Table 4.
Proposed mechanisms of cancer cell migration and metastasis under the influence of leptin
| Investigators and Cancer types | Nature of neoplastic progression | Mechanisms or involved intracellular signaling pathways | Observed phenomena |
|---|---|---|---|
| Cao et al. 2016 [148] MCF-7 and MDA-MB-231 breast cancer cells, and xenograft model |
Migration and metastasis | p38 MAPK and ERK1/2 | Leptin-induced tumor-associated M2 macrophage-derived IL-8 promoted the migration and invasion/metastasis of cancer cells in both in vitro and xenograft model |
| Cheng et al. 2011 [129] K1 and B-CPAP papillary thyroid cancer cells |
Migration | AKT and ERK pathways | Leptin enhanced the migratory activity |
| Ding et al. 2016 [206] HepG2 hepatocellular carcinoma and MCF-7 breast cancer cells |
Migration | STAT3, ERK1/2, and AKT | APPL1 positively mediated leptin signaling and promoted leptin-induced proliferation and migration of cancer cells |
| Dong et al. 2013 [108] AGS, MKN-28 and MKN-45 gastric cancer cells |
Migration | AKT and ERK1/2 | Leptin upregulated MT1-MMP expression and enhanced the interaction of MT1-MMP with KIF1B, which contributed to cancer cell invasion |
| Dong et al. 2014 [109] AGS and MKN-45 gastric cancer cells |
Migration | Rho/ROCK pathway | Leptin enhanced cancer cell migration by upregulating ICAM-1 |
| Fan et al. 2015 [120] PANC-1 and AsPC-1 pancreatic cancer cells, and clinical samples |
Migration and metastasis | JAK2/STAT3 pathway | Leptin upregulated the expression of MMP-13 |
| Fava et al. 2008 [207] Intrahepatic cholangiocarcinoma HuH-28 cells |
Migration | STAT3 and ERK1/2 | Leptin increased the growth and migration of cancer cells |
| Feng et al. 2013 [14] A549 lung cancer cells |
Metastasis | TGF-β | Leptin promoted the metastasis by inducing EMT in a TGF-β-dependent manner |
| Frankenberry et al. 2004 [208] androgen-independent DU145 and PC-3 prostate cancer cells |
Migration | MAPK and PI3K (mainly) | Leptin enhanced cancer cell migration, and induced expression of VEGF, TGF-β1, and bFGF |
| Ghasemi et al. 2017 [209] OVCAR3, SKOV3 and CaoV-3 ovarian cancer cells |
Migration | RhoA/ROCK, PI3K/AKT, JAK/STAT pathways and NF-κB activation | Leptin induced cancer cell invasion via upregulating uPA |
| Ghasemi et al. 2017 [210] SKOV3 and OVCAR3 ovarian cancer cells |
Migration | ERK and JNK pathways | Leptin regulated cancer cell invasion by promoting MMP-7 expression |
| Guo and Gonzalez-Perez 2011 [142] Mouse 4T1, EMT6 and MMT breast cancer cells |
Migration | JAK2/STAT3, MAPK, PI3K/mTOR, p38 MAPK and JNK signaling pathways | Leptin upregulated cell proliferation/migration and pro-angiogenic factors Notch, IL-1 and VEGF/VEGFR-2 |
| Huang et al. 2011 [152] PC-3, DU145, and LnCaP prostate cancer cells |
Migration | IRS-1, PI3K, AKT, and NF-κB | Leptin increased the migration of cancer cells. Moreover, leptin upregulated αvβ3 integrin expression |
| Huang et al. 2017 [211] MCF-7 and T47D breast cancer cells |
Migration | PI3K/AKT/SREBP2 pathway | Leptin enhanced the proliferation, migration and invasion of cancer cells via ACAT2 upregulation |
| Knight et al. 2011 [212] MCF-7 and MDA-MB-231 breast cancer cells |
Migration | EGFR, Notch1, and survivin | Leptin increased the migration potential of cancer cells |
| Li et al. 2016 [144] THP1 human monocytes, and MCF-7, SK-BR-3 and MDA-MB-231 breast cancer cells, and xenograft model |
Migration and metastasis | NF-κB signaling in TAMs, and PI3K-AKT/ATF-2 signaling in cancer cells | Leptin stimulated IL-18 expression in both TAMs and breast cancer cells |
| Martín et al. 2017 [213] Human astrocytoma 1321N1 cells |
Migration | EGFR, and ERK, AKT/mTOR pathways | Leptin and sPLA2-IIA increased growth and migration in these cells |
| Mendonsa et al. 2015 [214] Murine Panc02 and human Panc1 pancreatic cancer cells |
Migration | PI3K/AKT pathway | Leptin increased migration of cancer cells |
| Mishra et al. 2017 [215] Breast epithelial and cancer cells: MCF10A, MCF10AT1, MCF-7 and MDA-MB-231 |
