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Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Stoneman 816, Boston, Massachusetts 02215, USA1 Department of Pathology, University of Athens, M Asias 75 Athens 11527, Greece2 Division of Nutritional Epidemiology, The National Institute of Environmental Medicine, Karolinska Institutet, Nobels väg 13, Box 210 SE, Stockholm 17177, Sweden
(Correspondence should be addressed to C S Mantzoros; Email: cmantzor{at}bidmc.harvard.edu)
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Abstract |
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Introduction |
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The beneficial effects of adiponectin on metabolic outcomes and carcinogenesis may be mediated through the two identified cell membrane receptors, adiponectin receptor 1 (AdipoR1) and AdipoR2 (Kadowaki & Yamauchi 2005). We have previously reported that adiponectin receptors are expressed and elevated in breast tumor tissues (Korner et al. 2007), and additional studies by our group and others suggest that adiponectin receptors are also expressed and may play a role in prostate cancer as well (Mistry et al. 2006, Michalakis et al. 2007). Obesity has been established as a risk factor for colorectal carcinoma in numerous prospective (Giovannucci et al. 1996, Martinez et al. 1997, Ford 1999, Moore et al. 2004, Pischon et al. 2006), case–control (Caan et al. 1998), and meta-analysis (Dai et al. 2007) studies. Additional observational research suggests that circulating adiponectin may mediate in part this association, with low adiponectin conferring an increased risk of disease (Otake et al. 2005, Wei et al. 2005). However, it remains unknown whether adiponectin receptors are expressed in the gastrointestinal tract, and expression of AdipoR1 and AdipoR2 has not been previously studied in colorectal carcinomas or gastrointestinal stromal tumors (GISTs). Given the reciprocal relationship often observed between serum levels of a ligand and tissue expression of its receptors, we hypothesized that adiponectin receptors would be elevated in colorectal carcinomas.
GIST, even as the most common of the mesenchymal tumors of the GI tract, has a low incidence rate of 15 cases per million per year (Joensuu & Kindblom 2004). Risk factors for this malignancy may include older age, male gender, or black race (Tran et al. 2005), but no study has demonstrated any association between adiposity and GIST. Therefore, we hypothesized that adiponectin receptor expression would be unaltered in GIST tissue relative to respective non-tumor tissue and may be considered as a negative control group for the evaluation of our hypothesis regarding the association of obesity with adiponectin receptor expression in colorectal carcinomas.
Thus, we have examined immunohistochemically the expression of AdipoR1 and AdipoR2 in colorectal carcinomas, GISTs, and non-tumor GI tissue specimens. We also confirmed using rtPCR the expression of AdipoR1 and AdipoR2 in colorectal cancer and matched normal colon tissue from five patients and assessed the effect of adiponectin, at physiological concentrations, to alter intracellular signaling pathways in vitro. Elevated expression of adiponectin receptors in colorectal carcinomas would be consistent with deficiency of the ligand and could in part explain and expand current understanding of the observational association between low adiponectin and risk of certain cancers including colorectal cancer, reported by observational studies.
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Materials and methods |
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Available for analysis were 40 formalin-fixed paraffin-embedded colorectal adenocarcinoma tissue specimens and 12 non-tumor colorectal specimens from American male and female patients with colorectal carcinoma. Of the colorectal carcinoma specimens, 15 (37.5%) were in the sigmoid colon, 9 (22.5%) in the ascending colon, 7 (17.5%) in the rectum, 4 (10.0%) in the transverse colon, 3 (7.5%) in the cecum, and 2 (5.0%) in the descending colon. Of the colorectal cancer specimens, nine of the tumor specimens were matched to non-tumor tissues from the same patient.
We had 45 GIST specimens and 13 non-tumor stomach/small bowel specimens from American men and women with GIST. Locations of the tumor specimens were 22 (48.9%) in the stomach, 5 (11.1%) each in the jejunum and duodenum, 4 (8.9%) in the small intestine, 2 (4.4%) each in the ileum, omentum, mesentery, and rectum, and 1 (2.2%) in the abdominal cavity. All specimens were purchased in the form of tissue array slides mounted to standard silanized slides (Imgenex, San Diego, CA, USA). Of the GIST specimens, nine of the tumor specimens were matched to non-tumor tissues from the same patient.
