|Year : 2014 | Volume
| Issue : 2 | Page : 347-353
Clinical significance of adiponectin expression in colon cancer patients
Mustafa Canhoroz1, Ozkan Kanat2, Ozlem Saraydaroglu3, Emine Buluc3, Nilufer Avci2, Erdem Cubukcu2, Omer Fatih Olmez2, Osman Manavoglu2
1 Department of Medical Oncology, Faculty of Medicine, Firat University, Elazig, Turkey
2 Department of Medical Oncology, Faculties of Medicine, Uludag University, Bursa, Turkey
3 Department of Medical Pathology, Faculties of Medicine, Uludag University, Bursa, Turkey
|Date of Web Publication||14-Jul-2014|
Department of Medical Oncology, Firat University Faculty of Medicine, Elazig, 23100
Source of Support: None, Conflict of Interest: None
Purpose: Surgery is the definitive treatment for early colon cancers. Adjuvant therapies are used with the aim of eradicating micrometastases and improving cure rates. Recent studies have proposed that adiponectin might be responsible for obesity-related malignancies. We investigated the prognostic value of this cytokine.
Materials and Methods: Patients who underwent surgical removal of stage II or III (TNM staging) primary tumors and were followed for at least three years were included in the study given adequate specimen for immunohistochemical evaluation. Based on these criteria, 53 patients were included.
Results: Mean age was 58.3 ± 10.1 years (35-78 years). The mean follow-up time was 41 months (10-96 months). Immunohistochemical evaluation identified 21 patients (39.6%) with cytoplasmic adiponectin present in their specimens. The rates of recurrence were 42.9% (9/21) and 34.4% (11/32) in patients with and without adiponectin expression, respectively. In cases with adiponectin expression, mean disease - free survival was 60.3 ± 9.03 months, and in cases without adiponectin expression, mean disease - free survival was 68.7 ± 6.67 months (P = 0.414). Mean overall survival of patients with adiponectin expression was 65 months compared to 67 months for patients without (P = 0.786).
Conclusion: Adiponectin, which is secreted by adipose tissue, may have a role in the development and progression of cancer via its pro-apoptotic and/or anti-proliferative effects. Adiponectin expression in tumor tissues is likely to have a negative effect on disease - free survival in patients with stage II/III colon cancer; however, no statistically significant effect was demonstrated.
结果：平均年龄为58.3±10.1岁（35~78岁）。平均随访时间为41个月（10~96个月）。免疫组化结果显示21例（39.6%）病人的标本存在胞浆脂联素表达。脂联素表达阳性和阴性的患者复发率分别为42.9%（9／21）和34.4%（11／32）。脂联素的表达阳性病例中，平均无病生存时间为为60.3±9.03个月，脂联素的表达阴性病例中，平均无病生存为68.7±6.67个月（P = 0.414）。有脂联素表达患者的平均总生存时间65个月，而无表达组为67个月（P = 0.786）。
结论：脂联素，它是由脂肪组织分泌的，可能在癌症的发生和发展中起作用，通过其促凋亡和/或抗增殖的影响。II / III期结肠癌患者中，脂联素高表达可能是结肠癌患者预后不良指标，但统计分析结果并不支持该结论。
Keywords: Adiponectin, colon cancer, obesity-related malignancies
|How to cite this article:|
Canhoroz M, Kanat O, Saraydaroglu O, Buluc E, Avci N, Cubukcu E, Olmez OF, Manavoglu O. Clinical significance of adiponectin expression in colon cancer patients. J Can Res Ther 2014;10:347-53
|How to cite this URL:|
Canhoroz M, Kanat O, Saraydaroglu O, Buluc E, Avci N, Cubukcu E, Olmez OF, Manavoglu O. Clinical significance of adiponectin expression in colon cancer patients. J Can Res Ther [serial online] 2014 [cited 2018 Nov 14];10:347-53. Available from: http://www.cancerjournal.net/text.asp?2014/10/2/347/136634
| > Introduction|| |
Obesity is a major health concern worldwide, particularly in developed countries. In European countries, it is estimated that 35-50% of the population is overweight or obese.  Obesity is defined as a body mass index (BMI) of 30 kg/m 2 or greater and results from hypertrophy and hyperplasia of the adipocytes due to excessive energy intake.  Obesity is related to life-threatening conditions, including coronary artery disease, hypertension and type 2 diabetes mellitus. Moreover, recent studies have found that obesity is a risk factor for certain cancers,  such as colon, breast, endometrial, esophageal, kidney, and pancreatic cancers, as well as, multiple myelomas, leukemias, and lymphomas. , Previous studies have reported that a two point increase in BMI increases colon cancer risk by approximately 7%, and a 2 cm increase in waist circumference increases colon cancer risk by around 4%.  Obesity-related colon cancers account for 14-35% of the total incidence in the United States and Europe.  Therefore, the risk of obesity-related colon cancer might be reduced by weight loss. 
