Role of oxidative stress and the microenvironment in breast cancer development and progression

Abstract

Breast cancer is a highly complex tissue composed of neoplastic and stromal cells. Carcinoma-associated fibroblasts (CAFs) are commonly found in the cancer stroma, where they promote tumor growth and enhance vascularity in the microenvironment. Upon exposure to oxidative stress, fibroblasts undergo activation to become myofibroblasts. These cells are highly mobile and contractile and often express numerous mesenchymal markers. CAF activation is irreversible, making them incapable of being removed by nemosis. In breast cancer, almost 80% of stromal fibroblasts acquire an activated phenotype that manifests by secretion of elevated levels of growth factors, cytokines, and metalloproteinases. They also produce hydrogen peroxide, which induces the generation of subsequent sets of activated fibroblasts and tumorigenic alterations in epithelial cells. While under oxidative stress, the tumor stroma releases high energy nutrients that fuel cancer cells and facilitate their growth and survival. This review describes how breast cancer progression is dependent upon oxidative stress activated stroma and proposes potential new therapeutic avenues.

Keywords: Breast cancer; Cancer-associated fibroblasts; Microenvironment; Myofibroblasts; Oxidative stress; Reactive oxygen species; Stroma-associated fibroblasts.

Figure 3.1

Breast tumor microenvironment. The tumor microenvironment consists of cancer, stromal, and nonmalignant cells supporting tumor growth and vascularization. Under oxidative stress, activated stromal cells generate tumor enhancing signals. Activated fibroblasts acquire a contractile phenotype and mobility affecting cancer cell migration and invasion. Immune cells infiltrate the tumor tissue and secrete cytokines supporting further microenvironmental stress. (See Page 1 in Color Section at the back of the book.)

Figure 3.2

Oxidative stress activates stroma fibroblasts. In breast cancer, under oxidative stress, stroma-associated fibroblasts acquire an activated state and can be identified by numerous markers including α-smooth muscle actin (α-SMA), fibroblast specific protein (FSP), fibroblast activation protein (FAP), PDGF receptors-β, desmin, endosialin, tenascin-c, palladin, vimentin, pro-collagen, stromelysin-3, and cadherin-11. Oxidative stress can cause cell senescence, locking activated fibroblast in a nonproliferative state and creating a senescence-associated secretory phenotype, which manifests in releasing factors that affect neighboring cells. Activation of fibroblasts, followed by secretion of numerous factors including metalloproteinases (MMP-2, MMP-3, MMP9), growth factors (HGF-2, EGF, IGF, TGFβ, VEGF), the polysaccharide hyaluronan and tenascin-c significantly promotes proliferation and growth of premalignant epithelial cells and cancer cells, invasiveness, metastasis, and angiogenesis in breast cancer. (See Page 2 in Color Section at the back of the book.)

Figure 3.3

Interactions between CAFs and breast cancer cells in the tumor microenvironment. In the tumor microenvironment close interactive pathways are established, cross-linking breast cancer cells and stromal cells. Upregulated NADPH oxidase complex (NOX) bound in cell membranes is a source of large amounts of ROS released from these cells. Cancer cells secrete ROS, cytokines, and growth factors, prompting a reactive response in the stroma. Activated stromal cells influence cancer cell malignancy by increasing oxidative stress, collagen deposition, MMP, and growth factor secretion. Oxidative stress-induced loss of expression of membrane-bound scaffolding protein, caveolin-1 (Cav-1), in cancer-associated fibroblasts via autophagy also results in an activated tumor microenvironment. The uncontrolled expansion of cancer cells depends upon high ATP production and high glucose availability. CAFs release lactate via monocarboxylate transporter 4 (MCT4) and monocarboxylate transporter 1 (MCT1) on cancer cells facilitating lactate uptake. Thus, by providing high energy metabolites activated fibroblasts maintain continuous cancer progression. (See Page 3 in Color Section at the back of the book.)