Knockdown of Leptin Receptor Affects Macrophage Phenotype in the Tumor Microenvironment Inhibiting Breast Cancer Growth and Progression

Abstract

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.

Obesity and Overweight Are Associated with Minimal Extrathyroidal Extension, Multifocality and Bilaterality of Papillary Thyroid Cancer

“…Obesity and PTC incidence have become major public health problems worldwide [ 2 , 3 , 17 ]. Some authors have noticed that the detection rate of thyroid nodules is much higher in female individuals than in male individuals and that thyroid nodules are significantly associated with sex, age, BMI and metabolic-related diseases [ 26 ].…”

“…Obesity is defined as an excessive accumulation of body fat. The incidence of obesity has dramatically increased in recent decades and has become a major public health problem worldwide [ 1 , 2 , 3 ]. The prevalence of obesity tripled from 3.2% to 10.8% in men and doubled in women from 6.4% to 14.9% between 1975 and 2014 [ 4 ].…”

“…Considering the facts that the prevalence of PTC is increasing in many parts of the world [ 17 ], that the same trend is observed for obesity [ 2 , 3 , 17 ] and that people with high BMI are more predisposed to PTC morbidity [ 12 , 20 ], we asked the following question: (A) could PTC in obese people present more aggressive features? Subsequently, we considered (B) whether a higher BMI may result in more frequent clinical manifestations and a higher prevalence of PTC.…”

Leptin and Cancer: Updated Functional Roles in Carcinogenesis, Therapeutic Niches, and Developments

“…The loss of LEPR expression in breast cancer was also observed to modulate the tumor microenvironment. With LEPR loss, cancer cells exhibited a less aggressive phenotype, and macrophage recruitment was abolished; the phagocytic activity and cytokine production of macrophages also appeared to decrease [ 56 ]. Cotreatment with leptin and adipose tissue-derived fibroblast growth factor-2 (FGF2) was reported to induce the malignant transformation of breast epithelial MCF-10A cells, and this effect was found to be attenuated by ruxolitinib and AG490, two separate inhibitors of Jak2, which is downstream of the leptin receptor, suggesting the critical interplay of leptin, leptin receptor and Jak2 in cancer progression [ 57 ].…”

Current Landscape: The Mechanism and Therapeutic Impact of Obesity for Breast Cancer

“…The following in vitro assay further confirmed the role of leptin in promoting BC cell migration and invasion, via the SDF-1/CXCR4 axis activated by leptin. The absence of leptin receptor modified BC phenotype less aggressive in vitro and reduced the macrophage recruitment in vivo , proposing an innovative role of leptin receptor in modulating BC features ( 39 ).…”