Surgery is the definitive treatment for locoregional colon cancer. Recurrences are caused by occult micrometastases present at the time of surgery. Adjuvant therapies aim to eradicate micrometastases and to improve cure rates. In stage III (node positive) patients, adjuvant chemotherapy reduces the risk of recurrence by 30% and the risk of mortality by 22-32%. The benefits of adjuvant chemotherapy for stage II patients are less clear. ,, In randomized trials and meta-analyses, the absolute benefits of 5-FU based regimes have been estimated at 5% for patients with surgically removed tumors. Although other clinical trials exist, they are relatively small and do not have clinical significance. Despite direct evidence, ASCO recommends that adjuvant chemotherapy be administered when clinically available to high-risk patients (T4 signet ring cell or mucinous tumors and less than 13 lymph nodes were removed). The recommendation is based on the MOSAIC trial, which studied stage III patients and performed other subtype analysis. ,,,
Adipose tissue was previously considered a storage tissue, but has recently been described as the largest endocrine organ.  Adiponectin is secreted by adipose tissue, increases insulin sensitivity, and has anti-atherogenic and anti-diabetic effects. ,, A number of studies suggest that adiponectin might be involved in the development and progression of obesity-related malignancies. , Epidemiologic studies also report that low adiponectin levels are associated with increased risk for breast cancer ,, and endometrial cancer , in women, as well as, for prostate ,, and colorectal cancer (CRC) in men. , Adiponectin's effects on insulin resistance, hyperinsulinemia, neovascularization, and inflammatory processes, as well as, its pro-apoptotic and anti-proliferative effects in tumor cells, may contribute to the development and progression of cancer. ,, Williams et al.  demonstrated increased adiponectin receptor expression in CRC tumor cells. Barresi et al.  also determined that adiponectin receptor expression was associated with histologic grade and tumor microvascular intensity.
We investigated whether adiponectin expression is correlated with clinical and histopathologic features and may be used as a prognostic and/or predictive parameter.
| > Materials and methods|| |
Data collected from CRC patients treated at the medical oncology department between 1997 and 2007 were analyzed. Of the 322 CRC cases, 76 who underwent surgical removal of stage II/III primary tumors and received follow-up treatment for at least three years, were initially selected. Primary tumor sections of only 53 patients were archived in the Pathology Department at our institution and available for immunohistochemical evaluation.
The following data were obtained from patient files: age, gender, time of diagnosis, tumor localization, tumor invasion (T), nodal involvement (N), tumor stage, histologic grade, presence of perineural/lymphovascular/venovascular invasion, adjuvant chemotherapy status, additional risk factors, disease free survival (DFS), overall survival (OS), and length of follow-up. OS is defined as the time period between the time of diagnosis and the time of death, whereas DFS is defined as the time period between diagnosis and the first recurrence. Presence of recurrence is defined as positive radiological imaging for metastatic or recurrent mass, and/or progressive increase in tumor markers.
Adiponectin expression in specimens was detected using immunohistochemical (IHC) analysis. Adiponectin antibody (Novus Biologicals, 100-65810) was diluted 1/100 and then applied. IHC staining was performed using the streptovidin-avidin-biotin method. Tissue sections (4μm thick) were placed on slides containing lysine, then deparaffinized at 60°C in an oven overnight. The slides were immersed in xylene and 96% citrate buffer (pH 6.0) three times, 5 min each. The slides were then heated in a microwave (750 watt) for 20 min; distilled water was added in 5 min intervals. After heating, phosphate buffer saline (PBS) was applied twice. Slides were dried and kept in 3% hydrogen peroxide at room temperature for 15 min. PBS was applied again, and protein block was applied for 10 min. Sections were incubated with primary antibodies for one hour. PBS was applied three times, and biolynated link (secondary antibody) was applied for 15 min, followed by PBS again and application of DAB chromogen for 10 min.
Sections were washed with distilled water and then analyzed under a light microscope by an experienced pathologist. The slides were assessed according to staining extension and intensity. Sections with significant involvement and extension of 5% or greater were considered positive.
