Lean People with Dysglycemia Have a Worse Metabolic Profile Than Centrally Obese People Without Dysglycemia

Clinical Cancer Research

Zhou

Gucalp

et al. 2016

170

202

Purpose Obesity, insulin resistance, and elevated levels of circulating proinflammatory mediators are associated with poorer prognosis in early-stage breast cancer. To investigate whether white adipose tissue (WAT) inflammation represents a potential unifying mechanism, we examined the relationship between breast WAT inflammation and the metabolic syndrome and its prognostic importance. Experimental Design WAT inflammation was defined by the presence of dead/dying adipocytes surrounded by macrophages forming crown-like structures of the breast (CLS-B). Two independent groups were examined in cross-sectional (Cohort 1) and retrospective (Cohort 2) studies. Cohort 1 included 100 women undergoing mastectomy for breast cancer risk reduction (n=10) or treatment (n=90). Metabolic syndrome-associated circulating factors were compared by CLS-B status. The association between CLS-B and the metabolic syndrome was validated in Cohort 2 which included 127 women who developed metastatic breast cancer. Distant recurrence free survival (dRFS) was compared by CLS-B status. Results In Cohorts 1 and 2, breast WAT inflammation was detected in 52/100 (52%) and 52/127 (41%) patients, respectively. Patients with breast WAT inflammation had elevated insulin, glucose, leptin, triglycerides, C-reactive protein, and interleukin-6; and lower HDL cholesterol and adiponectin (P<0.05) in Cohort 1. In Cohort 2, breast WAT inflammation was associated with hyperlipidemia, hypertension, and diabetes (P<0.05). Compared to patients without breast WAT inflammation, the adjusted hazard ratio for dRFS was 1.83 (95% CI, 1.07 to 3.13) for patients with inflammation. Conclusions WAT inflammation, a clinically occult process, helps to explain the relationship between metabolic syndrome and worse breast cancer prognosis.

Section: Discussionmentioning

confidence: 99%

Systemic Correlates of White Adipose Tissue Inflammation in Early-Stage Breast Cancer

Clinical Cancer Research

Zhou

Gucalp

et al. 2016

170

202

“…For example, insulin resistance and inflammation have been reported in individuals who have a normal BMI. [17][18][19] Conversely, a minority of individuals with elevated BMI are metabolically healthy. [20][21][22] Accordingly, the current definition of obesity on the basis of BMI has recently been called into question, 23,24 and BMI is inadequate for the identification of patients with adipose inflammation.…”

Section: Introductionmentioning

confidence: 99%

Obesity and Cancer Mechanisms: Tumor Microenvironment and Inflammation

Gucalp

Dannenberg

et al. 2016

JCO

693

522

There is growing evidence that inflammation is a central and reversible mechanism through which obesity promotes cancer risk and progression. MethodsWe review recent findings regarding obesity-associated alterations in the microenvironment and the local and systemic mechanisms through which these changes support tumor growth. ResultsLocally, hyperadiposity is associated with altered adipose tissue function, adipocyte death, and chronic low-grade inflammation. Most individuals who are obese harbor inflamed adipose tissue, which resembles chronically injured tissue, with immune cell infiltration and remodeling. Within this distinctly altered local environment, several pathophysiologic changes are found that may promote breast and other cancers. Consistently, adipose tissue inflammation is associated with a worse prognosis in patients with breast and tongue cancers. Systemically, the metabolic syndrome, including dyslipidemia and insulin resistance, occurs in the setting of adipose inflammation and operates in concert with local mechanisms to sustain the inflamed microenvironment and promote tumor growth. Importantly, adipose inflammation and its protumor consequences can be found in some individuals who are not considered to be obese or overweight by body mass index. ConclusionThe tumor-promoting effects of obesity occur at the local level via adipose inflammation and associated alterations in the microenvironment, as well as systemically via circulating metabolic and inflammatory mediators associated with adipose inflammation. Accurately characterizing the obese state and identifying patients at increased risk for cancer development and progression will likely require more precise assessments than body mass index alone. Biomarkers of adipose tissue inflammation would help to identify high-risk populations. Moreover, adipose inflammation is a reversible process and represents a novel therapeutic target that warrants further study to break the obesity-cancer link.

“…However, metabolic syndrome disorders that are classically associated with elevated BMI have been reported to occur in a subset of individuals with a normal BMI (31, 32). When found in individuals with a normal BMI, these disorders are collectively termed metabolic obesity in normal weight (33, 34) and as such, misclassification of cardiometabolic health and risk of cardiometablic diseases occurs when using BMI categories (35).…”

Section: Introductionmentioning

confidence: 99%

Metabolic Obesity, Adipose Inflammation and Elevated Breast Aromatase in Women with Normal Body Mass Index

Cancer Prevention Research

Brown

Zhou

et al. 2017

124

127

Obesity is associated with breast white adipose tissue (WAT) inflammation, elevated levels of the estrogen-biosynthetic enzyme, aromatase, and systemic changes that have been linked to the pathogenesis of breast cancer. Here we determined whether metabolic obesity, including changes in breast biology and systemic effects, occurs in a subset of women with normal body mass index (BMI). Breast WAT and fasting blood were collected from 72 women with normal BMI (< 25 kg/m2) undergoing mastectomy for breast cancer risk reduction or treatment. WAT inflammation was defined by the presence of crown-like structures of the breast (CLS-B) which are comprised of dead or dying adipocytes surrounded by macrophages. Severity of inflammation was measured as CLS-B/cm2. The primary objective was to determine if breast WAT inflammation is associated with aromatase expression and activity. Secondary objectives included assessment of circulating factors and breast adipocyte size. Breast WAT inflammation was present in 39% of women. Median BMI was 23.0 (range 18.4 to 24.9) in women with breast WAT inflammation versus 21.8 (range 17.3 to 24.6) in those without inflammation (P=.04). Breast WAT inflammation was associated with elevated aromatase expression and activity, which increased with severity of inflammation (P<.05). Breast WAT inflammation correlated with larger adipocytes (P=.01) and higher circulating levels of C-reactive protein, leptin, insulin, and triglycerides (P≤.05). A subclinical inflammatory state associated with elevated aromatase in the breast, adipocyte hypertrophy, and systemic metabolic dysfunction occurs in some normal BMI women and may contribute to the pathogenesis of breast cancer.