High serum levels of IL-6 correlate with poor outcome in breast cancer patients. However, no data are available on the relationship between IL-6 and mammary stem/progenitor cells, which may fuel the genesis of breast cancer in vivo. Herein, we address this issue in the MCF-7 breast cancer cell line and in primary human mammospheres (MS), multicellular structures enriched in stem/progenitor cells of the mammary gland. MS from node invasive breast carcinoma tissues expressed IL-6 mRNA at higher levels than did MS from matched nonneoplastic mammary glands. In addition, IL-6 mRNA was detected only in basal-like breast carcinoma tissues, an aggressive breast carcinoma variant showing stem cell features. IL-6 treatment triggered Notch-3-dependent upregulation of the Notch ligand Jagged-1 and promotion of MS and MCF-7-derived spheroid growth. Moreover, IL-6 induced Notch-3-dependent upregulation of the carbonic anhydrase IX gene and promoted a hypoxia-resistant/invasive phenotype in MCF-7 cells and MS. Finally, autocrine IL-6 signaling relied upon Notch-3 activity to sustain the aggressive features of MCF-7-derived hypoxia-selected cells. In conclusion, these data support the hypothesis that IL-6 induces malignant features in Notch-3-expressing stem/progenitor cells from human ductal breast carcinoma and normal mammary gland.

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As the cellular component of articular cartilage, chondrocytes are responsible for maintaining in a low-turnover state the unique composition and organization of the matrix that was determined during embryonic and postnatal development. In joint diseases, cartilage homeostasis is disrupted by mechanisms that are driven by combinations of biological mediators that vary according to the disease process, including contributions from other joint tissues. In osteoarthritis (OA), biomechanical stimuli predominate with upregulation of both catabolic and anabolic cytokines and recapitulation of developmental phenotypes, whereas in rheumatoid arthritis (RA), inflammation and catabolism drive cartilage loss. In vitro studies in chondrocytes have elucidated signaling pathways and transcription factors that orchestrate specific functions that promote cartilage damage in both OA and RA. Thus, understanding how the adult articular chondrocyte functions within its unique environment will aid in the development of rational strategies to protect cartilage from damage resulting from joint disease. This review will cover current knowledge about the specific cellular and biochemical mechanisms that regulate cartilage homeostasis and pathology. IntroductionAdult articular cartilage is an avascular tissue composed of a specialized matrix of collagens, proteoglycans, and noncollagen proteins, in which chondrocytes constitute the unique cellular component. Although chondrocytes in this context do not normally divide, they are assumed to maintain the extracellular matrix (ECM) by low-turnover replacement of certain matrix proteins. During aging and joint disease, this equilibrium is disrupted and the rate of loss of collagens and proteoglycans from the matrix may exceed the rate of deposition of newly synthesized molecules. Originally considered an inert tissue, cartilage is now considered to respond to extrinsic factors that regulate gene expression and protein synthesis in chondrocytes. Numerous studies in vitro and in vivo during the last two decades have confirmed that articular chondrocytes are able to respond to mechanical injury, joint instability due to genetic factors, and biological stimuli such as cytokines and growth and differentiation factors that contribute to structural changes in the surrounding cartilage matrix [1]. Mechanical influences on chondrocyte function are considered to be important in the pathogenesis of osteoarthritis (OA), but chondrocyte responses to molecular signals may vary in different regions, including the calcified cartilage, and also occur at different stages over a long time course (Figure 1). In rheumatoid arthritis (RA), the inflamed synovium is the major source of cytokines and proteinases that mediate cartilage destruction in areas adjacent to the proliferating synovial pannus (Figure 2) [2]. However, the basic cellular mechanisms regulating chondrocyte responses are very different in OA and RA. Moreover, mechanistic insights from in vitro studies ideally should be interpreted in light...