Intergroup homogeneity was compared using Fisher's Chi-square test, and survival analyses and curves were performed using the Kaplan-Meier test. The log-rank test was used to compare survival curves. P values less than 0.15 were subjected to multivariate analysis performed using the Cox regression test. Confidence intervals of 95% and P values less than 0.05 were considered statistically significant. Statistical analyses were performed using SPSS 13.0.
| > Results|| |
Fifty-three cases were analyzed. Thirty-two patients were male (60.4%) and 21 patients (39.6%) were female. The mean patient age was 58.3 ± 10.1 years (35-78 years). Mean follow up was 41 months (10-96 months). Pathologic features (tumor localization, T staging, lymph node involvement, histologic grade, perineural invasion, lymphovascular invasion, and venovascular invasion) and clinical features (obstruction, perforation and adjuvant chemotherapy) of the patients are summarized in [Table 1].
During follow-up, 20 patients (37.7%) had recurrences; 6 patients had local recurrences (intraabdominal lymph node, peritoneal involvement) and 14 patients had distant metastases. The mean DFS was 65.4 ± 5.43 months and the mean OS was 66.2 ± 5.05 months for all patients. IHC staining revealed adiponectin expression in tumor tissue of 21 patients (39.6%). The staining had a cytoplasmic pattern. Extra-tumoral staining patterns were considered insignificant.
Using Cox-regression analysis, associations between OS and stage, grade, perineural invasion, venovascular invasion, adiponectin expression, and the presence of risk factors were investigated. Overall, this model was statistically significant (P = 0.000). Stage had the most significant effect (P = 0.002); progression from stage II to III caused an 8.57-fold increase in risk. Other effective factors were perineural invasion (P = 0.003, OR = 6.55), lymphovascular invasion (P = 0.015, OR = 5.31), presence of risk factors (P = 0.010, OR = 4.69) and grade (P = 0.044, OR = 2.85). Venovascular invasion (P = 0.057, OR = 0.198) and adiponectin expression in tumoral tissue (P = 0.589, OR = 0.589) were statistically insignificant [Table 2].
|Table 2: Using cox-regression analysis, associations between OS and clinicopathologic factors|
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The association between adiponectin and OS was reevaluated using the Kaplan-Meier test. In the adiponectin expressing group, 9 out of 21 patients (42.9%) had recurrences, whereas of the patients without adiponectin, 11 out of 32 had recurrences (34.4%). The mean OS was 65 months for the adiponectin expressing group and 67 months (P = 0.786) for patients without adiponectin. In the OS diagrams, the overall survival curves overlap [Figure 1].
Using Cox-regression analysis, associations between DFS and stage, grade, perineural invasion, venovascular invasion, adiponectin expression, and the presence of risk factors were also investigated. Overall, this model was statistically significant (P = 0.000). Stage had the most significant effect (P = 0.003); progression from stage II to III caused a 6.05-fold increase in risk. Other significant factors were perineural invasion (P = 0.011, OR = 4.75), lymphovascular invasion (P = 0.015, OR = 5.32), presence of risk factors (P = 0.017, OR = 3.89), and grade (P = 0.023, OR = 3.28). Venovascular invasion (P = 0.083, OR = 0.248) and adiponectin expression in tumoral tissue (P = 0.838, OR = 1.10) were statistically insignificant [Table 3].
|Figure 1: Overall survival curves for adiponectin expression (*adipon:adiponectin)|
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|Table 3: Using cox-regression analysis, associations between DFS and clinicopathologic factors|
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The association between adiponectin and DFS was reevaluated using the Kaplan-Meier test. Mean DFS was 60.3 ± 9.03 months for the adiponectin expressing group, versus 68.7 ± 6.67 months (P = 0.414) for the group without adiponectin expression. In the DFS diagrams, the disease free survival curves did not overlap [Figure 2].
|Figure 2: Disease free survival curves for adiponectin expression (*adipon:adiponectin)|
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The associations between adiponectin expression and pathologic and clinical features were analyzed using the chi-square test [Table 4]. Stage, grade, tumor localization, pT, pN, gender, perineural invasion, venovascular invasion, lymphovascular invasion, clinical risk factors, and recurrence rates were not associated with adiponectin expression.
|Table 4: Association between adiponectin expression and clinical and pathologic parameters|
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Upon evaluating an association between tumor localization and adiponectin expression, only two cases had tumors localized at the transverse colon, so the chi-square test could not be performed. Instead, cases were reclassified as either tumors of the left colon or tumors with other localizations. After reclassification, the associated P value was 0.131.
