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. 2018 May 4;11:2519–2531. doi: 10.2147/OTT.S157255

Low circulating total adiponectin, especially its non-high-molecular weight fraction, represents a promising risk factor for colorectal cancer: a meta-analysis

Weiqun Lu 1,2, Zhiliang Huang 1,2, Nan Li 1,2, Haiying Liu 1,2,✉
PMCID: PMC5942166  PMID: 29765231

Abstract

Aim

The principal goal of this meta-analysis is to test the hypothesis that circulating total adiponectin or certain fractions may represent a promising biological candidate in modulating the risk of colorectal cancer.

Methods

The processes of paper identification, paper selection and data extraction were accomplished independently by two authors. Effect-size estimates were expressed as weighted mean difference (WMD) and 95% confidence interval (95% CI). A total of 31 papers including 48 qualified studies (7,554 patients with colorectal cancer and 9,798 controls) were meta-analyzed.

Results

Pooling all studies found that circulating total adiponectin was significantly lower in patients with colorectal cancer than in controls (WMD: −0.76 µg/mL, 95% CI: −1.20 to −0.32, p=0.001), with significant heterogeneity (I2: 94.2%) and low publication bias (Egger’s p=0.336). By adiponectin fractions, the difference in high-molecular weight (HMW) adiponectin was comparable between the two groups (WMD: −0.22 µg/mL, 95% CI: −0.70 to 0.25, p=0.350), while non-HMW adiponectin was significantly lower in patients with colorectal cancer than in controls (WMD: −0.27 µg/mL, 95% CI: −0.35 to −0.19, p<0.001), with marginal heterogeneity (I2: 52.3%). Subgroup analysis revealed that effect-size estimates were heterogeneous when grouping studies by cancer subtype, region, study design, matching status, gender and obesity. Further meta-regression analysis indicated that age and gender were significant potential sources of heterogeneity. The results showed the studied subgroups were not subject to publication bias (Egger’s p<0.1).

Conclusion

Our data collectively indicate that low circulating total adiponectin, especially its non-HMW fraction, represents a promising risk factor for colorectal cancer. Further studies are needed to explore underlying mechanisms.

Keywords: colorectal cancer, total adiponectin, high-molecular weight adiponectin, non-high-molecular weight adiponectin, risk factor

Introduction

Adiponectin of molecular mass 28 kDa is a member of the adipocytokines, and it is secreted exclusively by mature adipocytes.1 Biologically speaking, adiponectin possesses a well-defined set of properties, including insulin sensitization, anti-inflammation, anti-atherosclerosis, proapoptosis and antiproliferation.2,3 In circulation, adiponectin exists in forms of trimer, hexamer and high-molecular weight (HMW) complex, and these fractions are proven to have different biological activities.4 For example, HMW adiponectin has a close relationship to insulin sensitivity, while the relevance between non-HMW adiponectin and anti-inflammation is more obvious.5 Mounting evidence from human studies reveal that low total adiponectin in circulation represents a predisposing status for development of colorectal cancer.6–8 By contrast, other researchers failed to confirm this claim,9–11 and some of them even found a higher concentration of circulating total adiponectin in patients with colorectal cancer than in controls.12,13 Several systematic reviews and meta-analyses have summarized published data involving the association between circulating total adiponectin and colorectal cancer risk,14–20 while interpretation of pooled findings in most cases is clouded by the presence of substantial heterogeneity and none considered adiponectin fractions as separate factors. With growing epidemiological data, our understanding on circulating adiponectin and its fractions and colorectal cancer needs replenishment and renewal. Hence, the principal goal of the present study is to test the hypothesis that circulating total adiponectin or certain fractions may represent a promising biological candidate in modulating the risk of colorectal cancer, assessed through a comprehensive meta-analysis. A secondary goal is to explore possible sources of heterogeneity of effect size across studies through both subgroup analysis and meta-regression analysis.

Methods

Guideline

The present study was carried out in strict accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline.21

Paper identification

Potentially eligible papers were identified through searching public databases of MEDLINE (PubMed), EMBASE, Web of Knowledge and Scholar (Google). All identified papers from each database were merged together and then duplicates removed. The key items used for paper identification included (“colorectal” or “colon” or “rectal”) in title and (“cancer” or “carcinoma” or “tumor” or “tumour” or “neoplasm” or “adenoma”) in title and (“adiponectin” or “adipocytokine” or “adipokine”) in title/abstract. The process of paper identification was completed independently and in duplicate (Weiqun Lu and Zhiliang Huang) using the same key items mentioned above.

Eligibility criteria

Eligibility criteria consisted of both inclusion criteria and exclusion criteria. Papers were included only when the following conditions were met simultaneously: (i) publication using the English language; (ii) either cross-sectional or nested case–control study design; (iii) involvement of only human beings; and (iv) availability of circulating plasma or serum adiponectin concentration for patients with colorectal or colon or rectal cancer and cancer-free controls. Papers were excluded when any of the following conditions was true: (i) non-original contribution; (ii) narrative or systematic review or meta-analysis; (iii) conference abstract; and (iv) case report or case series.

