Obesity, defined as the abnormal or excessive expansion of white adipose tissue, has reached pandemic proportions and is recognized as an important health concern since it is a common root for several comorbidities, including malignancies. Indeed, the current knowledge of the white adipose tissue, which shifts its role from an energy storage tissue to an important endocrine and metabolic organ, has opened up new avenues for the discovery of obesity’s effects on tumor biology. In this review, we will report the epidemiological studies concerning the strong impact of obesity in several types of cancer and describe the mechanisms underlying the heterotypic signals between cancer cell lines and adipocytes, with particular emphasis on inflammation, the insulin/IGF-1 axis, and adipokines. Among the adipokines, we will further describe the in vitro, in vivo, and clinical data concerning the role of leptin, recognized as one of the most important mediators of obesity-associated cancers. In fact, leptin physiologically regulates energy metabolism, appetite, and reproduction, and several studies have also described the role of leptin in affecting cancer development and progression. Finally, we will summarize the newest pharmacological strategies aimed at mitigating the protumorigenic effects of leptin, underlining their mechanisms of action.

Aberrant leptin (Ob) signaling, a hallmark of obesity, has been recognized to influence breast cancer (BC) biology within the tumor microenvironment (TME). Here, we evaluated the impact of leptin receptor (ObR) knockdown in affecting BC phenotype and in mediating the interaction between tumor cells and macrophages, the most abundant immune cells within the TME. The stable knockdown of ObR (ObR sh) in ERα-positive and ERα-negative BC cells turned the tumor phenotype into a less aggressive one, as evidenced by in vitro and in vivo models. In xenograft tumors and in co-culture experiments between circulating monocytes and BC cells, the absence of ObR reduced the recruitment of macrophages, and also affected their cytokine mRNA expression profile. This was associated with a decreased expression and secretion of monocyte chemoattractant protein-1 in ObR sh clones. The loss of Ob/ObR signaling modulated the immunosuppressive TME, as shown by a reduced expression of programmed death ligand 1/programmed cell death protein 1/arginase 1. In addition, we observed increased phagocytic activity of macrophages compared to control Sh clones in the presence of ObR sh-derived conditioned medium. Our findings, addressing an innovative role of ObR in modulating immune TME, may open new avenues to improve BC patient health care.

Glioblastoma multiforme (GBM) is the most malignant form of glioma, which represents one of the commonly occurring tumors of the central nervous system. Despite the continuous development of new clinical therapies against this malignancy, it still remains a deadly disease with very poor prognosis. Here, we demonstrated the existence of a biologically active interaction between leptin and Notch signaling pathways that sustains GBM development and progression. We found that the expression of leptin and its receptors was significantly higher in human glioblastoma cells, U-87 MG and T98G, than in a normal human glial cell line, SVG p12, and that activation of leptin signaling induced growth and motility in GBM cells. Interestingly, flow cytometry and real-time RT-PCR assays revealed that GBM cells, grown as neurospheres, displayed stem cell-like properties (CD133+) along with an enhanced expression of leptin receptors. Leptin treatment significantly increased the neurosphere forming efficiency, self-renewal capacity, and mRNA expression levels of the stemness markers CD133, Nestin, SOX2, and GFAP. Mechanistically, we evidenced a leptin-mediated upregulation of Notch 1 receptor and the activation of its downstream effectors and target molecules. Leptin-induced effects on U-87 MG and T98G cells were abrogated by the selective leptin antagonist, the peptide LDFI (Leu-Asp-Phe-Ile), as well as by the specific Notch signaling inhibitor, GSI (Gamma Secretase Inhibitor) and in the presence of a dominant-negative of mastermind-like-1. Overall, these findings demonstrate, for the first time, a functional interaction between leptin and Notch signaling in GBM, highlighting leptin/Notch crosstalk as a potential novel therapeutic target for GBM treatment.

