas and cancer; however, increased serum resistin concentration in patients with other cancers has been reported. Kan JH et al. observed significantly higher resistin level in breast cancer group 5.23±6.9 ng/mL vs. control 1.46± 2.0 ng/mL. They also noticed that the risk of breast cancer was significantly increased in the highest tertile group for serum resistin level compared to the lowest tertile one [40]. Chronic inflammation role in cancer development is well known. Inflammation may be represented by similar biomarkers as early carcinogenesis in various organs. Thus, the correlation between plasma resistin levels and breast cancer risk in the study by Kan JH et al. has been explained by accompanying inflammation [41]. Increased serum resistin concentration has been evaluated in other precancerous colon states. Konrad A et al. observed in patients with IBD significantly higher resistin levels compared with controls. They also noticed that resistin concentrations were significantly correlated with elevated white blood cell count, C-reactive protein (CRP), and disease activity [40]. Oppositely, Karmiris K et al. did not find a correlation between resistin and C-reactive protein in IBD patients [42]. Moreover, Mu H et al. found out that resistin induces not only human endothelial cell proliferation and migration but also promotes capillary-like tube formation. Resistin upregulates the mRNA expression of vascular endothelial growth factor receptors (VEGFR-1 and VEGFR-2) and matrix metalloproteinases (MMP-1 and MMP-2) at both mRNA and protein levels which play a pivotal role in carcinogenesis and metastasis formation [43]. Calabro P et al. found in human aortic smooth muscle, the increased proliferative effect in cells after stimulation with increasing concentrations of resistin through both ERK 1/2 and Akt signaling pathways [44]. To date, the role of resistin in colorectal carcinogenesis is not fully elucidated yet. We can speculate that resistin may promote colonocytes proliferation, however, further research are necessary. To our best knowledge, this is the first study in which resistin serum concentration was investigated both in CC and colorectal adenomas. In our study, we did not observe any differences in resistin serum concentration in colon adenomas of different grade of cellular dysplasia, histopatology, and adenomas localization.

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We have observed the correlation between adiponectin and leptin serum concentration in patients with colorectal adenomas and cancer. Therefore, we can assume that both these adipohormones may possibly play a significant and opposite role in both CC and even in CA formation, however, both adipohormones deserve further attention. On the basis of the present data, we can speculate that increased mucosal proliferation in colorectal carcinogenesis is stimulated with leptin and not inhibited with adiponectin due to the relative decreased concentration of the latter in colorectal cancer tissue. Based on our data, the decrease of leptin serum concentration in colorectal adenoma and CC patients is independent on BMI and weight loss. Due to the decrease in leptin and adiponectin serum concentration with the malignant transformation progression, we speculate that the estimation of those adipohormones might provide an additional tool for colorectal neoplasia prognosis. The possible role of all mentioned adipohormones in colorectal carcinogenesis prognosis needs further investigations. Acknowledgement

Supported by grant no 503-1002-1 and 507-11-333.

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