Paper selection

Two authors (Weiqun Lu and Zhiliang Huang) selected the papers that met the above inclusion criteria through reviewing the title or abstract or the full text, if necessary, of each identified article. When disagreement happened during the selection process, it was resolved by discussion or seeking help from the third author (Haiying Liu).

Data extraction

From each qualified paper, data for analysis including, if available, the first author’s name, publication year, country where the study was conducted, study design, cancer subtype, matching status, source of controls, selection of controls, sample size, assay method for circulating adiponectin, sample type, age, gender, body mass index (BMI), waist–hip ratio (WHR), waist circumference, physical activity, physical inactivity, smoking habit, family history, diabetes mellitus, glucose, insulin, C-reactive protein (CRP) and adiponectin were extracted and entered into databases by two authors (Weiqun Lu and Zhiliang Huang). Extracted data were compared, and disagreement was resolved through consensus and discussion.

Statistical analysis

Data were statistically analyzed by the Stata/SE software version 14.0 (StataCorp LP, College Station, TX, USA). Weighted mean difference (WMD) was adopted to assess the difference in circulating adiponectin concentration between patients and controls in both overall and subgroup analyses, and its 95% confidence interval (95% CI) was estimated accordingly under the random-effects model based on the DerSimonian–Laird method. Heterogeneity was first evaluated with the I2 statistic, and then was explored through both subgroup and meta-regression analyses. The I2 statistic is expressed as a percentage figure, and the higher the figure, the more likely the heterogeneity becomes. It is widely accepted the significance cutoff point of I2 statistic is set at 50%. Publication bias was assessed by the Begg’s funnel plot, filled funnel plot and Egger’s regression asymmetry test. The Egger’s regression asymmetry test records significance if the probability value is <10%.

Results

Qualified studies

A total of 339 papers were identified through searching public databases, and 295 of them were excluded after reading the title and abstract. Further, after full-text reviewing, 13 papers were excluded as they failed to meet our predefined inclusion criteria, leaving 31 eligible papers for meta-analysis in this study.5–13,22–43 Thereof, 16 papers provided data by cancer type, gender or race, and so there were 48 qualified studies.

Study characteristics

Table 1 shows the baseline characteristics of all qualified studies. After removing shared controls, this meta-analysis involved 7,554 patients with colorectal cancer and 9,798 controls. Of 48 qualified studies, only one study focused on HMW adiponectin.39 In addition, eight studies also measured HMW adiponectin, and non-HMW adiponectin was recorded in six studies.

Table 1.

