No abstract

Recent studies have shown that three-dimensional (3D) culture environments allow the study of cellular responses in a setting that more closely resembles the in vivo milieu. In this context, hydrogels have become popular scaffold options for the 3D cell culture. Because the mechanical and biochemical properties of culture matrixes influence crucial cell behavior, selecting a suitable matrix for replicating in vivo cellular phenotype in vitro is essential for understanding disease progression. Gelatin methacrylate (GelMA) hydrogels have been the focus of much attention because of their inherent bioactivity, favorable hydration and diffusion properties, and ease-of-tailoring of their physicochemical characteristics. Therefore, in this study we examined the efficacy of GelMA hydrogels as a suitable platform to model specific attributes of breast cancer. We observed increased invasiveness in vitro and increased tumorigenic ability in vivo in breast cancer cells cultured on GelMA hydrogels. Further, cells cultured on GelMA matrixes were more resistant to paclitaxel treatment, as shown by the results of cell-cycle analysis and gene expression. This study, therefore, validates GelMA hydrogels as inexpensive, cell-responsive 3D platforms for modeling key characteristics associated with breast cancer metastasis, in vitro.

The activity of the nuclear factor-Y (NF-Y) transcription factor is restricted to proliferating cells in vitro. We engineered transgenic mice that enabled bioluminescence imaging of NF-Y activity in every area of the body. We visualized areas of proliferation, and we highlight for the first time a role of NF-Y activity in hepatocyte proliferation during liver regeneration.

Chemoresistance leading to disease relapse is one of the major challenges to improve outcome in head and neck cancers. Cancer Stem Cells (CSCs) are increasingly being implicated in chemotherapy resistance, this study investigates the correlation between CSC behavior and acquired drug resistance in in vitro cell line models. Cell lines resistant to Cisplatin (Cal‐27 CisR, Hep‐2 CisR) and 5FU (Cal‐27 5FUR) with high Resistance Indices (RI) were generated (RI ≥ 3) by short‐term treatment of head and neck squamous cell carcinoma (HNSCC) cell lines with chemotherapeutic drugs (Cisplatin, Docetaxel, 5FU), using a dose‐incremental strategy. The cell lines (Cal‐27 DoxR, Hep‐2 DoxR, Hep‐2 5FUR) that showed low RI, nevertheless had a high cross resistance to Cisplatin/5FU (P < 0.05). Cal‐27 CisR and DoxR showed 12–14% enrichment of CD44+ cells, while CisR/5FUR showed 4–6% increase in ALDH1A1+ cells as compared to parental cells (P < 0.05). Increased expression of stem cell markers (CD44, CD133, NOTCH1, ALDH1A1, OCT4, SOX2) in these cell lines, correlated with enhanced spheroid/colony formation, migratory potential, and increased in vivo tumor burden (P < 0.05). Inhibition of ALDH1A1 in Cal‐27 CisR led to down regulation of the CSC markers, reduction in migratory, self‐renewal and tumorigenic potential (P < 0.05) accompanied by an induction of sensitivity to Cisplatin (P < 0.05). Further, ex vivo treatment of explants (n = 4) from HNSCC patients with the inhibitor (NCT‐501) in combination with Cisplatin showed a significant decrease in proliferating cells as compared to individual treatment (P = 0.001). This study hence suggests an ALDH1A1‐driven, CSC‐mediated mechanism in acquired drug resistance of HNSCC, which may have therapeutic implications. © 2016 Wiley Periodicals, Inc.

EGCG (Epigallocatechin-3-gallate) is the major active principle catechin found in green tea. Skepticism regarding the safety of consuming EGCG is gaining attention, despite the fact that it is widely being touted for its potential health benefits, including anti-cancer properties. The lack of scientific data on safe dose levels of pure EGCG is of concern, while EGCG has been commonly studied as a component of GTE (Green tea extract) and not as a single active constituent. This study has been carried out to estimate the maximum tolerated non-toxic dose of pure EGCG and to identify the treatment related risk factors. In a fourteen day consecutive treatment, two different administration modalities were compared, offering an improved [i.p (intraperitoneal)] and limited [p.o (oral)] bioavailability. A trend of dose and route dependant hepatotoxicity was observed particularly with i.p treatment and EGCG increased serum lipid profile in parallel to hepatotoxicity. Fourteen day tolerable dose of EGCG was established as 21.1 mg/kg for i.p and 67.8 mg/kg for p.o. We also observed that, EGCG induced effects by both treatment routes are reversible, subsequent to an observation period for further fourteen days after cessation of treatment. It was demonstrated that the severity of EGCG induced toxicity appears to be a function of dose, route of administration and period of treatment.