Obesity has a noteworthy role in breast tumor initiation and progression. Among the mechanisms proposed, the most validated is the development of chronic low-grade inflammation, supported by immune cell infiltration along with dysfunction in adipose tissue biology, characterized by an imbalance in adipocytokines secretion and alteration of their receptors within the tumor microenvironment. Many of these receptors belong to the seven-transmembrane receptor family, which are involved in physiological features, such as immune responses and metabolism, as well as in the development and progression of several malignancies, including breast cancer. These receptors are classified as canonical (G protein-coupled receptors, GPCRs) and atypical receptors, which fail to interact and activate G proteins. Among the atypical receptors, adiponectin receptors (AdipoRs) mediate the effect of adiponectin, the most abundant adipocytes-derived hormone, on breast cancer cell proliferation, whose serum levels are reduced in obesity. The adiponectin/AdipoRs axis is becoming increasingly important regarding its role in breast tumorigenesis and as a therapeutic target for breast cancer treatment. The objectives of this review are as follows: to point out the structural and functional differences between GPCRs and AdipoRs, and to focus on the effect of AdipoRs activation in the development and progression of obesity-dependent breast cancer.

In the breast tumor microenvironment (TME), adipocytes exert a selective pressure on the behavior of breast cancer stem cells (BCSCs), which are involved in endocrine therapy resistance. In obesity, adipocytes secrete reduced levels of adiponectin, which promotes the growth and progression of ERα-positive breast cancer (BC). Here, we examined how low adiponectin levels affect the enrichment of the BCSC subpopulation and the mechanisms contributing to the maintenance of endocrine therapy resistance in BC. Flow cytometry, qRT-PCR, and Western blotting analysis were performed to assess stemness, the cell cycle, and apoptosis markers in MCF-7 wild-type (WT) and tamoxifen-resistant (TR) mammospheres. nLC-MS/MS was employed to profile and compare the proteome of BCSCs. Differentially expressed proteins were intersected with data from the Metacore^TM dataset. Our study demonstrated that adiponectin increased the percentage of CD44⁺/CD24⁻/ALDH1⁺ stem-like cells in TR MCF-7 mammospheres. Specifically, adiponectin contributed to the maintenance of BCSC bulk in TR MCF-7 cells through a slow cycling rate, supported by decreased levels of Cyclin D1 and Ki67 and increased p21 and p27 expression, and through escape from apoptosis, sustained by reduced ROS production and preserved maintenance of mitochondrial membrane potential. Our results provide new insights into the contribution of adiponectin to poor ERα-positive BC outcomes. Deeply understanding adiponectin’s role in stemness may disclose novel therapeutic approaches to treat hormone-resistant obese BC patients.

Glioblastoma (GBM) is the most common malignant brain tumor, with a poor prognosis and low survival. Its treatment includes complete surgical resection followed by radiotherapy combined with temozolomide (TMZ). GBM contains glial stem cells (GSCs), which contribute to tumor progression, invasiveness, and drug resistance. The histone deacetylase (HDAC) inhibitor valproic acid (VA) has been shown to be a potent antitumor and cytostatic agent. In this study, we tested the effects of VA on glioma cell proliferation, migration, and apoptosis using T98G monolayer and spheroid cells. T98G and U-87MG glioblastoma cell viability was determined by MTT. Cell cycle and ROS levels were analyzed by flow cytometry, and gene and protein levels were detected, respectively, by RT-PCR and immunoblotting. VA reduces cell viability in 2D and 3D T98G and U-87MG cells and blocks the cell cycle at the G0/G1 with decreased levels of cyclin D1. VA addresses apoptosis and ROS production. In addition, VA significantly decreases the mRNA levels of the mesenchymal markers, and it counteracts cell migration, also decreasing MMP2. The results confirm the inhibitory effect of VA on the growth of the T98G and U-87MG cell lines and its ability to counteract migration in both 2D and 3D cellular models.