The baseline characteristics of all qualified studies

Study Year Region Cancer subtype Control features Study design Matching status ADI assay (ELISA) Sample size
Sample source Adiponectin (µg/mL)
Age (years)
Male gender
BMI (kg/m2)
Patients Controls Patients Controls Patients Controls Patients Controls Patients Controls
Saetang et al25 (CRC) 2016 East Asia CRC W/o colonic polyps Retrospective NA Thermo Fisher 82 30 Serum 17.56 19.49 62.4 59.1 NA NA NA NA
Saetang et al25 (colon) 2016 East Asia Colon W/o colonic polyps Retrospective NA Thermo Fisher 52 30 Serum 15.65 19.49 62.4 59.1 NA NA NA NA
Saetang et al25 (rectum) 2016 East Asia Rectum W/o colonic polyps Retrospective NA Thermo Fisher 30 30 Serum 20.49 19.49 62.4 59.1 NA NA NA NA
Inamura et al29 (HPFS) 2016 USA CRC W/o CRC Nested Yes ALPCO 155 296 Plasma 5.00 5.60 66.2 66.2 1.000 1.000 26.1 25.3
Inamura et al29 (NHS) 2016 USA CRC W/o CRC Nested Yes ALPCO 152 297 Plasma 7.90 8.20 58.5 66.2 0.000 0.000 25.2 24.7
Zekri et al13 2015 Middle East CRC W/o CRC Retrospective NA RayBiotech 34 29 Serum 11.28 6.59 41.3 66.2 0.588 0.552 NA NA
Demir et al37 2015 Middle East CRA W/o CRC Retrospective NA eBioscience 32 30 Serum 8.57 9.70 53.5 66.2 0.625 0.500 29.1 26.1
Chandler et al11 2015 USA CRC W/o CRC Nested Yes ALPCO 275 275 Plasma 6.00 6.24 58.8 66.2 0.000 0.000 26.8 26.3
Ochs-Balcom et al26 (white) 2014 USA CRA W/o CRA Nested NA R&D 217 650 Plasma 10.58 11.64 57.4 66.2 0.521 0.369 29.1 32.3
Ochs-Balcom et al26 (AA) 2014 USA CRA W/o CRA Nested NA R&D 175 378 Plasma 7.76 8.02 58.2 66.2 0.406 0.241 31.7 32.3
Aleksandrova et al5 (colon) 2014 Europe Colon W/o CRC Nested Yes ALPCO 794 794 Serum 6.70 6.80 58.6 66.2 0.530 0.530 26.8 26.3
Aleksandrova et al5 (rectum) 2014 Europe Rectum W/o CRC Nested Yes ALPCO 466 466 Serum 6.50 6.80 58.0 66.2 0.457 0.457 26.6 26.4
Aleksandrova et al40 (men) 2014 Europe Colon W/o CRC Nested Yes ALPCO 292 292 Serum 5.40 5.30 59.3 66.2 1.000 1.000 27.3 26.5
Aleksandrova et al40 (women) 2014 Europe Colon W/o CRC Nested Yes ALPCO 370 370 Serum 8.30 8.40 58.6 66.2 0.000 0.000 26.4 26.1
Abe Vicente et al43 2014 USA CRC Healthy Retrospective NA R&D 39 40 Serum 4.60 3.60 61.0 66.2 0.590 0.650 23.9 23.9
Song et al24 (men) 2013 USA CRC W/o CRC Nested Yes Linco 270 519 Plasma 4.99 5.32 65.8 66.2 1.000 1.000 26.2 25.4
Song et al24 (women) 2013 USA CRC W/o CRC Nested Yes Linco 346 686 Plasma 8.04 8.19 59.0 66.2 0.000 0.000 26.0 25.5
Danese et al38 (men) 2013 Europe CRA W/o CRC Retrospective Yes Mediagnost 21 26 Plasma 7.86 5.83 63.0 66.2 0.525 0.650 26.0 26.0
Danese et al38 (women) 2013 Europe CRA W/o CRC Retrospective Yes Mediagnost 19 14 Plasma 11.81 9.89 NA NA NA NA NA NA
Kemik et al8 (colon) 2012 Middle East Colon Healthy Retrospective NA Linco 32 40 Serum 4.80 6.50 49.5 40.4 0.563 0.550 15.9 21.5
Kemik et al8 (rectum) 2012 Middle East Rectum Healthy Retrospective NA Linco 35 40 Serum 4.70 6.50 44.8 40.4 0.543 0.550 16.2 21.5
Ho et al30 2012 USA CRC W/o CRC Nested NA Millipore 457 834 Plasma 27.20 29.10 NA NA NA NA NA NA
Hillenbrand et al31 (men) 2012 Europe CRC Healthy Retrospective NA Millipore 42 30 Serum 14.20 11.80 65.5 46.0 1.000 1.000 27.2 NA
Hillenbrand et al31 (women) 2012 Europe CRC Healthy Retrospective NA Millipore 25 30 Serum 21.90 22.50 66.0 44.0 0.000 0.000 26.4 NA
Gulcelik et al32 2012 Middle East Colon W/o cancer Retrospective NA B-Bridge 27 40 Serum 9.51 13.91 52.1 52.4 0.593 0.250 26.8 26.8
Chen et al39 (E) 2012 East Asia CRC W/o colonic polyps Retrospective NA Adlitteram 71 102 Plasma 10.10 13.20 62.1 58.3 1.000 1.000 23.5 22.9
Chen et al39 (A) 2012 East Asia CRC W/o colonic polyps Retrospective NA Adlitteram 94 102 Plasma 9.30 13.20 61.8 58.3 1.000 1.000 22.4 22.9
Aleksandrova et al41 (colon) 2012 Europe Colon W/o CRC Nested Yes ALPCO 755 755 Serum 6.71 6.84 58.6 58.6 0.542 0.542 26.9 26.3
Aleksandrova et al41 (rectum) 2012 Europe Rectum W/o CRC Nested Yes ALPCO 451 451 Serum 6.38 6.79 58.0 58.0 0.452 0.452 26.5 26.4