Immunohistochemistry analysis
The 5 µm paraffin tissue sections were deparaffinized, rehydrated, microwaved for 25 min in 10 mmol/l citrate buffer, and incubated for 30 min in methanol containing 0.5% H2O2. After incubation in 16% normal goat serum for 1 h at room temperature, the slides were incubated for 1 h with the primary antibodies at room temperature. The primary antibodies used were the rabbit anti-human AdipoR1 (raised against amino acid residues 357–375) antiserum and the rabbit anti-human AdipoR2 (raised against amino acid residues 374–386) antiserum (both from Phoenix Pharmaceuticals Inc., Belmont, CA, USA) used at 1:500 and 1:200 dilution respectively. The secondary antibody was a biotinylated anti-rabbit antibody (1:400 dilution) and was applied for 30 min at room temperature, followed by the Vectastain Elite ABC Reagent (Vector Laboratories, Burlingame, CA, USA) for 30 min. The POD reaction was developed with diaminobenzidine, and the slides were counterstained with hematoxylin. Intensity and distribution of positive staining was evaluated on a scale of 0 to +++ by an expert pathologist (S T-B).
Real-time PCR
Adiponectin receptors expression was studied in human-matched paired cDNA samples from normal and colon cancer tissue of five patients (Human Colon Matched cDNA Pair Panel, Clontech). cDNA (30 ng) per 50 µl reaction were amplified using TaqMan Gene Expression system (Applied Biosystems, Foster City, CA, USA), specific primers and FAM tagged probes set (Applied Biosystems) and the Standard real-time 7500 protocol (Applied Biosystems), with an initial polymerase activation step at 95 °C for 10 min and 40 cycles including a 15-s melting step at 95 °C and a 1-min annealing-elongation step at 60 °C (Afonina et al. 1997). TATA box-binding protein (TBP) was used as endogenous control. Similarly, adiponectin receptor expression was detected in the human colorectal cancer cell lines CaCO2, HT-29, and SW480 (ATCC, Manassas, VA, USA) with real-time PCR, after RNA extraction with Trizol (Invitrogen) and first-strand cDNA synthesis, using Superscript III (Invitrogen), according to the manufacturer protocol. The analysis of relative gene expression was based on 
Ct values obtained from real-time PCR (Livak & Schmittgen 2001). PCR products were separated in 2% agarose gels, in 0.5xTBE, in a horizontal Mini-sub cell GT electrophoresis apparatus (Bio-Rad), under a 100 V constant voltage and visualized using Bio-Rad gel documentation system (Bio-Rad).
Western blotting
CaCO2, HT-29, and SW480 (ATCC) were cultured in DMEM, high-glucose, 10% FBS in medium (Invitrogen) and subcultured beyond 80% confluency. For immunoblotting purposes, cells were trypsinized and seeded in 12-well plates, let to adhere overnight, and subsequently starved for 24 h. Cells were treated with full-length recombinant human adiponectin (R&D systems, Minneapolis, MN, USA), AMP-activated protein kinase activator 5-Aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR, Sigma) or recombinant IGF I (Sigma). After treatment for the indicated time, cellular proteins were collected in 1% SDS. Total protein content was determined using the BCA assay (Pierce, Holmdel, NJ, USA). Lysates containing equal amounts of protein were separated on NuPAGE Novex 4–12% acrylamide gradient Bis–Tris gels (Invitrogen), using manufacturer's 4-morpholinepropanesulfonic acid (MOPS)/SDS running buffer, as previously described (Moos et al. 1988). After transfer on nitrocellulose membranes using a semi-dry apparatus (Bio-Rad), blots were blocked with 2% BSA (Sigma) in TBS-T and incubated overnight with primary antibodies against the phosphorylated proteins. Strips were then washed with TBS-T, incubated with secondary anti-rabbit-HRP antibody (1:5000, Chemicon, Billerica, MA, USA), and signal was detected with an ECL system (Amersham). For normalization purposes, membranes were stripped with the Mild Reblot stripping reagent (Chemicon) and re-blotted with antibodies against the total form of kinases. All primary antibodies: anti-phospho-p44/42 MAPK (ERK1/2, Thr202/Tyr204), anti-p44/42 MAPK, anti-phospho-AMPK
(Thr172), anti-AMPK, anti-phospho-S6 ribosomal protein (Ser235/236), and anti-S6 ribosomal protein were from Cell Signaling (Danvers, MA, USA).
