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. Author manuscript; available in PMC: 2022 Aug 1.
Published in final edited form as: Life Sci. 2021 Apr 19;278:119524. doi: 10.1016/j.lfs.2021.119524

The Bifurcated role of Adiponectin in Colorectal Cancer

Debrup Chakraborty 1,#, Wei Jin 1,#, Jing Wang 1
PMCID: PMC8205988  NIHMSID: NIHMS1699673  PMID: 33887344

Abstract

The association of adiponectin with metabolism and cancer is well established. Since its discovery in 1990, adiponectin, as one of the adipose tissue-secreted adipokines, has been very widely studied in biomedical research. Low levels of circulatory adiponectin have been reported in obesity, inflammatory diseases and various types of cancers including colorectal cancer (CRC), which is highly linked with obesity and gut inflammation. However, the function and underlying mechanisms of adiponectin in CRC is not well understood. In addition, there are contradictory reports on the role of adiponectin in cancer. Therefore, further investigation is needed. In this review, we explore the information available on the relationship between adiponectin and CRC with respect to proliferation, cell survival, angiogenesis and inflammation. We also highlighted the knowledge gaps, filling in which could help us better understand the function and mechanisms of adiponectin in CRC.

Keywords: Adiponectin, adiponectin receptor, colorectal cancer (CRC), angiogenesis, inflammation

Graphical Abstract

graphic file with name nihms-1699673-f0003.jpg

Introduction

The physiological function of adiponectin in human was first reported in 2000 [1]. Adiponectin is one of the highly abundant adipokines secreted mainly from the adipocytes and is detectable in the circulation. Experimental evidences demonstrated that adiponectin is one of the key regulators of lipid and glucose metabolism and prevents obesity by increasing fatty acid oxidation, improving insulin sensitivity and reducing excess secretion of pro-inflammatory cytokines [2]. Epidemiological studies demonstrated that obesity is one of the major risk factors for the development and progression of various types of cancer [3, 4]. High levels of circulatory adiponectin has been shown to be associated with improved outcome in diabetes and low levels of adiponectin is associated with obesity and poor prognosis of many cancers including the cancers of colon, breast, endometrium and prostate [5]. Therefore, adiponectin, being a common molecular target associated with metabolic diseases and cancers, has gained attention in cancer research, especially in cancers that are linked with obesity like colorectal cancer (CRC) [6, 7].

CRC is one of the leading causes of cancer related death in the United States. According to the most recent report of American Cancer Society, it was estimated that for the year 2020 there would be around 147,000 new cases with approximately 53,000 death. It is striking that nearly 10% of the population with CRC was expected to be below 50 years of age [8]. CRC is highly obesity-linked and closely associated with inflammation and infection, gut microbiota and infiltration of immune cells in the colon. Multiple reports indicated the association of CRC with metabolic abnormal conditions such as type 2 diabetes and non-alcoholic fatty liver disease [9–11], in which the function of adiponectin is well documented [1]. A decrease in circulatory adiponectin is observed in the progression of gastrointestinal tumors while similar trend is also reported in patients with colon adenoma [6, 12]. However, experimental data indicated both positive and inverse correlation of adiponectin with obesity-linked cancers [6, 13], suggesting a dichotomized role of adiponectin in cancer. Recent compelling evidences implied that the role of adiponectin might vary depending upon many factors, such as the stages of the colon tumor [7], the presence of pro- or anti-inflammatory cytokines in the microenvironment secreted by inflammatory cells, lymphocytes or stromal cells.

In this review, we summarize the evidences that indicate different functions of adiponectin in CRC. We speculate that, apart from affecting the survival and proliferation of colon cancer cells, adiponectin modulates the inflammatory responses and influences the tumor microenvironment that ultimately determines the fate of tumors in a context-dependent manner. We also raise the questions regarding the function of adiponectin in CRC that remain to be answered and ponder at the prospect of targeting adiponectin in clinical applications.

A brief introduction of adiponectin and its receptors

Adiponectin is one of adipokines secreted by the adipose tissue and is highly abundant in the circulation. Depending upon sex, physical and metabolic condition, the circulatory level of adiponectin may vary from 5 to 15 μg/ml [14]. Adiponectin plays an important role in energy homeostasis by regulating lipid metabolism and cellular glucose uptake. Extensive data indicate a negative correlation between the circulatory levels of adiponectin and the occurrence of obesity, diabetes, atherosclerosis, inflammation and certain types of cancers [15].

