CD44v5 domain regulates crosstalk between TNBC cells and tumor-associated macrophages by enhancing the IL-4R/STAT3 axis.

Triple-negative breast cancer (TNBC) has greater infiltration of M2-like macrophages (TAMs), which enhances cancer cell invasion and leads to a poor prognosis. TNBC progression is mediated by both tumor cells and the tumor microenvironment (TME). Here we elucidate the mechanism of the interaction between TNBC cells and TAMs. In this study, we confirmed that CD44v5 is highly expressed in TNBC, which drives TNBC cell metastasis and promotes TAM polarization by co-localizing with IL4Rα and inhibiting its internalization and degradation, thereby promoting activation of the STAT3/IL6 signaling axis. At the same time, TAMs also facilitate TNBC cell metastasis by secreting IL-4, IL-6, and other cytokines, in which the IL-4/IL-4R/STAT3/IL-6 signaling axis plays the same role for TNBC cells responding to TAMs. Moreover, we found that the above progress could be suppressed when the CD44v5 domain was blocked. We demonstrated that the CD44v5/IL-4R/STAT3/IL-6 signaling pathway plays a key role in TNBC cell metastasis, and in TNBC cells inducing TAM polarization and responding to TAMs, promoting metastasis. Collectively, we suggest that the CD44v5 domain may be a promising target for regulating the TME of TNBC as well as treating TNBC.

Dipeptidyl Peptidase-4-Mediated Fibronectin Processing Evokes a Profibrotic Extracellular Matrix.

Fibronectin serves as a platform to guide and facilitate deposition of collagen and fibrillin microfibrils. During development of fibrotic diseases, altered fibronectin deposition in the extracellular matrix (ECM) is generally an early event. After this, dysregulated organization of fibrillins and fibrillar collagens occurs. Because fibronectin is an essential orchestrator of healthy ECM, perturbation of its ECM-organizational capacity may be involved in development of fibrosis. To investigate this, we employed recessive dystrophic epidermolysis bullosa as a disease model with progressive, severe dermal fibrosis. Fibroblasts from donors with recessive dystrophic epidermolysis bullosa in 2-dimensional and 3-dimensional cultures displayed dysregulated fibronectin deposition. Our analyses revealed that increase of profibrotic dipeptidyl peptidase-4-positive fibroblasts coincides with altered fibronectin deposition. Dipeptidyl peptidase-4 inhibitors normalized deposition of fibronectin and subsequently of fibrillin microfibrils and collagen I. Intriguingly, proteomics and inhibitor and mutagenesis studies disclosed that dipeptidyl peptidase-4 modulates ECM deposition through the proteolysis of the fibronectin N-terminus. Our study provides mechanistic insights into the observed profibrotic activities of dipeptidyl peptidase-4 and extends the understanding of fibronectin-guided ECM assembly in health and disease.

Heavy metals and lead isotopes in soils, road dust and leafy vegetables and health risks via vegetable consumption in the industrial areas of Shanghai, China.

Vegetable fields have a high risk of heavy metal contamination from pollution sources in suburban and industrial areas of cities. Eighty-seven soil samples, 106 leafy vegetables and 48 road dust samples were collected from industrial areas of Shanghai, China. We studied the levels of heavy metals, health risk through consumption of leafy vegetables, and sources of Pb in soils, road dust and leafy vegetables. Soil Cd, Zn, Pb, Cu, Hg and As concentrations exceeded the soil background values in 73.6%, 97.7%, 52.3%, 37.8%, 95.1% and 20.2% soil samples, respectively, but were below the criteria for agricultural soil in China, with the exception of Hg. The concentrations of Cd, Zn, Pb, Cu and As in road dust were significantly higher than concentrations in soils, while Hg concentration in road dust was lower. Cd, Zn, Pb, Hg and Cu concentrations in soils and Zn, Pb and Cu concentrations in road dust were greatest near the municipal solid waste incineration power plant. Heavy metal concentrations in the edible tissues of vegetables were not correlated with their total values in soils and varied among vegetable species. The trends in transfer factors (TFs) in different vegetables were Cd>Zn>Cu>As>Hg>Pb. There was low health risk from heavy metal exposure by consumption of vegetables based on Hazard Quotients (HQM): As was the major contributor to HQM, followed by Cd and Pb. Parent material of the Yangtze River Estuary was the major source of Pb in soils, while coal-fired, stationary industrial emissions and municipal waste incineration emissions were the major sources of Pb in dust and vegetables based on use of the lead isotopic tracing method. Accumulation of Pb in leafy vegetables was through foliar uptake and directly related to atmospheric Pb.

[Distribution Characteristics and Health Risk for Heavy Metals in Vegetables Near the Industrial Areas in Shanghai].

The concentrations of Cd, Zn, Pb, Cu, Hg, and As in vegetables collected from the industrial areas in suburban Shanghai were analyzed before and after washing. Results showed that the average concentrations (fresh weight) of Cd, Zn, Pb, Cu, Hg, and As in washed vegetables were 0.023, 4.444, 0.112, 0.826, 0.004, and 0.094 mg·kg-1, respectively. Amaranth accumulated the highest Cd, Zn, Pb, and Cu, while pakchoi accumulated the highest Hg and As. There was no significant difference of heavy metals between different sites. Washing vegetables prior to cooking reduced the health risk for heavy metals related to the consumption of vegetables. A health risk evaluation indicated that more than 55% of the Total Target Hazard Quotient (TTHQ) came from As, while the other elements contributed less than 1, indicating that the health risk from vegetable consumption was mainly caused by As. Children have higher health risks than adults when eating the same vegetables.