Obesity-Altered Adipose Stem Cells Promote Radiation Resistance of Estrogen Receptor Positive Breast Cancer through Paracrine Signaling.

Rachel A Sabol,Benjamin T Freeman,Fokhrul Hossain,Maxwell B Sandler,Lucio Miele,Alifiani B Hartono,Alexandra Denys,Vidal A Villela,Mark A A Harrison,Rachel M Wise,Bruce A Bunnell

doi:10.3390/ijms21082722

Abstract

Obesity is associated with poorer responses to chemo- and radiation therapy for breast cancer, which leads to higher mortality rates for obese women who develop breast cancer. Adipose stem cells (ASCs) are an integral stromal component of the tumor microenvironment (TME). In this study, the effects of obesity-altered ASCs (obASCs) on estrogen receptor positive breast cancer cell’s (ER+BCCs) response to radiotherapy (RT) were evaluated. We determined that BCCs had a decreased apoptotic index and increased surviving fraction following RT when co-cultured with obASCs compared to lnASCs or non-co-cultured cells. Further, obASCs reduced oxidative stress and induced IL-6 expression in co-cultured BCCs after radiation. obASCs produce increased levels of leptin relative to ASCs from normal-weight individuals (lnASCs). obASCs upregulate the expression of IL-6 compared to non-co-cultured BCCs, but BCCs co-cultured with leptin knockdown obASCs did not upregulate IL-6. The impact of shLeptin obASCs on radiation resistance of ER+BCCs demonstrate a decreased radioprotective ability compared to shControl obASCs. Key NOTCH signaling players were enhanced in ER+BBCs following co-culture with shCtrl obASCs but not shLep obASCs. This work demonstrates that obesity-altered ASCs, via enhanced secretion of leptin, promote IL-6 and NOTCH signaling pathways in ER+BCCs leading to radiation resistance.

Highlights

Breast cancer (BC) is the most prevalent and second most fatal cancer in women, claiming approximately 40,000 lives every year [1,2]
Time-lapse imaging of MCF7, ZR-75, and T47D cell lines alone or co-cultured with six pooled donors of leptin relative to ASCs from normal-weight individuals (lnASCs) or obesity-altered ASCs (obASCs) and gamma irradiated at a dose of 2 Gy demonstrates that ionizing radiation (IR) induces apoptosis more efficiently in BCCs alone compared to BCCs that had previously been transwell co-cultured with Adipose stem cells (ASCs)
While there was no significant difference between lnASCs and obASCs after 5 Gy (Figure 1B), there is a difference in apoptosis between lnASCs and obASCs (Figure 1A)

Summary

Introduction

Breast cancer (BC) is the most prevalent and second most fatal cancer in women, claiming approximately 40,000 lives every year [1,2]. BC prognosis has improved over the past two decades due to better screening methods and improving therapies; challenges associated with standard therapy remain unresolved. Radiotherapy (RT) has been a treatment for many malignancies, including breast cancer, for over a century and has been shown to substantially increase patient survival [1]. The main challenges associated with this treatment are damage to the surrounding normal tissue and radioresistance, characterized by the unresponsiveness of some cancer cells to RT. Breast-conserving therapy, which is indicated for both invasive BC and ductal carcinoma in situ, is comprised of lumpectomy and RT. An overview of BC randomized control trials demonstrated no difference in outcomes between mastectomy and breast conserving therapy [3,4]. RT reduces the long-term risk for local recurrence [5]

Methods

Results

Discussion

Conclusion