Al-Harithy and Al-Zahrani42 (men) 2012 Middle East CRC Healthy Retrospective Yes ALPCO 31 30 Serum 5.59 6.38 55.0 49.0 1.000 1.000 24.8 29.1
Al-Harithy and Al-Zahrani42 (women) 2012 Middle East CRC Healthy Retrospective Yes ALPCO 29 30 Serum 4.47 8.89 53.5 52.0 0.000 0.000 26.8 28.8
Gialamas et al34 2011 Europe CRC Healthy Retrospective Yes RI 104 208 Serum 9.45 10.38 69.8 69.1 0.625 0.625 NA NA
Chronis et al10 (NOAA) 2011 Europe CRA W/o CRA Retrospective NA Linco 22 138 Serum 10.90 10.20 65.1 63.5 0.545 0.587 26.4 27.4
Chronis et al10 (AA) 2011 Europe CRA W/o CRA Retrospective NA Linco 46 138 Serum 11.20 10.20 66.2 63.5 0.565 0.587 27.1 27.4
Catalan et al7 2011 Europe Colon Healthy Retrospective NA R&D 11 18 Plasma 4.07 8.09 66.0 44.0 NA NA 26.9 29.3
Al Khaldi et al12 2011 Middle East Colon Healthy Retrospective Yes Linco 58 68 Plasma 8.60 4.10 53.0 60.0 0.500 0.500 27.9 26.0
Yamaji et al22 (men) 2010 East Asia CRA W/o CRA Nested NA NA 523 480 Plasma 3.98 4.37 NA NA 1.000 1.000 NA NA
Yamaji et al22 (women) 2010 East Asia CRA W/o CRA Nested NA NA 255 255 Plasma 6.81 7.36 NA NA 0.000 0.000 NA NA
Nakajima et al27 2010 East Asia CRA W/o CRC Retrospective Yes Otsuka 115 115 Serum 8.90 8.90 63.7 63.5 0.600 0.600 22.9 23.1
Kemik et al28 2010 Middle East Colon Healthy Retrospective NA Linco 126 36 Serum 4.30 6.50 43.5 40.4 0.421 0.444 NA NA
Gonullu et al33 2010 Middle East CRC Healthy Retrospective NA Bio-Source 36 37 Serum 5.50 6.20 56.6 51.0 0.500 0.541 27.2 27.0
Erarslan et al36 (CRA) 2009 Middle East CRA W/o colonic polyps Retrospective NA RayBiotech 31 50 Serum 7.40 9.20 63.0 59.0 0.548 0.540 26.0 29.2
Erarslan et al36 (CRC) 2009 Middle East CRC W/o colonic polyps Retrospective NA RayBiotech 23 50 Serum 7.10 9.20 57.0 59.0 0.609 0.540 24.6 29.2
Stocks et al9 (men) 2008 Europe CRC W/o cancer Nested Yes R&D 125 245 Plasma 7.00 6.60 59.8 NA 1.000 1.000 NA NA
Stocks et al9 (women) 2008 Europe CRC W/o cancer Nested Yes R&D 181 350 Plasma 11.40 11.40 59.7 NA 0.000 0.000 NA NA
Ferroni et al35 2007 Europe CRC W/o CRC Retrospective NA BioVendor 60 35 Serum 8.30 13.10 64.0 63.0 0.517 0.514 NA NA
Wei et al23 2005 USA CRC W/o CRC Nested Yes Linco 179 177 Plasma 7.40 7.80 66.6 66.5 1.000 1.000 25.9 25.4
Otake et al6 2005 East Asia CRA W/o colonic polyps Retrospective NA Otsuka 51 52 Plasma 7.00 10.60 59.0 58.0 0.686 0.654 23.6 22.8
Study Year WHR
WC (cm)
DM
Physical activity (h/week)
Physical inactivity
Smoking
Family history
Glucose (mmol/L)
Insulin (µ U/mL)
CRP (mg/L)
Patients Controls Patients Controls Patients Controls Patients Controls Patients Controls Patients Controls Patients Controls Patients Controls Patients Controls Patients Controls
Saetang et al25 (CRC) 2016 NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA
Saetang et al25 (colon) 2016 NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA
Saetang et al25 (rectum) 2016 NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA
Inamura et al29 (HPFS) 2016 NA NA NA NA NA NA 32.1 30.4 NA NA 0.610 0.550 0.790 0.860 NA NA NA NA NA NA
Inamura et al29 (NHS) 2016 NA NA NA NA NA NA 15.2 14.8 NA NA 0.560 0.510 0.840 0.850 NA NA NA NA NA NA
Zekri et al13 2015 NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA
Demir et al37 2015 NA NA 102.8 95.0 0.000 0.000 NA NA NA NA NA NA NA NA 5.48 5.47 12.05 6.93 NA NA
Chandler et al11 2015 NA NA NA NA NA NA 15.4 16.5 NA NA 0.098 0.113 0.120 0.098 NA NA NA NA NA NA
Ochs-Balcom et al26 (white) 2014 0.92 0.90 99.6 95.1 0.078 0.086 NA NA NA NA 0.553 0.489 0.267 0.246 4.79 4.73 7.70 6.20 3.00 2.30
Ochs-Balcom et al26 (AA) 2014 0.97 0.93 105.0 104.1 0.252 0.226 NA NA NA NA 0.703 0.608 0.166 0.238 5.55 5.22 15.30 9.90 2.40 2.30
Aleksandrova et al5 (colon) 2014 NA NA 90.7 88.5 NA NA NA NA 0.152 0.116 0.237 0.215 NA NA NA NA NA NA NA NA
Aleksandrova et al5 (rectum) 2014 NA NA 90.4 89.7 NA NA NA NA 0.146 0.133 0.281 0.288 NA NA NA NA NA NA NA NA
Aleksandrova et al40 (men) 2014 0.96 0.94 97.8 94.8 NA NA NA NA 0.178 0.147 0.281 0.253 NA NA NA NA NA NA 2.80 1.90
