Adipocyte-Derived Fibroblasts Promote Tumor Progression and Contribute to the Desmoplastic Reaction in Breast Cancer

Abstract

Cancer-associated fibroblasts (CAF) comprise the majority of stromal cells in breast cancers, yet their precise origins and relative functional contributions to malignant progression remain uncertain. Local invasion leads to the proximity of cancer cells and adipocytes, which respond by phenotypical changes to generate fibroblast-like cells termed as adipocyte-derived fibroblasts (ADF) here. These cells exhibit enhanced secretion of fibronectin and collagen I, increased migratory/invasive abilities, and increased expression of the CAF marker FSP-1 but not a-SMA. Generation of the ADF phenotype depends on reactivation of the Wnt/b-catenin pathway in response to Wnt3a secreted by tumor cells. Tumor cells cocultivated with ADFs in two-dimensional or spheroid culture display increased invasive capabilities. In clinical specimens of breast cancer, we confirmed the presence of this new stromal subpopulation. By defining a new stromal cell population, our results offer new opportunities for stroma-targeted therapies in breast cancer. Cancer Res; 73(18); 5657-68. Ó2013 AACR.

Small bone marrow adipocytes predict poor prognosis in acute myeloid leukemia

“…14 We also found that growth differentiation factor 15, a member of the transforming growth factor-beta family, secreted by leukemic cells may be involved in the generation of small adipocytes (data not shown). FFA was released by adipocytes during lipolysis.…”

Stromal Fibroblasts Induce CCL20 through IL6/C/EBPβ to Support the Recruitment of Th17 Cells during Cervical Cancer Progression

“…Thus, Th17 infiltration apparently increases during later stages of cervical carcinogenesis and is associated with severity of invasive disease. Fibroblasts can promote inflammation during progression of different cancer types (39), expressing proinflammatory cytokines and chemokines, like IL6, IL1b, and Gro-a (40). Our study adds CCL20 as a novel, important immune cell attracting chemokine to the list of mediators produced by cancer-instructed fibroblasts.…”

Carcinoma-associated fibroblasts: orchestrating the composition of malignancy

“…While a majority of CAFs are thought to arise from activation of resident fibroblasts (see below), studies in genetically modified mouse models have demonstrated that about one-third of CAFs derive from other sources: bone marrow (BM)-derived cells (Quante et al 2011;Lecomte et al 2012;McDonald et al 2015), adipocytes (Bochet et al 2013), endothelial cells (Zeisberg et al 2007), or even, perhaps, epithelial cells (Radisky et al 2007) that undergo mesenchymal transition when instructed by systemic factors secreted by the tumor (Chen et al 2015a). This complexity has led some investigators to propose that a CAF is a "cell state" rather than a "cell type" (Madar et al 2013).…”