Impact of Tumor Microenvironment and Epithelial Phenotypes on Metabolism in Breast Cancer

Abstract

Purpose Cancer cells have altered metabolism, with increased glucose uptake, glycolysis, and biomass production. This study performed genomic and metabolomic analyses to elucidate how tumor and stromal genomic characteristics influence tumor metabolism. Experimental Design Thirty-three breast tumors and six normal breast tissues were analyzed by gene expression microarray and by mass spectrometry for metabolites. Gene expression data and clinical characteristics were evaluated in association with metabolic phenotype. To evaluate the role of stromal interactions in altered metabolism, cocultures were performed using breast cancer cells and primary cancer-associated fibroblasts (CAFs). Results Across all metabolites, unsupervised clustering resulted in two main sample clusters. Normal breast tissue and a subset of tumors with less aggressive clinical characteristics had lower levels of nucleic and amino acids and glycolysis byproducts, while more aggressive tumors had higher levels of these Warburg-associated metabolites. While tumor intrinsic subtype did not predict metabolic phenotype, metabolic cluster was significantly associated with expression of a wound response signature. In cocultures, CAFs from basal-like breast cancers increased glucose up take and basal-like epithelial cells increased glucose oxidation and glycogen synthesis, suggesting interplay of stromal and epithelial phenotypes on metabolism. Cytokine arrays identified hepatocyte growth factor (HGF) as a potential mediator of stromal-epithelial interaction, and antibody neutralization of HGF resulted in reduced expression of glucose transporter 1 (GLUT1) and decreased glucose uptake by epithelium. Conclusions Both tumor/epithelial and stromal characteristics play important roles in metabolism. Warburg-like metabolism is influenced by changes in stromal-epithelial interactions, including altered expression of HGF/Met pathway and GLUT1 expression.

Benign Breast Tissue Composition in Breast Cancer Patients: Association with Risk Factors, Clinical Variables, and Gene Expression

“…For example, risk factors that alter stromal content may have effects on vascular permeability, tight junction signaling, metabolic signaling, loss of contact inhibition and cell polarity. Indeed, our previous experimental work has shown that stromal-epithelial interactions altered metabolism and glucose uptake of breast cancers (41). Thus, these gene expression changes may lead to novel hypotheses about breast cancer microenvironments.…”

Caveolae and signalling in cancer

“…In basal-like breast cancers, CAFs have increased glucose uptake, and carcinoma cells have increased OXPHOS 168 . Transcription factor A mitochondrial (TFAM) is a key transcription factor in mitochondrial biogenesis and metabolism 169 .…”

Plasma metabolomic analysis of human hepatocellular carcinoma: Diagnostic and therapeutic study

“…Actually clinical reports from the medical staff show these subjects most suffer from advanced tumor stages. Therefore, their pathological states could be confirmed by enhanced glucose consumption and lactate production [29]. The amount of characteristic metabolites of TACE group was less than that of HCC group.…”