Aleksandrova et al40 (women) 2014 0.81 0.81 84.3 82.6 NA NA NA NA 0.127 0.097 0.200 0.170 NA NA NA NA NA NA 3.30 2.70
Abe Vicente et al43 2014 NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA
Song et al24 (men) 2013 0.96 0.94 98.0 95.3 NA NA 31.9 31.0 NA NA 0.050 0.049 0.196 0.139 NA NA NA NA 1.34 1.13
Song et al24 (women) 2013 0.79 0.78 81.0 79.5 NA NA 16.6 16.9 NA NA 0.145 0.123 0.139 0.120 NA NA NA NA 1.52 1.67
Danese et al38 (men) 2013 NA NA 97.5 95.9 NA NA NA NA NA 0.294 NA NA NA NA 5.53 5.38 NA NA 1.90 1.80
Danese et al38 (women) 2013 NA NA 94.2 81.1 NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA
Kemik et al8 (colon) 2012 NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA 9.10 3.50
Kemik et al8 (rectum) 2012 NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA 9.10 3.50
Ho et al30 2012 NA NA NA NA 0.000 0.000 NA NA 0.296 0.294 0.540 0.458 0.182 0.155 NA NA 6.50 5.30 NA NA
Hillenbrand et al31 (men) 2012 NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA
Hillenbrand et al31 (women) 2012 NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA
Gulcelik et al32 2012 NA NA NA NA 0.000 0.000 NA NA NA NA NA NA NA NA NA NA NA NA NA NA
Chen et al39 (E) 2012 0.89 0.86 NA NA 0.000 0.000 NA NA 0.690 0.725 0.380 0.304 NA NA NA NA NA NA NA NA
Chen et al39 (A) 2012 0.85 0.86 NA NA 0.000 0.000 NA NA 0.777 0.725 0.415 0.304 NA NA NA NA NA NA NA NA
Aleksandrova et al41 (colon) 2012 0.88 0.87 90.4 88.1 NA NA NA NA 0.144 0.114 0.567 0.538 NA NA NA NA NA NA 3.10 2.30
Aleksandrova et al41 (rectum) 2012 0.89 0.88 90.4 89.9 NA NA NA NA 0.151 0.131 0.609 0.603 NA NA NA NA NA NA 2.40 2.30
Al-Harithy and Al-Zahrani42 (men) 2012 1.23 0.95 72.6 75.7 NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA
Al-Harithy and Al-Zahrani42 (women) 2012 0.95 1.01 61.0 84.6 NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA
Gialamas et al34 2011 1.01 0.94 NA NA 0.279 0.173 NA NA 0.279 0.178 0.490 0.519 NA NA NA NA NA NA NA NA
Chronis et al10 (NOAA) 2011 NA NA 99.3 99.9 0.000 0.000 NA NA NA NA 0.318 0.304 NA NA 5.34 5.58 5.80 5.90 NA NA
Chronis et al10 (AA) 2011 NA NA 99.2 99.9 0.000 0.000 NA NA NA NA 0.261 0.304 NA NA 5.70 5.58 7.10 5.90 NA NA
Catalan et al7 2011 NA NA NA NA 0.000 0.000 NA NA NA NA NA NA NA NA 6.06 5.50 3.80 12.00 11.96 4.31
Al Khaldi et al12 2011 NA NA 106.0 102.5 0.000 0.000 NA NA NA NA NA NA NA NA 7.30 5.80 10.40 11.00 NA NA
Yamaji et al22 (men) 2010 NA NA NA NA NA NA NA NA NA NA 0.138 0.135 NA NA NA NA NA NA NA NA
Yamaji et al22 (women) 2010 NA NA NA NA NA NA NA NA NA NA 0.216 0.102 NA NA NA NA NA NA NA NA
Nakajima et al27 2010 NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA
Kemik et al28 2010 NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA 9.80 3.50
Gonullu et al33 2010 0.92 0.93 NA NA 0.000 0.000 NA NA NA NA NA NA NA NA 5.33 5.15 10.50 6.10 NA NA
Erarslan et al36 (CRA) 2009 NA NA 94.0 102.0 0.000 0.000 NA NA NA NA NA NA NA NA 5.34 5.24 8.60 12.90 NA NA
Erarslan et al36 (CRC) 2009 NA NA 84.0 102.0 0.000 0.000 NA NA NA NA NA NA NA NA 5.12 5.24 9.70 12.90 NA NA
Stocks et al9 (men) 2008 NA NA NA NA 0.000 0.000 NA NA NA NA NA NA NA NA NA NA NA NA NA NA
Stocks et al9 (women) 2008 NA NA NA NA 0.000 0.000 NA NA NA NA NA NA NA NA NA NA NA NA NA NA
Ferroni et al35 2007 NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA
Wei et al23 2005 0.95 0.94 97.0 95.0 NA NA 28.6 28.9 NA NA 0.051 0.054 0.207 0.126 NA NA NA NA NA NA
Otake et al6 2005 NA NA NA NA 0.000 0.000 NA NA NA NA NA NA NA NA 5.83 5.11 8.50 6.10 NA NA
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Abbreviations: ADI, adiponectin; ELISA, enzyme-linked immunosorbent assay; CRC, colorectal cancer; HPFS, Health Professionals Follow-up Study; NHS, Nurses’ Health Study; CRA, colorectal adenoma; AA, advanced adenoma; NOAA, without advanced adenoma; W/o, without; BMI, body mass index; WHR, waist–hip ratio; WC, waist circumference; DM, diabetes mellitus; CRP, C-reactive protein; NA, not available.

