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Review
. 2023 Aug 24;15(17):4250.
doi: 10.3390/cancers15174250.

Role of Leptin and Adiponectin in Carcinogenesis

Agnes Bocian-Jastrzębska  1 , Anna Malczewska-Herman  1 , Beata Kos-Kudła  1
Affiliations
Review

Role of Leptin and Adiponectin in Carcinogenesis

Agnes Bocian-Jastrzębska et al. Cancers (Basel). .

Abstract

Hormones produced by adipocytes, leptin and adiponectin, are associated with the process of carcinogenesis. Both of these adipokines have well-proven oncologic potential and can affect many aspects of tumorigenesis, from initiation and primary tumor growth to metastatic progression. Involvement in the formation of cancer includes interactions with the tumor microenvironment and its components, such as tumor-associated macrophages, cancer-associated fibroblasts, extracellular matrix and matrix metalloproteinases. Furthermore, these adipokines participate in the epithelial-mesenchymal transition and connect to angiogenesis, which is critical for cancer invasiveness and cancer cell migration. In addition, an enormous amount of evidence has demonstrated that altered concentrations of these adipocyte-derived hormones and the expression of their receptors in tumors are associated with poor prognosis in various types of cancer. Therefore, leptin and adiponectin dysfunction play a prominent role in cancer and impact tumor invasion and metastasis in different ways. This review clearly and comprehensively summarizes the recent findings and presents the role of leptin and adiponectin in cancer initiation, promotion and progression, focusing on associations with the tumor microenvironment and its components as well as roles in the epithelial-mesenchymal transition and angiogenesis.

Keywords: adiponectin; angiogenesis; epithelial–mesenchymal transition; leptin; tumor microenvironment.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Leptin and a schematic representation of leptin-induced signaling pathways. The binding of leptin to its receptor leads to the formation of the ObR/JAK2 complex, which results in phosphorylation (P) and activation of STAT3 and STAT5, which are translocated to the nucleus and activate transcription of target genes, including the gene for SOCS3. Chronic stimulation leads to an increase in SOCS3, which negatively regulates leptin signaling by inhibiting JAK2 activity. JAK2 phosphorylation also leads to activation of SHP2, leading to increased MAPK/ERK1/2 signaling and phosphorylation of IRS1/2, which recruits PI3K to activate downstream signals. mTOR is an important downstream target of PI3K/Akt in the leptin signaling pathway, promoting cell growth and survival. In addition, leptin regulates metabolism through AMPK/ACC signaling in the brain and peripheral organs. AMPK activation may occur via a STAT3-independent signaling pathway. Blocking AMPK activation inhibits the phosphorylation of ACC stimulated by leptin. ACC, acetyl-CoA carboxylase; Akt, protein kinase B; AMPK, 5′-AMP-activated protein kinase; CaMKK2, calcium/calmodulin-dependent protein kinase; ERK, extracellular-signal-regulated kinase; IRS, insulin receptor substrates; JAK2, Janus kinase 2; MAPK, mitogen activated protein kinase; mTOR, the mammalian target of rapamycin; ObR, leptin receptor; PI3K, phosphatidylinositol 3-kinase; SHP2, Src Homology 2 domain; SOCS3, suppressors of cytokine signaling 3; STAT3, activator of transcription 3; STAT5, activator of transcription 5. Black arrows indicate activation of the target protein, whereas a small perpendicular red line at the end of the red lines indicates inhibitory effects. The figure was created by mindthegraph.com (accessed on 6 March 2023).
Figure 2
Figure 2
Adiponectin and a schematic representation of adiponectin-induced signaling pathways. The binding of adiponectin to its receptor leads to the recruitment of APPL1 and APPL2, thereby activating a number of downstream signaling pathways. Adiponectin effects are mostly mediated via the AMPK and PPARα pathways. Stimulation of AMPK results in activation of SIRT1, essential in adiponectin’s regulation of glucose and lipid homeostasis, as well as enhanced eNOS activity, through which adiponectin interacts with endothelial cells. Moreover, activation of AMPK suppresses PI3K, mTOR and IKK/NF-κB signaling, exerting a cytoprotective effect of adiponectin. Adiponectin binding to AdipoRs, independently of AMPK, stimulates ceramidase activity and enhances ceramide catabolism and the formation of its metabolite—S1P, which is involved in angiogenesis. Activation of IRS1/2 by adiponectin causes increased PI3K/Akt/mTOR signaling, controlling cell survival, growth and apoptosis. Adiponectin signaling also activates other downstream intracellular signaling cascades through PKA, JNK and p38MAPK. Via SOCS3, adiponectin inhibits STAT3 activation, which increases proliferation, survival and invasion of cancer cells and suppresses anti-tumor immunity. ACC, acetyl-CoA carboxylase; AdipoR, adiponectin receptor; Akt, protein kinase B; AMPK, 5′-AMP-activated protein kinase; APPL1, adaptor protein containing a pleckstrin homology domain 1 protein; APPL2, adaptor protein containing a pleckstrin homology domain 2 protein; eNOS, endothelial nitric oxide synthase; IKK, IκB kinase; IRS, insulin receptor substrates; JNK, -Jun N-terminal kinase; MAPK, mitogen activated protein kinase; mTOR, the mammalian target of rapamycin; NF-κB, nuclear factor-κB; PI3K, phosphatidylinositol 3-kinase; PPARα, peroxisome proliferator-activated receptor gamma; S1P, sphingosine-1-phosphate; SIRT1, sirtuin 1; SOCS3, suppressors of cytokine signaling 3; STAT3, activator of transcription 3. Black arrows indicate activation of target protein, whereas small perpendicular red lines at the ends of the red lines indicate inhibitory effects. The figure was created by mindthegraph.com (accessed on 6 March 2023).
Figure 3
Figure 3
Composition of the tumor microenvironment. A schematic diagram shows the different components of the tumor microenvironment. The dynamic and bidirectional interactions of tumor cells with their microenvironment, consisting of cellular and non-cellular parts, are fundamental to the stimulation of tumor growth, invasion and metastasis. The figure was created by mindthegraph.com (accessed on 6 March 2023).
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