Proliferation assay
CaCO2, HT-29, and SW480 (ATCC) were cultured in DMEM, high-glucose, 10% FBS medium (Invitrogen) and subcultured beyond 80% confluency. For proliferation experiments, cells were trypsinized and seeded in 96-well plates at 5x103 cells/well. Cells were let to adhere overnight and then treated with recombinant human adiponectin (R&D systems), ranging from 1 to 10 µg/ml, in serum-free or 1% FBS medium, for 60 and 120 h. Subsequently, medium was discarded, cells were quickly washed with PBS, and incubated with 100 µl serum-free medium and 10 µl Vybrant 3-(4,5-dimethylthiazol-2-gl)-2,5-diphenyltetrazolium bromide (MTT) solution (Invitrogen) for 2 h (Carmichael et al. 1987). Formazan crystals were dissolved with the addition of 100 µl of 10% SDS in 0.01 M HCl per well and absorbance was measured in an optical reader Power-Wave XS (BIOTEK, Winooski, VT, USA) at 570 nm. Experiments were performed twice in triplicates.
Statistical analysis
Descriptive characteristics of patients providing tumor and non-tumor specimens of colorectal cancer were compared using unpaired t-tests and 
2-tests for continuous and categorical measures. Case characteristics are presented as proportions. Unmatched analyses of expression of adiponectin receptors were conducted using 2-tests. For matched analyses, difference in relative expression was assessed using non-parametric Wilcoxon rank sum tests, and pair concordance was determined using McNemar's test for matched data. The analyses of GIST were conducted using the same methods and procedures as colorectal cancer. A fold increase was calculated for receptor expression of each paired sample and 95% confidence intervals (CI) were calculated for the group of paired samples. A level of =0.05 was set to determine statistical significance. All analyses were performed using SPSS version 11.5 (SPSS Inc., Chicago, IL, USA).
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Results |
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Real-time PCR analysis of matched cDNA colon samples showed a significant 1.6-fold (157%) increase of adipoR1 between cancerous and normal tissue (µ=1.57, 95% CI=(1.02, 2.12)). However, only a trend but no significant difference between normal and tumor tissue adipoR2 expression was found (µ=1.35, 95% CI=(0.71, 2.00)). Using immunohistochemistry in a larger number of samples, we found that tumor tissue was significantly more likely to show positive or strong positive expression of adiponectin receptors AdipoR1 and AdipoR2 than non-tumor tissue in colorectal specimens (Fig. 2, Table 3). Of colorectal carcinoma specimens, 95% displayed positive or strongly positive expression of AdipoR1 and 88% for AdipoR2, when compared with 8% and 0% respectively for non-tumor colorectal tissues (P for both <0.0001). For nine subjects of colorectal carcinoma cases, we had matched tumor and non-tumor tissues from the affected organ. Patients with matched colorectal specimens had a mean age of 53.3 years and seven of the nine subjects were men. Five of the matched specimens were sigmoid colon, two transverse colon, one ascending colon, and one rectum, and one patient had stage II disease, six stage III, and two stage IV. In colorectal carcinomas, tumor tissues showed significantly higher expression of AdipoR1 in seven of nine cases (78%, P=0.02) and AdipoR2 in six of nine cases (67%, P=0.04; Table 3). Results did not change when excluding the singular rectal cancer, which had marginal expression of both receptors. In addition, no significant differences in the expression of AdipoR1 and AdipoR2 were found among different stages of colorectal cancers. AdipoR1 expression was positive or strongly positive in all stages (P=0.31), except for two (10.5%) stage III specimens, where it was detected at marginal levels. Low AdipoR2 expression was found in 7.7, 15.8, and 12.5% of stage II, III, and IV stages samples respectively, with the rest of the samples showing positive or strongly positive staining. Similarly to AdipoR1, no association between AdipoR2 levels and colorectal cancer stage was found (P=0.79).
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GIST
Tumor tissue did not show more positive or strongly positive expression of adiponectin receptors AdipoR1 and AdipoR2 than non-tumor tissue in GIST specimens (Table 4, Fig. 3). AdipoR1 was positively expressed in 47% of tumors and 64% of control tissues. Positive expression of AdipoR2 was apparent in 38% of GIST and 23% of control stomach and small bowel tissue. Differences in receptor expression between GIST and control tissue were not statistically significant (P=0.50 for AdipoR1, P=0.51 for AdipoR2).
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Thus, there appears to be no significant differences in either adiponectin receptor expression between GIST and non-tumor stomach/small bowel tissue. Furthermore, we found no significant difference in adiponectin receptor expression between tumor sizes and risk categories of GIST cases (low, intermediate, high) for either AdipoR1 or AdipoR2 (Table 5).