Overall analysis

Overall analysis was based on 41 qualified studies, and the funnel plot illustrating the difference in total adiponectin concentrations between patients with colorectal cancer and controls is presented in Figure 1. Pooling effect size of all studies found that total adiponectin was significantly lower in patients with colorectal cancer than in controls (WMD: −0.76 µg/mL, 95% CI: −1.20 to −0.32, p=0.001). However, this significant finding was clouded by strong evidence of statistical heterogeneity (I2: 94.2%, p<0.001).

Figure 1.

Figure 1

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Forest plot for overall difference in total adiponectin between patients with colorectal cancer and controls.

Note: Weights are from random-effects analysis.

Abbreviations: WMD, weighted mean difference; CI, confidence interval.

Figure 2 shows another funnel plot quantifying the differences in adiponectin fractions – HMW adiponectin and non-HMW adiponectin – between patients with colorectal cancer and controls. The difference in HMW adiponectin was comparable between the two groups (WMD: −0.22 µg/mL, 95% CI: −0.70 to 0.25, p=0.350), with significant heterogeneity (I2: 97.3%, p<0.001). By contrast, non-HMW adiponectin was significantly lower in patients with colorectal cancer than in controls (WMD: −0.27 µg/mL, 95% CI: −0.35 to −0.19, p<0.001), with only marginal heterogeneity (I2: 52.3%, p=0.063).

Figure 2.

Figure 2

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Forest plot for differences in two adiponectin fractions (HMW and non-HMW) between patients with colorectal cancer and controls.

Note: Weights are from random-effects analysis.

Abbreviations: HMW, high molecular weight; WMD, weighted mean difference; CI, confidence interval.

Subgroup analysis

Table 2 summarizes the differences in total adiponectin between patients and controls by grouping studies according to cancer subtype, region, study design, matching status, sample source, gender, BMI, WHR and diabetes mellitus, respectively.

Table 2.

Subgroup analysis of the difference in circulating adiponectin between patients with colorectal cancer and controls

Characteristics Subgroups Studies (number) WMD 95% CI pD I2 pH pE
Cancer subtype CRC 20 −0.736 −1.519 to 0.047 0.065 94.0% <0.001 0.514
CRA 10 −0.892 −1.573 to −0.211 0.010 80.1% <0.001 0.473
Colon 10 −1.073 −2.095 to −0.050 0.040 97.3% <0.001 0.403
Rectum 4 −0.681 −1.358 to −0.005 0.048 75.4% 0.007 0.778
Region East Asia 6 −1.707 −2.979 to −0.436 0.008 95.1% <0.001 0.213
America 10 −0.343 −0.599 to −0.087 0.009 36.7% 0.115 0.683
Europe 15 −0.749 −1.451 to −0.047 0.037 94.3% <0.001 0.541
Middle East 10 −0.787 −3.015 to 1.442 0.489 97.1% <0.001 0.787
Study design Retrospective 22 −1.179 −2.536 to 0.177 0.088 96.2% <0.001 0.489
Nested 19 −0.266 −0.380 to −0.152 <0.001 12.4% 0.303 0.409
Matching status NA 21 −1.472 −2.452 to −0.491 0.003 96.1% <0.001 0.411
Yes 20 −0.099 −0.389 to 0.191 0.504 79.0% <0.001 0.693
Sample source Plasma 18 −0.714 −1.358 to −0.070 0.030 95.1% <0.001 0.783
Serum 23 −0.803 −1.430 to −0.176 0.012 93.3% <0.001 0.303
Sample size (median) ≤230 21 −1.189 −2.609 to 0.231 0.101 96.4% <0.001 0.511
>230 20 −0.271 −0.385 to −0.157 <0.001 12.1% 0.304 0.262
Gender Men 9 −0.671 −1.255 to −0.086 0.025 90.4% <0.001 0.536
Women 8 −0.329 −0.693 to 0.035 0.077 49.6% <0.001 0.206
BMI <25 kg/m2 7 −1.627 −3.092 to −0.163 0.029 92.1% <0.001 0.434
≥25 kg/m2 24 −0.527 −1.016 to −0.039 0.034 92.4% <0.001 0.611
WHR <0.9 m 5 −0.878 −1.798 to 0.043 0.062 94.7% <0.001 0.112
≥0.9 m 9 −0.522 −0.939 to −0.106 0.014 60.6% 0.009 0.496
DM Without 12 −1.385 −3.003 to 0.233 0.093 96.1% <0.001 0.349
TNM stage I–II 9 −1.280 −2.115 to −0.446 0.003 90.1% <0.001 0.103
III–IV 9 −1.196 −2.033 to −0.358 0.005 92.6% <0.001 0.219
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Notes: pD, the p-value for WMD; I2, inconsistency index; pH, the p-value for heterogeneity; pE, the p-value for Egger’s regression asymmetry test.

