Obesity Promotes Cooperation of Cancer Stem-Like Cells and Macrophages to Enhance Mammary Tumor Angiogenesis.

Lauren E Hillers-Ziemer,Gretchen Paderta,Jennelle Lebeau,Margaret Hietpas,Rachel Q Mcmahon,Lisa M Arendt,Jessica Mccready

doi:10.3390/cancers12020502

Lauren E Hillers-Ziemer, Gretchen Paderta + Show 5 more

Open Access

https://doi.org/10.3390/cancers12020502

Copy DOI

Abstract

Obesity is correlated with worsened prognosis and treatment resistance in breast cancer. Macrophage-targeted therapies are currently in clinical trials, however, little is known about how obesity may impact treatment efficacy. Within breast adipose tissue, obesity leads to chronic, macrophage-driven inflammation, suggesting that obese breast cancer patients may benefit from these therapies. Using a high fat diet model of obesity, we orthotopically transplanted cancer cell lines into the mammary glands of obese and lean mice. We quantified changes in tumor invasiveness, angiogenesis and metastasis, and examined the efficacy of macrophage depletion to diminish tumor progression in obese and lean mice. Mammary tumors from obese mice grew significantly faster, were enriched for cancer stem-like cells (CSCs) and were more locally invasive and metastatic. Tumor cells isolated from obese mice demonstrated enhanced expression of stem cell-related pathways including Sox2 and Notch2. Despite more rapid growth, mammary tumors from obese mice had reduced necrosis, higher blood vessel density, and greater macrophage recruitment. Depletion of macrophages in obese tumor-bearing mice resulted in increased tumor necrosis, reduced endothelial cells, and enhanced recruitment of CD8+ T cells compared to IgG-treated controls. Macrophages may be an important clinical target to improve treatment options for obese breast cancer patients.

Highlights

Almost 40% of the adult population in the United States is considered clinically obese [1].Obesity, defined as a body mass index of greater than 30.0 kg/m2, is a known risk factor for the development of postmenopausal breast cancer [2,3]
To identify strain-specific differences, FVB/N and C57Bl/6 female mice were randomized into groups and fed either control diet (CD) or high fat diet (HFD) for 16 weeks to induce obesity
We have previously observed that mice of both strains fed a HFD for 16 weeks have increased mammary gland weights and adipocyte size compared with CD-fed mice, as well as the formation of crown-like structures [28], consistent with changes observed in breast tissue of obese women [29]

Summary

Introduction

Obesity, defined as a body mass index of greater than 30.0 kg/m2 , is a known risk factor for the development of postmenopausal breast cancer [2,3]. Regardless of menopausal status, obese women diagnosed with breast cancer often have larger primary tumors, greater incidence of lymph node involvement, and poorly differentiated tumors compared to patients with a body mass index within normal range [2]. Obese patients have shorter disease-free survival rates [4,5] and a higher risk of breast cancer-related mortality than lean patients [6]. Cancer stem-like cells (CSCs), which comprise a minor population of tumor cells, are thought to underlie clinically aggressive tumor behavior such as local and distant tumor recurrence and increased resistance to conventional

Methods

Results

Discussion

Conclusion