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

Luca Gelsomino,Giuseppina Daniela Naimo,Salvatore Panza,Sebastiano Andò,Rocco Malivindi,Cinzia Giordano,Loredana Mauro,Ines Barone,Daniela Bonofiglio,Stefania Catalano,Giuseppina Augimeri

doi:10.3390/cancers12082078

Luca Gelsomino, Giuseppina Daniela Naimo + Show 9 more

Open Access

https://doi.org/10.3390/cancers12082078

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Journal: Cancers	Publication Date: Jul 27, 2020
Citations: 20	License type: CC BY 4.0

Affiliation: University of Calabria

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.

Highlights

Worldwide, obesity is considered an epidemic health problem as its prevalence is rising both in developed and developing countries [1,2]
Leptin and its receptor are overexpressed in breast carcinoma especially in higher-grade tumors and are associated with distant metastasis and poor prognosis [10,11,12]
We demonstrated, using lentivirus-mediated knockdown strategy, that Ob/ObR signaling integrity in both estrogen receptor (ER)-positive and -negative breast epithelial cancer cells is necessary to maintain the aggressive phenotype of tumor cells and to sustain the pro-tumoral behavior of macrophages in the context of tumor microenvironment (TME)

Summary

Introduction

Obesity is considered an epidemic health problem as its prevalence is rising both in developed and developing countries [1,2]. This growing incidence has deep clinical implications, since obesity is associated with an expanding set of chronic diseases, such as diabetes, hypertension, cardiovascular, kidney and respiratory diseases and different types of malignancies, including breast cancer [3]. Cancers 2020, 12, 2078 dysfunctional adipose tissue, which produces abundant levels of sex hormones, lipid metabolites, proinflammatory cytokines and adipokines. The change in cytokine/adipokine levels is considered to be one of the key features of obesity-related breast cancer [7]. Leptin and its receptor are overexpressed in breast carcinoma especially in higher-grade tumors and are associated with distant metastasis and poor prognosis [10,11,12]

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