Abbreviations: WMD, weighted mean difference; CI, confidence interval; CRC, colorectal cancer; CRA, colorectal adenoma; BMI, body mass index; WHR, waist–hip ratio; DM, diabetes mellitus; TNM, tumor node metastasis; NA, not available.

By cancer subtype, significant difference in total adiponectin was observed in patients with colorectal adenoma (CRA), colon cancer and rectum cancer, respectively, relative to controls (WMD: −0.892, −1.073 and −0.681 µg/mL, p=0.010), with significant heterogeneity (I2: 80.1%, 97.3% and 75.4%).

By geographic region, besides Middle East, total adiponectin was significantly lower in patients than in controls from America, Europe and especially East Asia (WMD: −1.707 µg/mL, p=0.008), and only in America, there was no evidence of heterogeneity (I2: 36.7%).

By study design, significant difference was observed only in nested case–control studies (WMD: −0.266 µg/mL, p<0.001), without heterogeneity (I2: 12.4%).

By matching status, studies with matched patients and controls failed to identify any significance (WMD: −0.099 µg/mL, p=0.504) (I2: 79.0%), while in studies with unclear matching status, there was significant difference in total adiponectin between patients and controls (I2: 96.1%).

By sample source, total adiponectin was significantly and comparably reduced in studies collecting plasma and serum samples for adiponectin measurement (WMD: −0.714 and −0.803 µg/mL, p=0.030 and 0.012, I2: 95.1% and 93.3%, respectively).

By sample size, grouping studies by median total sample size showed that the reduction of total adiponectin was obvious in studies with total sample size >230 (WMD: −0.271 µg/mL, p<0.001), and the likelihood of heterogeneity was low (I2: 12.1%).

By gender, total adiponectin was reduced significantly in male patients relative to male controls (WMD: −0.671 µg/mL, p=0.025) (I2: 90.4%), and there was no observable significance in females.

By obesity, studies were grouped by mean or median BMI at 25 kg/m2, and significant reduction in total adiponectin was noted in both groups, especially in studies with BMI <25 kg/m2 (WMD: −1.627 µg/mL, p=0.029) (I2: 92.1%). In addition, when studies were grouped by mean or median WHR at 0.9 m, there was significant reduction in studies with WHR ≥0.9 m (WMD: −0.522 µg/mL, p=0.014).

After restricting to studies involving subjects free of diabetes mellitus, the reduction in total adiponectin was not statistically significant, and there was significant heterogeneity.

By tumor node metastasis stage, the reduction in magnitude of total adiponectin was slightly stronger in patients with stage I–II colorectal cancer (WMD: −1.280 µg/mL, p=0.003) than in patients with stage III–IV cancer (WMD: −1.196 µg/mL, p=0.005), and significance was detected in both subgroups with significant heterogeneity but a low probability of publication bias.

Meta-regression analysis

Table 3 lists the results of meta-regression analysis by incorporating all characteristics to assess whether they can explain the heterogeneity between total adiponectin and colorectal cancer. Age and smoking in both patients and controls were significant potential sources of heterogeneity, and BMI, waist circumference and CRP can account for heterogeneity only in patients (p<0.05).

Table 3.

The meta-regression analysis of all characteristics in both patients with colorectal cancer and controls

Characteristics Studies (number) Patients
Controls
Coefficient p-value Coefficient p-value
Age 36 −0.21 0.012 0.18 0.019
Gender 38 −8.45 0.076 8.37 0.073
BMI 29 0.41 0.039 −0.35 0.091
WHR 14 5.04 0.387 −10.47 0.282
WC 19 0.14 0.008 −0.09 0.177
DM 15 −3.71 0.913 8.86 0.840
Physical activity 6 −0.05 0.785 0.04 0.842
Physical inactivity 9 1.46 0.836 −7.74 0.315
Smoking 20 −10.59 0.032 10.59 0.043
Family history 9 −0.66 0.842 0.34 0.909
Glucose 10 0.93 0.640 2.37 0.609
Insulin 10 0.28 0.316 0.03 0.930
CRP 12 −0.37 0.015 0.20 0.698
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Abbreviations: BMI, body mass index; WHR, waist–hip ratio; WC, waist circumference; DM, diabetes mellitus; CRP, C-reactive protein.

Publication bias

Overall comparison of total adiponectin between patients with colorectal cancer and controls was not subject to publication bias, which was illustrated by both Begg’s and filled funnel plots in Figure 3, as well as by the Egger’s regression asymmetry test (p=0.336). For comparisons in subgroup analysis, there was consistently low likelihood of publication bias across all subgroups (Egger’s test, p<0.1), as presented in Table 2.

Figure 3.

Figure 3

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Begg’s and filled funnel plots for difference in circulating total adiponectin between patients with colorectal cancer and controls.

Abbreviations: mdadi, mean value of total adiponectin; SE, standard error.

