Cancer Letters

Cancer Letters

Volume 380, Issue 1, 28 September 2016, Pages 114-121
Cancer Letters

Original Articles
Adipocytes contribute to the growth and progression of multiple myeloma: Unraveling obesity related differences in adipocyte signaling

https://doi.org/10.1016/j.canlet.2016.06.010Get rights and content

Highlights

  • BMI negatively correlates with adipose-derived stem cell viability.

  • Adipocytes increase p-STAT3/STAT3 signaling in multiple myeloma cells.

  • Adipocytes increase multiple myeloma cell viability in a BMI-dependent manner.

  • Adipocytes from obese patients increase adhesion of multiple myeloma cells.

  • Adipocytes increase endothelial cell tube formation in a BMI-dependent manner.

Abstract

The prevalence of obesity over the last several decades in the United States has tripled among children and doubled among adults. Obesity increases the incidence and progression of multiple myeloma (MM), yet the molecular mechanisms by which adipocytes contribute to cancer development and patient prognosis have yet to be fully elucidated. Here, we obtained human adipose-derived stem cells (ASCs) from twenty-nine normal (BMI = 20–25 kg/m2), overweight (25–30 kg/m2), obese (30–35 kg/m2), or super obese (35–40 kg/m2) patients undergoing elective liposuction. Upon differentiation, adipocytes were co-cultured with RPMI-8226 and NCI-H929 MM cell lines. Adipocytes from overweight, obese and super obese patients displayed increased PPAR-gamma, cytochrome C, interleukin-6, and leptin protein levels, and decreased fatty acid synthase protein. 8226 MM cells proliferated faster and displayed increased pSTAT-3/STAT-3 signaling when cultured in adipocyte conditioned media. Further, adipocyte conditioned media from obese and super obese patients significantly increased MM cell adhesion, and conditioned media from overweight, obese and super obese patients enhanced tube formation and expression of matrix metalloproteinase-2. In summary, our data suggest that adipocytes in the MM microenvironment contribute to MM growth and progression and should be further evaluated as a possible therapeutic target.

Introduction

Multiple myeloma (MM), a plasma cell neoplasia, represents approximately 10% of all hematologic cancers [1]. Despite a dramatic improvement in the average prognosis of MM patients over the last two decades due to more effective drugs and treatment strategies, MM remains an incurable malignancy [2]. In addition to established risk factors such as age, African ancestry, male sex, monoclonal gammopathy of undetermined significance, and family history, in recent years, numerous epidemiological studies have identified obesity as a risk factor for MM [3], [4], [5], [6]. Obesity significantly increases both the relative risk of developing MM and MM-associated mortality [3], [4], [5], [6]. Despite this epidemiological association, the molecular underpinnings by which obesity contributes to MM growth and progression are relatively unknown.

MM is characterized by clonal expansion of abnormal plasma cells in the bone marrow [7]. The bone marrow microenvironment plays a supportive role in growth, migration, proliferation, survival, and drug resistance of MM cells [8], [9]. Within human bone marrow adipocytes are the most abundant cell type [10]. Adipocytes, although traditionally thought of as having functions limited to energy storage, are now considered a major endocrine organ [11]. Adipocytes secrete various adipokines and inflammatory factors and reciprocal signaling between adipocytes and cancer cells is reported to contribute to tumor initiation, growth and metastasis in several types of cancer [11]. Adipocytes from overweight and obese individuals display an altered cytokine and lipid profile when compared to adipocytes from normal weight individuals, as adipocytes from individuals with a higher BMI have increased production of inflammatory markers and leptin and decreased production of anti-inflammatory cytokines and the tumor suppressor adiponectin [12], [13]. This exaggerated inflammatory response may increase genomic instability, disturb DNA repair, promote tumor progression, cause local immunosuppression, or induce epigenetic changes [14], [15].

In this study we co-cultured human MM cell lines with adipocytes from normal, overweight, obese or super obese patients who received elective liposuction. We found a positive correlation between BMI and adhesion and angiogenesis of MM cells. Moreover, we identified hormonal, lipid, and signaling factor dysregulation in obese adipocytes that can contribute to MM growth and progression.

Section snippets

Cell lines

Human MM cell lines RPMI 8226 and NCI-H929 (ATCC; Manassas, VA) were cultured in RPMI 1640 medium containing 10% fetal bovine serum (FBS), 1% PenStrep, and 1% GlutaMAX (Life Technologies; Grand Island, NY) at 37 °C and 5% CO2.

Stem cell isolation

Lipoaspirates from patients undergoing elective liposuction at the office of DaVinci Plastic Surgery (Washington, DC) were used in this study. All patients gave informed consent prior to surgery. Lipoaspirate cells were washed extensively to remove contaminating red blood

BMI negatively correlates with ASC viability and positively correlates with markers of differentiation and lipid signaling in adipocytes

Cells from twenty-nine patients undergoing elective liposuction were used in this study (Table 2). Samples from patients were divided into four categories based on BMI of the patient: normal (BMI = 20–25 kg/m2), overweight (BMI = 25–30 kg/m2), obese (BMI = 30–35 kg/m2), and super obese (BMI = 35–40 kg/m2). Patients with chronic diseases or illnesses were excluded from this study. The mean age of patients did not statistically differ between categories (normal = 39.1 +/− 11.0;

Discussion

The obesity epidemic is increasingly a global problem, as obesity has more than doubled worldwide in the last 35 years and obesity-related cancer deaths have dramatically increased in modern times [22], [23]. BMI is routinely used as a measure of adiposity. Epidemiological studies have correlated BMI with cancer mortality, as each 5 kg/m2 increase in BMI is associated with an increase of 10% in cancer-related death [24]. With obesity rates on the rise and the epidemiological connection between

Conflict of interest

The author declares no competing financial interests.

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