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Expression of both adiponectin receptors was confirmed in three different cancer cell lines: CaCO2, HT-29 and SW480 (Fig. 4), similar to the results in human colon cancer cells. AdipoR2 was expressed in lower levels in colon cancer cell lines. Treatment with adiponectin in physiological dose (10 µg/ml) for 0–40 min resulted in the activation of distinct molecular pathways, involving ERK1/2, AMPK, and S6 phosphorylation, as shown in Fig. 4. However, 60-h treatment with adiponectin (1–10 µg/ml) had no effect on cell viability when compared with the control. No promoting effect on cell proliferation was found with cell treatment up to 120 h.
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Discussion |
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One of the major risk factors for colorectal carcinoma is obesity, as well as conditions leading to obesity including lack of physical activity and diets high in sugar, refined grains, and low in fiber (Potter et al. 1993, Chao et al. 2004, Cottet et al. 2005, Gunter & Leitzmann 2006). Similarly, individuals with insulin resistance (IR) or type 2 diabetes have up to 3 times the risk of developing colorectal carcinoma as non-diabetic individuals, and previous work has demonstrated that insulin increases proliferation and inhibits apoptosis in colorectal cancer cell lines (Gunter & Leitzmann 2006). In addition, IR induces changes in levels of IGFs, whose receptors are expressed in colon tissues, which further promote cellular proliferation and inhibit apoptosis (Giovannucci 2001).
Adiponectin has well-documented insulin-sensitizing effects (Ouchi et al. 1999, 2001, Yokota et al. 2000, Gavrila et al. 2003), which may in part explain the reduction in cancer risk associated with higher circulating levels of this adipokine. Physical activity and a Mediterranean pattern diet, which may decrease colorectal cancer risk (Trichopoulou et al. 2000, Chao et al. 2004, Cottet et al. 2005, Larsson et al. 2006), have both been associated with increased adiponectin levels (Bluher et al. 2006, Mantzoros et al. 2006). In addition, adiponectin has anti-inflammatory effects and may also play a role in suppressing neovascularization, which is required for tumor proliferation (Barb et al. 2006). Recently published prospective cohort (Wei et al. 2005) and case–control (Otake et al. 2005) studies have found a >50% increased risk of colorectal carcinoma in subjects with low concentrations of adiponectin. It remains uncertain, however, whether the beneficial effects of adiponectin observed in colorectal carcinoma are indirect, i.e., through changes in insulin resistance and IGF status, or whether adiponectin may act directly on the tumor cells to inhibit proliferation and/or induce apoptosis. Presence of adiponectin receptors in tumor tissues may support a direct impact of adiponectin on colorectal carcinogenesis. We clearly demonstrate not only that colon carcinoma cells express both of the classical adiponectin receptors, but also that the expression is stronger than in healthy tissue specimens from these patients. Similar to other endocrine systems, the upregulation of both adiponectin receptors in tumor cells may be a cellular response to lower circulating adiponectin levels in patients with colorectal cancer and/or a compensatory response of their malignant cells. In addition, we found that adiponectin stimulates the transient activation of intracellular signaling pathways in CaCO2, HT-29 and SW 480 cell lines, including ERK1/2, AMPK, and S6 ribosomal subunit phosphorylation. Recently, Kim et al. (2007) reported that AMPK activation could induce apoptosis in HT-29 colon cancer cells, while ERK1/2 is widely involved in the enhancement of cell proliferation and especially cell migration (Roberts & Der 2007). We have previously shown that adiponectin activated both the AMPK and ERK 1/2 signaling pathways but inhibited proliferation in the T47D breast cancer cell line (Korner et al. 2007). Moreover, recombinant adiponectin and adenovirus-mediated overexpression of this adipokine substantially reduced the mammary tumorigenesis of MDA-MB-231 cells in female nude mice (Wang et al. 2006). Adiponectin has also been found to inhibit prostate cancer cell growth (Bub et al. 2006). More recently, adiponectin, acting through its specific membrane receptors AdipoR1 and AdipoR2, was shown to inhibit the growth and peritoneal metastasis of gastric cancer in vivo (Ishikawa et al. 2007). Cellular proliferation was not altered in the limited time period studied herein but more detailed and longer studies are needed, especially, as adiponectin's effect on kinase activation was transient, reaching its maximum levels 20 min after its administration.