Discussion

The most noteworthy finding of this present study is that in line with the conclusions of most previous studies,14–20 our data indicated that low total adiponectin in circulation was a significant risk factor for colorectal cancer. Moreover, for the first time, we pooled data according to adiponectin fractions and found that only non-HMW adiponectin differed significantly between patients with colorectal cancer and controls. We further identified age, gender, smoking, obesity, study design, matching status and sample size as potential sources of heterogeneity. To our knowledge, this is thus far the largest meta-analysis dealing with the relationship of circulating adiponectin and its fractions with colorectal cancer.

The connection between obesity and colorectal cancer is well established,44,45 and a great deal of supporting evidence from clinical and epidemiological data has suggested that this connection is probably mediated by abnormal adiponectin in circulation.46 Adiponectin is the most abundant hormone secreted by adipose tissue, and its anti-inflammatory and insulin-sensitizing properties may, at least in part, expound on the etiologic link between obesity and colorectal cancer.47,48 Moreover, accumulating evidence has highlighted a contributory role of adiponectin in anti-carcinogenesis.49,50 In vitro studies have showed that adiponectin can promote endothelial apoptosis, repress the maturation and proliferation of colorectal cancer cells and control colony formation, likely through the activation of AMPK-mTOR signaling pathway.39,51,52 Based on the above evidence, it is more reasonable to presume that circulating adiponectin may be involved in the pathophysiological process of colorectal cancer.

Consistent with the findings of major published studies,14–20 we confirmed in this present study that low total adiponectin in circulation was a significant risk factor for colorectal cancer. As with most previous meta-analyses, heterogeneity is a serious issue that limits interpretation of effect estimates and requires careful exploration.53 As a secondary goal of this study, we employed both subgroup analysis and meta-regression analysis to seek possible causes of heterogeneity between studies. In particular, the reduction in total adiponectin was more obvious for CRA and colon cancer, and in studies enrolling subjects of male gender, from East Asia and with normal weight. In addition, the association of total adiponectin with colorectal cancer was markedly significant in studies with a nested case–control design and a large sample size, relative to studies with a retrospective case–control design and a small sample size, indicating the robustness of our observation. Colorectal cancer is a highly heterogeneous disease to which environmental exposure, germ-line susceptibility determinants and accumulated genetic and epigenetic changes contribute interactively.54 For example, cigarette smoking and alcohol drinking, which are more prevalent in men than in women, are established risk factors for the development and progression of colorectal gender-specific difference in adiponectin observed in the present study. Nevertheless, even though we have made great endeavors to seek causes of heterogeneity, there is still strong evidence of heterogeneity in some subgroups, indicating that residual confounding from other sources of heterogeneity in colorectal cancer risk is likely. We agree that further explorations are necessary, and especially analysis of individual participant data could yield further insights.

However, a growing body of research has reported diverse biological activities of different adiponectin fractions, mainly focusing on HMW (insulin sensitivity) and non-HMW (inflammation response) forms.5,24 In this context, the sufficient number of eligible studies in this meta-analysis enables us to investigate different adiponectin fractions, and our findings revealed that low non-HMW adiponectin in circulation was a significant risk factor for colorectal cancer and there was no observable significant difference for HMW adiponectin. As previously discussed, non-HMW adiponectin plays a major role in the inflammatory process.24 Systemic inflammation is a key manifestation of cancer progression and metastasis in many types of cancer including colorectal cancer.57 We thus develop a further presumption that non-HMW adiponectin may be involved in colorectal carcinogenesis by regulating inflammatory responses. Addressing this presumption is beyond the scope of this meta-analysis, and further experimental studies are required.

Finally, the present study needs to be interpreted cautiously, bearing in mind the following limitations. First, we only retrieved the literature for the papers published in English language, and selection bias cannot be ruled out. Second, all involved studies in this meta-analysis were observational in nature, either cross-sectional or nested, which hindered further causality inference. Third, as discussed above, sources of heterogeneity for a majority of comparisons were not fully accounted for, and additional considerations were necessary. For example, low circulating adiponectin was found to be associated with KRAS-mutant colorectal cancer risk but not with KRAS-wild-type cancer risk.29 Fourth, only data on circulating plasma/serum adiponectin were summa-rized, and it is expected that tissue adiponectin concentration in tumor environment may be more relevant to the evaluation of colorectal cancer risk than its circulating concentration. However, data on tissue adiponectin are rarely reported. Fifth, circulating adiponectin concentration was affected by medical treatment or drug intervention, which cannot be taken into account because of lack of data.

In conclusion, through a comprehensive meta-analysis of 7,554 patients with colorectal cancer and 9,798 controls, our data indicate that low total adiponectin, especially its non-HMW fraction, represents a promising risk factor for colorectal cancer. Although there is still residual confounding unaccounted for, we believe that this study can aid in better understanding cancer heterogeneity, highlighting the importance of anti-inflammation therapies to prevent or delay the occurrence of colorectal cancer and thereby providing new insight in its physiology. In addition, further studies are needed to explore underlying mechanisms.

Footnotes

Author contributions

WL and ZH searched the literature and identified potential papers, extracted the data, performed statistical analysis and drafted the manuscript. NL checked the data and results. HL designed the study and polished the language of the manuscript. All authors contributed toward data analysis, drafting and critically revising the paper, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.

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