Functional activity of adiponectin relies on its binding to the receptors, adiponectin receptor 1 (AdipoR1) and receptor 2 (AdipoR2), leading to the activation of downstream signaling. With more than 66% sequence homology between two receptors, AdipoR1 is predominantly expressed in the skeletal muscle while AdipoR2 in the liver [16]. Abrogation of these two receptors increases tissue triglyceride content, oxidative stress and inflammation, resulting in insulin resistance and glucose intolerance [16–18]. AdipoR1 and AdipoR2 double knockout mice showed increased glucose intolerance and elevated levels of blood glucose [17]. Liver specific expression of either AdipoR1 or AdipoR2 ameliorates hyperinsulinemia in obese diabetic mice. Activation of AdipoR1 leads to elevated AMPK activation in the liver and AdipoR2 increases PPARα activation. Activation of both AMPK and PPARα pathways improves glucose metabolism, insulin sensitivity and fatty acid oxidation [17]. Apart from AdipoR1 and AdipoR2, T-cadherin is also a receptor of adiponectin, which is discovered by Lodish’s group [19]. Although T-cadherin can bind to hexameric and high-molecular-weight adiponectin, it cannot transduce downstream signaling since T-cadherin lacks an intracellular domain [19] [20]. T-cadherin is highly expressed in cardiac tissue and vascular structures (aorta and renal arteries) [21], [19, 22].

Levels of adiponectin and its receptors in individuals with CRC

A significant number of research reported that the low adiponectin level is associated with the poor outcome of CRC [23, 24]. Clinical data including 40 patient samples showed that serum adiponectin level significantly increased in individuals with malignant colon tumors after chemo-and radiotherapy compared to those with benign tumors [25]. This study suggests a probable correlation of adiponectin levels with improved overall outcome after the treatment. According to the findings of Wei et al., 2005, individuals with the highest levels of adiponectin had around 60% less chance to get CRC than those with the least adiponectin levels irrespective of the status of BMI, waist circumference and physical activity, all of which have been shown to be strongly associated with insulin resistance, obesity and cancers [12]. These data indicate that adiponectin could be the key player in the initiation and development of CRC. However, conflicting findings depict no significant relationship between adiponectin levels and CRC occurrence [26]. These contradictory reports suggest that adiponectin has a complexed role in CRC, which makes it important to investigate its function at the molecular level to unveil key mechanisms of action in CRC.

The low levels of circulatory adiponectin in CRC prompts the investigation of the expression of AdipoR1 and AdipoR2. In one study, samples collected from 50 patients with CRC and 82 with adenomatous polyps were analyzed for the expression of AdipoR1 and R2. IHC staining results showed that expression of both AdipoR1 and AdipoR2 was dramatically decreased in CRC samples as compared with colorectal adenomas and non-neoplasia groups. These data indicate that low levels of adiponectin receptors are associated with the development of colorectal carcinomas [27].

Adiponectin in the survival and proliferation of colon cancer cells

Experimental evidences demonstrate a discordant role of adiponectin in the regulation of growth and proliferation of colon cancer cell lines in vitro. Researchers using colon cancer cells from mouse and human origin demonstrated that adiponectin negatively regulates cell survival, proliferation and migration in vitro [28–30]. Anti-proliferative potential of adiponectin is observed in IL-6 treated MC38 mouse colon carcinoma cells by downregulating STST-3 phosphorylation/activation [30]. Nigro et al., 2018 showed that adiponectin induced accumulation of reactive oxygen species (ROS) in colon cancer cells leading to increased cell death [28]. No change was observed in EMT-associated markers such as vimentin and E-cadherin, which indicated that adiponectin, may not directly influence the metastasis of colon tumors. Nevertheless, whether adiponectin influences the fate of the tumor cells once they metastasize to a distant organ is yet to be explored. In addition, adiponectin inhibited proliferation of human colon cancer cells (HCT116, HT29 and LoVo) with high basal level of AdipoR1 and R2 through the up-regulation of cyclin-dependent kinase inhibitors p21 and p27 and activation of AMPK [29]. Knockdown of AdipoR1 and AdipoR2 expression reversed the suppressive effect of adiponectin on cell proliferation. In contrast, Ogunwobi et al. in 2006 found that adiponectin facilitates proliferation of growth arrested HT-29 human colon cancer cells as well as colonic epithelial cells, indicating the potential of adiponectin in promoting proliferation in premalignant colon cells [31]. Notably, Baker S. Habeeb and colleges reported that full-length adiponectin (fAd) and globular adiponectin (gAd) inhibited the growth of colorectal cancer cells (DLD1, HT29 and colon26) in high glucose medium. Whereas fAD and gAd supported cell survival in glucose-deprived medium with an up-regulation of AdipoR1, AdipoR2, LC3B-1, LC32, phosphorated AMPKα and PPARα coupled with reduced expression of phosphorated mTOR, IGF-1 and phosphorated AKT [32]. Our data showed adiponectin has little effect in the proliferation rate of murine colon cancer cells in vitro (unpublished data by Chakraborty et al.). These in vitro studies suggest that adiponectin may play different role in proliferation of colon cancer cells in a context- and cell line-dependent manner. However, the effect of adiponectin on proliferation and survival of colon cancer cells in vivo is yet to be determined.