Metastasis | TGF-β1 pathway | Leptin-mediated changes represented EMT and a cancer stem cell-like phenotype |
| Noda et al. 2015 [216] LNCaP, DU145 and PC-3 prostate cancer cells |
Migration | PI3K/AKT | Leptin increased the cell proliferation, migration, and invasion. Leptin also increased the phosphorylation of FOXO1, the expression of cyclin D1, and decreased the expression of p21 protein |
| Ratke et al. 2010 [118] SW480, SW620, and HCT-116 colon cancer cells |
Migration | JAK, STAT3, Src kinase, FAK, PI3K, PKCδ | Leptin enhanced the migratory activity of cancer cells |
| Saxena et al. 2007 [217] HepG2 and Huh7 hepatocellular carcinoma cells |
Migration | JAK/STAT3, ERK, and PI3K | Leptin promoted cancer cell growth, invasiveness, and migration |
| Sobrinho Santos et al. 2017 [218] SCC-9 and SCC-4 oral squamous cell cancer cells, and clinical samples |
Migration | E-cadherin, Col1A1, MMP-2 and -9, mir-210 and HIF-1α | Leptin favored higher cell proliferation, migration, and reduced apoptosis. Furthermore, leptin decreased caspase-3 mRNA expression |
| Wang et al. 2013 [219] MCF-7 breast cancer cells |
Migration | JAK/STAT and PI3K/AKT signaling pathways | Leptin promoted migration and invasion. Leptin also increased the expression of MMP-9 and TGF-β |
| Wei et al. 2016 [220] MCF-7, SK-BR-3, and MDA-MB-468 breast cancer cells |
Migration and metastasis | PI3K/AKT signaling pathway | Leptin promoted EMT in breast cancer cells via upregulation of PKM2 |
| Yang et al. 2009 [153] JJ012 and SW1353 chondrosarcoma cells |
Migration | IRS-1, PI3K, AKT and NF-κB | Leptin increased migration and expression of αvβ3 integrin in human chondrosarcoma cells |
| Yeh et al. 2009 [221] C6 glioma cells |
Migration | p38 MAPK and NF-κB pathways | Leptin enhanced the migration and invasion of glioma cells. Leptin also upregulated the expression of MMP-13 |
| Yuan et al. 2014 [222] MCF-7 breast cancer cells |
Migration | ERK pathway | Leptin increased the proliferation and migration of cancer cells |
| Zou et al. 2016 [113] Gallbladder cancer cell subline GBC-SD, xenograft model, and clinical samples |
Migration | JAK2/STAT3/SOCS3 | Leptin promoted the proliferation, migration and invasion of cancer cells. Leptin upregulated VEGF-C and VEGF-D levels and activated MMP-3 and MMP-9 |
ACAT2: acetyl-CoA acetyltransferase 2, AKT: v-Akt murine thymoma viral oncogene or protein kinase B (a serine/threonine kinase), APPL1: adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1 (involved in the regulation of cell proliferation), ATF-2: activating transcription factor 2, bFGF: basic fibroblast growth factor, Col1A1: collagen type I alpha 1, EGFR: epidermal growth factor receptor, EMT: epithelial-mesenchymal transition, ERK: extracellular signal-regulated kinase, FAK: focal adhesion kinase, FOXO1: forkhead box O1, HIF-1α: hypoxia-inducible factor 1α, ICAM-1: Intercellular adhesion molecule-1, IL: interleukin, IRS: insulin receptor substrate, JAK: Janus kinase, JNK: c-Jun N-terminal kinase, KIF1B: kinesin family member 1B (involved in the transport of materials), MAPK: mitogen-activated protein kinase, mir-210: mir-210 microRNA (predominant hypoxia-responsive miRNA), MMP: matrix metalloproteinase, MT1-MMP: membrane type 1-matrix metalloproteinase, mTOR: mechanistic/mammalian target of rapamycin, NF-κB: nuclear factor-kappa B, PI3K: phosphatidylinositol-3-kinase, PKC: protein kinase C, PKM2: pyruvate kinase M2 isoform, Rho: G protein under the Ras homologue gene family, RhoA: Rho family small GTPase-member A, ROCK: Rho-associated coiled-coil-forming protein kinase, SOCS3: suppressor of cytokine signaling-3, sPLA2-IIA: secreted phospholipase A2-IIA, Src: avian sarcoma viral oncogene homolog, SREBP2: sterol regulatory element-binding protein 2, STAT3: signal transducer and activator of transcription 3, TAM: tumor-associated macrophage, TGF-β: transforming growth factor beta, uPA: urokinase plasminogen activator, VEGF: vascular endothelial growth factor, VEGFR-2: vascular endothelial growth factor receptor 2.