| > Discussion|| |
The present study included patients with stage II or III colon cancer, who underwent surgical treatment at our institution. Stage I patients, who do not need adjuvant chemotherapy, and patients with distant metastases at the time of diagnosis were excluded from the study. All except two patients were administered 5 fluorouracil (5-FU) based adjuvant therapy. Current standard therapy for stage III patients is a combination of 5-FU/leucovorin infusion and oxaliplatin (FOLFOX).  However, at the time of our study, oxaliplatin had just been approved in our country, so only one patient was administered FOLFOX; the rest were given bolus 5-FU/LV therapy. The MOSAIC trial reported that high-risk stage II patients had a higher rate of improved outcomes when administered FOLFOX as opposed to 5-FU/LV infusion (HR = 0.72; 95% CI, 0.50-1.02). No similar benefit was observed among low-risk stage II patients. 
Although, our population was administered therapy standard at the time of the study, stage III patients and high-risk stage II patients (T4 tumor, tumoral perforation, bowel obstruction, poorly differentiated tumor, venous invasion, less than 10 lymph nodes evaluated) were not appropriately treated according to current therapy guidelines. ,
According to a study which reviewed 18 randomized trials and a total of 20.918 patients, 2- and 3- years DFS for adjuvant therapy were described as appropriate parameters. , A recent study also stated that most recurrences occur within two years. The study estimated a recurrence rate of less than 1.5% per year after five years and less than 0.5% per year after eight years.  Based on these studies, ,, our follow-up period is appropriate for evaluation of such survival parameters.
CRC patients were operated on by experienced surgeons. The experience level of the surgeon seems to influence survival rates.  Although, some studies suggest the opposite.  Studies have also stated that the number of removed lymph nodes is associated with improved survival. ,, In most of the patients (46 of 53) 12 or more lymph nodes were removed, while in 7 cases surgeons failed to remove the appropriate number of nodes.
Emergency surgery had to be performed on 10 patients in our study; 8 had obstruction and 2 had perforation. According to the literature, 10% of CRC patients present with obstruction.  Obstruction is described as a poor prognostic factor, , and perforation is also considered an independent prognostic factor. ,
Specimens from 53 patients, who were comparable to the general CRC population, successfully underwent surgery, and were good candidates for adjuvant chemotherapy were analyzed for adiponectin expression and after IHC staining. Twenty-one patients had adiponectin expression. Williams et al. demonstrated the presence of adiponectin receptors in surgery specimens,  and in a study by Barresi et al., 12 of 45 CRC patients had cytoplasmic adiponectin expression in tumoral tissues.  In Barresi et al., adiponectin expression was higher in high grade tumors (P = 0.0002) and in tumors with high microvascular intensity (P = 0.0471). Due to technical issues, we could not assess microvascular intensity. There was no association between tumor grade and adiponectin expression (P = 0.477), but left colon tumors were found to have higher levels of adiponectin expression (P = 0.002). The variety of findings among studies may result from relatively small series, as well as, ethnic, geographic and cultural differences.
Adiponectin in the cytoplasm may be contained via endocytosis or excretion of the cell itself. The presence of adiponectin inside cells may indicate that adiponectin receptors are also functioning within the cells.  Adiponectin receptors (AdipoR1/R2) are expressed by normal gastrointestinal tissue, as well as, by most of the CRC tissues. Healthy tissues located in the upper gastrointestinal tract have more adiponectin expression than tissues located in the lower tract. In obesity-related CRCs, adiponectin receptor expression is higher than in surrounding normal tissues. Although, adiponectin receptor expression is higher in obesity related CRC than in surrounding normal tissues, no such association has been demonstrated in tumors unrelated to obesity like gastrointestinal stromal tumors.  Obesity is a major risk factor for CRC. Other risk factors, including sedentary lifestyle, and high carbohydrate and low fiber diets, are also associated with obesity.  Patients with insulin resistance or type 2 diabetes have a three-fold increased risk for CRC. In vitro studies have shown that insulin increases proliferation and inhibits apoptosis in CRC tumor cells.  Moreover, insulin resistance increases the levels of insulin-like growth factors, and these factors also inhibit apoptosis. 