Adiponectin in the angiogenesis of colon tumor

Tumor growth is accompanied by the formation of new blood vessels ensuring adequate supply of nutrients to the growing tumors. This process is known as angiogenesis. Studies have demonstrated that adiponectin promoted tumor angiogenesis in experimental mouse models [6, 7]. In two separate experiments authors inoculated SL4 (colon cancer cells) and PancO2 (pancreatic cancer cells) subcutaneously in mice. Results demonstrated that tumors in APN(−/−) mice were smaller in size with less vasculature evidenced by low expression of CD31 compared to the wild type mice. The same results were observed in a model of colon cancer metastasis in the liver when SL4 cells were injected into the spleen. Mechanistic studies revealed that adiponectin promoted the secretion of the chemokine CXCL1 from tumor cells, which stimulated angiogenesis by induction of senescence in the stromal fibroblasts in a p53 and p16 dependent manner. Studies in human chondrosarcoma demonstrated that adiponectin interacted with AdipoRs and promoted VEGF-A (vascular endothelial growth factor-A) expression through the activation of PI-3K/AKT/m-TOR/HIF-1α signaling [33].

Significant numbers of studies were undertaken to explore the role of adiponectin in angiogenesis in non-tumorigenic models. Pro-angiogenic potential of adiponectin was demonstrated by Shibata et al., in a mouse model of tissue ischemia (a condition associated with cardiovascular disease) [34]. Authors found that angiogenic repair was impaired in APN(−/−) mice and administration of globular adiponectin rescued the impaired phenotype. In a different study, Adya et al. demonstrated that adiponectin significantly increased the proliferation and angiogenesis of human microvascular endothelial cells (HMEC-1) in vitro [35]. Activity of adiponectin was dependent on the interaction of globular adiponectin with AdipoR1 and AdipoR2 leading to the upregulation of MMp-2, MMP-9 and VEGF expression. While these evidences support the pro-angiogenic function of adiponectin, there are other studies showing the anti-angiogenic potential of adiponectin [36]. Results from those studies indicated that adiponectin prevented vascular tube formation in HUVEC, hREC and hCEC cells in vitro. In addition, high glucose induced angiogenesis was prevented by adiponectin in RF-6A rhesus choroid-retinal endothelial cells in vitro [37]. These studies indicated that the role of adiponectin in angiogenesis is context-dependent. The bifurcation of the pro- or anti-angiogenic activity of adiponectin could potentially be manipulated by the neoplastic/malignant tumor cells to their own advantage to grow/proliferate/evade immune surveillance. Thorough investigation of adiponectin in angiogenesis of different types of cancer including CRC will be helpful in defining the impact of adiponectin in cancer.

Adiponectin and inflammation in CRC

Obesity-induced inflammation recruits large amount of macrophages to the adipose tissue, leading to hypoxic condition in adipocytes. Dysfunctional adipose tissue secretes pro-inflammatory adipokines such as tumor necrosis factor (TNF-α) and monocyte chemotactic protein-1 (MCP-1), which interact with the toll-like receptor 4 (TLR4) complex to activate the NF-κB signaling pathway, leading to chronic inflammation, which contributes to cancer initiation and development [38, 39]. Inflammation has been shown to play a pivotal role in the development and progression of CRC [40]. Epidemiological evidence suggested that elevated inflammation of the gut is a major risk factor for the development of CRC [41]. It is estimated that around 30% of patients with ulcerative colitis would develop CRC at certain stage of their life. Epidemiological studies suggest that adiponectin level is inversely correlated with obesity [42] and CRC [5]. Therefore, the role of adiponectin in inflammation and CRC is important to be investigated. Experimental evidence demonstrated that induced gut inflammation in mice led to the development of colon cancer indicating a direct link of inflammation with CRC [43]. In a significant study, Muthoh et al., showed that APN+/−; Apc+/min or APN−/−; Apc+/min mice formed significantly higher number of tumors in the intestine and had elevated levels of inflammatory cytokines such as PAI-1 than APN+/+; Apc+/min mice [44]. No significant difference was observed in leptin, TNF-α and MCP-1 levels. However, the underlying mechanisms by which loss of adiponectin expression increased tumor formation of Apc+/min mice remain unanswered.

