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

Abstract

R.A.S.); vvillela@tulane.edu (V.A.V.); acote1@lsuhsc.edu (A.D.); rwise@tulane.edu (R.M.W.); mharri26@tulane.edu (M.A.A.H.); msandle1@tulane.edu (M.B.S.)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.Int. J. Mol. Sci. 2020, 21, 2722 2 of 15 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. RT is a mainstay of BC therapy. 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]. Further, RT reduces the long-term risk for local recurrence [5].Beyond RT, systemic treatments such as endocrine therapy are also a mainstay in BC treatment; however, flexible guidelines and patient preferences often leave therapy choice to physicians' discretion although endocrine therapy is recommended for patients whose cancer display any level of estrogen expression [6,7]. Notably, it has been found that endocrine therapy and RT can be safely concurrently administered without danger of weakening disease control [6].Obesity has been implicated as a risk factor in RT resistance, metastasis, and overall poor prognosis in breast cancer [8][9][10]. Furthermore, moderate to severe obesity increases the likelihood of BC recurrence and BC-specific mortality [10,11]. O...

Anti‐obesity potentiality of Tapra fish ( Opisthopterus tardoore ) oil

“…It is secreted by adipocytes and it signals to the brain to inhibit food intake, and thus, help in decreasing weight (Ahima, 2008). So far, the idea of leptin as an anti‐obesity hormone was not clear because obesity is characteristically related to high leptin levels but not to leptin deficiency (Flier, 1998; Heymsfield et al., 1999; Sabol et al., 2020). In this study, we observed the selective downregulation of serum leptin levels in HFO which was supported by the existing literature published by many researchers (Flier, 1998; Gray, Steyn, Davies, & Vitetta, 2013).…”

Metabolic Syndrome and Breast Cancer: Prevalence, Treatment Response, and Prognosis

“…Moreover, it may stimulate the epithelial mesenchymal transition (EMT) (80), which has been confirmed to activate the EMT of breast cancer cells by upregulating pyruvate kinase M2 to activate the PI3K/ Akt pathway (81), increasing the activity of matrix metalloproteinases (MMPs), promoting the formation and maintenance of breast cancer stem cell (BCSC) survival, inducing the activation and proliferation of endothelial cells and modulating tumor-immune cell cross talk. Sabol et al (82) found through molecular experiments that adipose stem cells modified by obesity promoted the secretion of leptin and upregulated and activated the IL-6 and Notch signaling pathways in ER+ breast cancer cells, resulting in ER+ breast cancer radiation resistance. Leptin signaling affects the progression of ER-breast cancer (83).…”

Adipose-Derived Stem Cells from Obese Donors Polarize Macrophages and Microglia toward a Pro-Inflammatory Phenotype

“…Human female, subcutaneous, abdominal ASCs were obtained from LaCell LLC/Obatala Sciences Inc. (New Orleans, LA, USA). Individual ASC cell lines were previously fully characterized by our laboratory prior to being pooled [ 25 , 26 , 44 , 45 , 46 ]. Following pooling an abbreviated characterization was completed to ensure expression of basic stemness characteristics.…”