Studies have reported that adiponectin suppresses the proliferation of myelomonocytic leukemia cell series and increases apoptosis in a dose-dependent fashion.  It has also been indicated that adiponectin inhibits proliferation in breast, prostate, and hepatocellular cancer cell series. , In contrast, adiponectin increases proliferation of colonic epithelial cells.  These studies were performed under in vitro conditions- therefore, different results might be obtained in vivo- and included some conflicting results. , The anti-proliferative effect of adiponectin is poorly understood but is thought to occur partially through 5' protein kinase (AMPK) activation. AMPK activation causes inhibition of mTOR (the mammalian target of rapamycin), fatty acid synthase and acetyl-CoA carboxylase. It also reduces sterol regulator element binding protein 1c (SERBP-1c) expression, and therefore, suppresses de novo fatty acid synthesis. Furthermore, AMPK increases the levels of p21 and p53, proteins responsible for growth control and apoptosis regulation.  The effects of AMPK occur quickly and are short-lived, reaching a peak within 10 min and lasting 30-60 min.  Long-term administration of adiponectin causes a decline in c-myc and cyclin D1 levels, potentially via the β-catenin-Wnt pathway.  Chronic therapy with adiponectin decreases Akt phosphorylation, blocking glycogen synthase kinase-3β inhibition, and increases β-catenin catabolism. ,
In the present study, we investigated adiponectin expression in colorectal cancer cells. We also investigated the association between adiponectin expression and survival outcomes. Survival curves may indicate that adiponectin has a negative effect on DFS; however, no significant effect was found upon statistical analysis. Previous studies have determined that stage, lymphovascular invasion, perineural invasion, clinical risk factors, and tumor grades are parameters that influence DFS; our findings were consistent with the literature. The mean DFS was 60.3 ± 9.03 months in the presence of adiponectin expression compared to 68.7 ± 6.67 months without adiponectin expression (P = 0.414). Adiponectin expression was not associated with OS. Dissociation seen on DFS figure did not occur on OS figure. The mean DFS was 65 months in the presence of adiponectin expression compared to 67 months without adiponectin expression (P = 0.786).
While the negative effect of adiponectin on DFS was not statistically significant, the lack of significance may be due to the relatively small sample size. However, the negative effect was limited to DFS. Repeated therapies may reduce the importance of adiponectin expression; moreover, recurrent, macroscopic tumors with adequate vascularization may lower the importance, as well.
As in vitro studies indicate the anti-proliferative effects of adiponectin, we do not expect that adiponectin expression affects DFS negatively. However, possible explanations for a negative effect could be as follows:
1. Adiponectin may reduce the benefits of adjuvant therapy by keeping tumoral cells dormant using its anti-proliferative and anti-angiogenic effects.
5-FU/LV is an antimetabolite and affects the cells at S phase. As dormant cells are not in S phase, malignant cells may not be affected by chemotherapy and may eventually become clinically obvious. Macroscopic tumors have active cell division, so chemotherapy is effective. If this explanation is true, then adiponectin expression may be a negative predictive factor for adjuvant chemotherapy.
2. Tumor cells may have a mutation that causes unresponsiveness to adiponectin.
Within a cell, there are numerous signaling pathways that interact with each other. Adiponectin is thought to derive its effects through the AMPK, PI3K/Akt, and β-catenin-Wnt pathways. Mutations in these pathways or interactions with other pathways may desensitize the cell to the effects of adiponectin, and these mutations are expected to result in more aggressive tumors. Barresi et al.  found that poorly differentiated tumor cells had higher adiponectin expression. If this explanation is true, adiponectin expression may be a poor prognostic factor.
3. Adiponectin may have proliferative effects in tumor cells.
Ogunwobi et al. found that adiponectin has proliferative effects on colonic epithelial cells in vitro.  Adiponectin may affect colon cancer cells, as well, and may cause proliferation. If true, then adiponectin expression may be a marker for poor prognosis.
No statistically significant difference was observed between OS of patients with and without adiponectin expression. Other poor prognostic factors, including grade and invasion, were not correlated with adiponectin expression. These findings reduce the likelihood that adiponectin expression is a prognostic parameter and increase the possibility of adiponectin as a predictive parameter for adjuvant therapy.
Additional studies with larger patient groups are necessary to evaluate adiponectin expression as a useful predictive and/or prognostic parameter in clinical practice.
| > Conclusion|| |
In our study, adiponectin expression in tumor cells was associated with reduced DFS, but this result was not statistically significant. The lack of statistical significance may be due to our relatively small patient population; with larger groups, statistical significance may be demonstrated.
If further studies provide consistent results, adiponectin expression may prove useful as a predictive and/or prognostic factor in clinical practice.
| > References|| |
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]