Adiponectin is mostly regarded as an anti-inflammatory adipokine [45]. Studies demonstrated that adiponectin suppressed the activation of pro-inflammatory M1 macrophage and promoted proliferation of anti-inflammatory M2 macrophage [46, 47]. Low levels of adiponectin are reported to be associated with high-grade inflammation and adiponectin expression is decreased during the inflammatory process, indicating that adiponectin is inversely correlated with inflammation [48, 49]. However, an opposite phenomena was observed in human colon cancer cell line HT-29. When treated with adiponectin, expression of pro-inflammatory cytokines IL-8, cox2 and PGE2 was upregulated in vitro [50]. In addition, Lee et al. evaluated the dual role of adiponectin in inflammation in macrophages: short-term treatment with gAd activated the IκB/NF-κB pathway coupled with up-regulation of pro-inflammatory cytokine TNF-a in a dose-dependent manner. However, long-term treatment with gAd caused immune tolerance to TLR signaling, which increased expression of myeloid differentiation factor 88 (MyD88), tumor necrosis factor receptor associated factor 6 (TRAF6), TGF-β-activated kinase 1 (TAK1) and IL-receptor-associated kinase-1 (IRAK-1), resulting in an anti-inflammatory response [51]. Nevertheless, the paradoxes of adiponectin function in inflammation and inflammation-associated cancers are still unclear, warranting further investigation.

Unanswered questions and remarks

Despite extensive studies on adiponectin in cancer, there are still many questions that remain unanswered. More research is required to determine the underlying cause of low serum level of adiponectin in CRC patients and the function adiponection plays in CRC initiation, development and progression. Although adiponectin has been implicated in CRC initiation, it is not clear whether it also plays a role in CRC metastasis. If it does, the mechanisms by which adiponectin exerts its function are unknown. In addition, it is important to explore whether serum adiponectin level can be used as a predictor/indicator of CRC, especially at the early stage of CRC. Furthermore, the role of adiponectin in tumor microenvironment is yet to be fully understood. Development of CRC is influenced by multiple factors including genetics, intestinal microbiota, gut inflammation/infection, metabolic diseases, microenvironment at the metastatic sites and environmental factors. Therefore, it is of importance to dissect the mechanisms by which adiponectin affects various factors during the initiation, development and metastasis of CRC, understanding of which would facilitate the development of new biomarkers and therapeutic strategies to combat CRC.

Figure 1. Mechanisms of anti- or pro-tumorigenic function of adiponectin in colon cancer.

Figure 1.

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Once secreted from adipocytes, adiponectin travels through the circulation to different organs/tissues. Adiponectin binds to AdipoRs, and prevents cell cycle progression and inhibits cell proliferation by upregulation of p21/p27 siganling and down regulation of Akt/mTOR dependent pathway. On the other hand, adiponectin increases the secretion of CXCL1 from colon cancer cells. CXCL1 induces senescence in stromal fibroblasts in a p53- and p16-dependent manner and upregulates VEGF expression. Elevated VEGF increases angiogenesis in the colon tumor. (The figure is created with BioRender.com)

Figure 2. Dual role of adiponectin in inflammation.

Figure 2.

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The pro- or anti-inflammatory nature of adiponectin is context-dependent. Adiponectin suppresses the activation of pro-inflammatory M1 macrophage and promotes proliferation of anti-inflammatory M2 macrophage. In colon cancer cells, adiponectin increases pro-inflammatory cytokine secretion. (The figure is created with BioRender.com)

Acknowledgement:

We acknowledge Tanvi Brar for her help in editing the manuscript. The work is supported by NIH grants R01CA212241, R01CA215389 and R01CA208063 to JW.

Nonstandard Abbreviations:

CRC

Colorectal cancer

Acrp30

adipocyte complement-related protein of 30 kDa

AdipoRs

adiponectin receptors

AdipoR1

Adiponectin receptor R1

AdipoR2

Adiponectin receptor R2

AMPK

5’-adenosine monophosphate-activated protein kinase

APN

adiponectin

Footnotes

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Conflict of interest: None to declare.

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