Tumor-derived exosomal ADAM17 promotes pre-metastatic niche formation by enhancing vascular permeability in colorectal cancer.

BACKGROUND: Hematological metastasis has been recognized as a crucial factor contributing to the high rates of metastasis and mortality observed in colorectal cancer (CRC). Notably, exosomes derived from cancer cells participate in the formation of CRC pre-metastatic niches; however, the mechanisms underlying their effects are largely unknown. While our preliminary research revealed the role of exosome-derived disintegrin and metalloproteinase 17 (ADAM17) in the early stages of CRC metastasis, the role of exosomal ADAM17 in CRC hematogenous metastasis remains unclear. METHODS: In the present study, we isolated and purified exosomes using ultracentrifugation and identified exosomal proteins through quantitative mass spectrometry. In vitro, co-culture assays were conducted to evaluate the impact of exosomal ADAM17 on the permeability of the blood vessel endothelium. Vascular endothelial cell resistance, the cell index, membrane protein separation, flow cytometry, and immunofluorescence were employed to investigate the mechanisms underlying exosomal ADAM17-induced vascular permeability. Additionally, a mouse model was established to elucidate the role of exosomal ADAM17 in the modulation of blood vessel permeability and pre-metastatic niche formation in vivo. RESULTS: Our clinical data indicated that ADAM17 derived from the circulating exosomes of patients with CRC could serve as a blood-based biomarker for predicting metastasis. The CRC-derived exosomal ADAM17 targeted vascular endothelial cells, thus enhancing vascular permeability by influencing vascular endothelial cadherin cell membrane localization. Moreover, exosomal ADAM17 mediated the formation of a pre-metastatic niche in nude mice by inducing vascular leakage, thereby promoting CRC metastasis. Nonetheless, ADAM17 selective inhibitors effectively reduced CRC metastasis in vivo. CONCLUSIONS: Our results suggest that exosomal ADAM17 plays a pivotal role in the hematogenous metastasis of CRC. Thus, this protein may serve as a valuable blood-based biomarker and potential drug target for CRC metastasis intervention.

Microplastics exhibit lower carrying effects on the bioaccessibility and cytotoxicity of lead than montmorillonite clay particles.

Microplastics (MPs) in the environment are always colonized by microbes, which may have implications for carrying effect of pollutants and exposure risk in organisms. We present the crucial impacts and mechanisms of microbial colonization on the bioaccessibility and toxicity of Pb(II) loaded in disposable box-derived polypropylene (PP) and polystyrene (PS) MPs and montmorillonite (MMT) clay particles. After 45 d incubation, higher biomass measured by crystal violet staining were detected in MMT (1.23) than in PP and PS (0.400 and 0.721) indicating preferential colonization of microbes in clay particles. Microbial colonization further enhanced the sorption ability toward Pb(II), but inhibited the desorption and bioaccessibility of enriched Pb(II) in zebrafish and decreased the toxicity to gastric epithelial cells in an order of MMT > PS ≈ PP. The crucial effects were mainly because microbe-colonized substrates possessed higher oxygen functional groups and specific surface area and exhibited stronger interactions with Pb(II) and digestive component (i.e., pepsin) than pure substrates. This decreased the available soluble pepsin for complexing with sorbed Pb(II). The findings highlight the role of microbial colonization in modulating the exposure risks of artificial and natural substrate-associated pollutants and suggest that the risks of MPs may be overestimated compared to clay particles.

Release of millions of micro(nano)plastic fragments from photooxidation of disposable plastic boxes.

The widespread use of disposable plastic boxes is exacerbating the dangers of microplastics (MPs); however, little is known about the fragmentation behavior of MPs during aging. In this study, the dynamic evolution on the release of micro(nano)plastics and photoaging properties of two disposable plastic boxes (polypropylene (PP) and polystyrene (PS)) were investigated under light irradiation and mechanical abrasion. Results showed that the weight of PP and PS was decreased by 53 % and 100 %, respectively after 60 d of ultraviolet irradiation (UV60). Moreover, a large number of fragmented particles were produced from the combined light irradiation and abrasion, with 0.142 ± 0.006 and 0.141 ± 0.013 million micro(nano)plastics/mL particles from PP and PS boxes, respectively, and the nanometer range (<100 nm) accounted for 70.8 % and 46.8 %. The correlation model of the average size or alteration time versus carbonyl index (CI) was developed, which indicated that the fragmentation behavior was mainly related to the photooxidation, though mechanical abrasion also played a certain enhancing role. Additionally, PS was susceptible to the fragmentation and photooxidation compared to PP possibly since the phenyl ring of PS was more vulnerable to UV attack than the methyl of PP. The findings of this study clarify the dynamic fragmentation process of micro(nano)plastics of disposable plastic boxes and provide useful information to access environmental fate of MPs more holistically.

Photochlorination-induced degradation of microplastics and interaction with Cr(VI) and amlodipine.

Wastewater treatment plants (WWTPs) are the important source of microplastics (MPs) in the environment, and disinfection processes bear high potential to degrade MPs. This study investigated the physicochemical degradation, dissolved organic products and interaction with co-existed pollutants (heavy metal and pharmaceutical) on polyethylene (PE), polypropylene (PP) and polystyrene (PS) MPs during simulated disinfection processes. Compared to photo or chlorination, photochlorination significantly resulted in the physicochemical degradation, including morphology alteration, fragmentation, and chemical oxidation on PP and PS MPs, but showed relatively low effect on PE, indicating the different resistance among polymers to disinfected treatment. Photochlorination also caused the formation of chain-scission organic compounds and even chlorinated products from MPs (e.g. C11H19O4Cl for PP and monochlorophenol, dichlorophenol, chloroacetophenone and chlorobenzoic acid for PS), which may form disinfection byproducts to induce healthy risk. The adsorption potentials of MPs for Cr(VI) or amlodipine were enhanced by photochlorination since the cracking and formed oxygen functional groups enhanced the pore filling and surface precipitation of Cr(VI), and the electrostatic attraction and hydrogen bonding with amlodipine. The findings indicated the physicochemical degradation of MPs and the combined pollution with co-existed pollutants, highlighting the health risks of MP-derived organic products during the disinfection treatments (even in normal dosage) in WWTPs.

Exosome-Derived ADAM17 Promotes Liver Metastasis in Colorectal Cancer.

Exosomes derived from cancer cells are deemed important drivers of pre-metastatic niche formation at distant organs, but the underlying mechanisms of their effects remain largely unknow. Although the role of ADAM17 in cancer cells has been well studied, the secreted ADAM17 effects transported via exosomes are less understood. Herein, we show that the level of exosome-derived ADAM17 is elevated in the serum of patients with metastatic colorectal cancer as well as in metastatic colorectal cancer cells. Furthermore, exosomal ADAM17 was shown to promote the migratory ability of colorectal cancer cells by cleaving the E-cadherin junction. Moreover, exosomal ADAM17 overexpression as well as RNA interference results highlighted its function as a tumor metastasis-promoting factor in colorectal cancer in vitro and in vivo. Taken together, our current work suggests that exosomal ADAM17 is involved in pre-metastatic niche formation and may be utilized as a blood-based biomarker of colorectal cancer metastasis.