Thus, the simultaneous activation of several signaling pathways in colon cancer cells and/or the systemic insulin-sensitizing effects of adiponectin may account for the protective effect of this hormone seen in observational cohort studies. This remains to be studied by interventional studies in the future. Whether adiponectin receptor expression in colorectal tumors may also prove to have prognostic significance, similar to expression of estrogen receptors in breast cancer, remains to be studied in large prospective studies. Moreover, the increased expression of adiponectin receptors on colon cancer cells may represent a possible therapeutic target for the clinical use of adiponectin in patients with metastatic colon cancer. Further studies are necessary to confirm this potential mechanism for adiponectin to act directly on colonic epithelial cells to prevent carcinogenesis and/or to alter cancer cell growth and apoptosis.
GISTs have not previously been associated with obesity or insulin resistance. We therefore hypothesized that adiponectin receptor expression would be similar in GIST specimens and in the respective normal gastric/small bowel tissues and utilized such specimens as a negative control in our study. We found positive expression of AdipoR1 and AdipoR2 in less than half of all GIST specimens, but expression was not more pronounced than in control tissue. Because GIST is mesenchymal in origin and may not be comparable with the epithelial non-tumor GI specimens, we tested for variation in adiponectin expression among tumor specimens by low-, intermediate-, or high-risk categories and found no significant differences. The lack of strong expression of adiponectin receptors in the majority of GIST specimens, in contrast to results of this and previous studies in relation to colorectal carcinomas, does not support a major role for adiponectin in this tumor type. Additionally, when we used GIST specimens as negative controls for colorectal carcinomas, results showed that adiponectin receptor expression was significantly higher in colorectal carcinomas than in GIST. However, these variations may be due to differential expression of adiponectin receptors in the stomach or small bowel versus the colorectal region. Further studies including healthy subjects are needed to confirm these results and examine expression of adiponectin receptors in various regions of the GI tract in individuals free of any carcinoma.
In summary, we report that adiponectin receptors are expressed in normal GI tissue and that their relative expression is higher in upper parts of the GI tract. Moreover, adiponectin receptors are present in colon cancer cell lines and their activation with adiponectin in physiological concentrations results in activation of intracellular signaling pathways. Our data complement current observational evidence indicating that low circulating adiponectin concentrations may play a role in the development and/or progression of colorectal carcinomas. We have demonstrated in this study that both adiponectin receptors, AdipoR1 and AdipoR2, are expressed in nearly all colorectal carcinomas but not in non-malignant colorectal tissue and in some but not all GIST. The pathophysiological significance of the presence of adiponectin receptors as well as their potential predictive value in terms of colorectal cancer risk, relapse, and treatment outcomes need to be examined in detail in future studies.
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Acknowledgements |
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Footnotes |
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References |
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 E. Th. Petridou, T. N. Sergentanis, N. Dessypris, I. T. Vlachantoni, S. Tseleni-Balafouta, A. Pourtsidis, M. Moschovi, S. Polychronopoulou, F. Athanasiadou-Piperopoulou, M. Kalmanti, et al. Serum Adiponectin As a Predictor of Childhood Non-Hodgkin's Lymphoma: A Nationwide Case-Control Study J. Clin. Oncol., October 20, 2009; 27(30): 5049 - 5055. [Abstract] [Full Text] [PDF]
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 V Barresi, M Grosso, G Giuffre, G Tuccari, and G Barresi The expression of adiponectin receptors Adipo-R1 and Adipo-R2 is associated with an intestinal histotype and longer survival in gastric carcinoma J. Clin. Pathol., August 1, 2009; 62(8): 705 - 709. [Abstract] [Full Text] [PDF]
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 A. Yildirim, M. Bilici, K. Cayir, V. Yanmaz, S. Yildirim, and S. B. Tekin Serum Adiponectin Levels in Patients with Esophageal Cancer Jpn. J. Clin. Oncol., February 1, 2009; 39(2): 92 - 96. [Abstract] [Full Text] [PDF]
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 V. G. Kaklamani, K. B. Wisinski, M. Sadim, C. Gulden, A. Do, K. Offit, J. A. Baron, H. Ahsan, C. Mantzoros, and B. Pasche Variants of the Adiponectin (ADIPOQ) and Adiponectin Receptor 1 (ADIPOR1) Genes and Colorectal Cancer Risk JAMA, October 1, 2008; 300(13): 1523 - 1531. [Abstract] [Full Text] [PDF]
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