Cancer‐associated fibroblasts (CAFs) are “activated” fibroblasts in the tumor microenvironment (TME) and play a vital role in all steps of cancer development. Increasing evidence focusing on the function of CAFs suggests that CAFs are candidate therapeutic targets and that drugs targeting the modification of CAFs would suppress tumor progression and be beneficial to tumor treatment and prevention. In the present study, we found that curcumin reversed the phenotype of CAFs to that of peri‐tumor fibroblast (PTF)‐like cells by downregulating the expression of α‐SMA (a special marker for CAFs) and inhibiting the secretion of pro‐carcinogenic cytokines, including transforming growth factor‐β1 (TGF‐β1), matrix metalloproteinases 2 (MMP2), and stromal cell‐derived factor‐1 (SDF‐1). We further demonstrated that the conditioned medium (CM) derived from CAFs promoted the proliferation of Cal27, and this effect was confirmed by the xenograft model. More importantly, we found that curcumin blocked the CAF‐mediated enhancement of Cal27 proliferation in vitro and in vivo. In conclusion, our data suggest that curcumin reverses cell phenotype from CAF to PTF‐like cells and suppresses the CAF‐mediated proliferation and tumorigenicity of Cal27 by inhibiting TSCC CAFs.
The extracellular signal-regulated protein kinase 1/2 (Erk1/2) and p38 mitogen-activated protein-kinase pathways serve important roles in the regulation of osteogenic and chondrogenic differentiation in mesenchymal stem cells (MSCs). However, the exact mechanism remains unclear, and the effect is controversial. In the present study, the effects of Erk1/2 and p38 on the osteogenic and chondrogenic differentiation of dental pulp stem cells (DPSCs) were compared in vitro. The results indicated that inhibition of Erk1/2 is able to enhance the osteogenic differentiation of DPSCs and inhibit chondrogenic differentiation, whereas inhibition of p38 demonstrated the opposite effect. When compared with previous studies, the present study further confirmed that Erk1/2 and p38 serve important, but complicated, roles in regulating the differentiation of MSCs. Different chemical and physical stimuli, cell types, culture methods, times of inhibitor administration and the dosage of the inhibitor may influence the effect of Erk1/2 and p38 on the differentiation of MSCs. The present study aims to better understand the mechanisms that control the differentiation of MSCs and may be helpful in creating more effective tissue regeneration.
Preosteoblasts can indirectly enhance the osteoblastic/cementoblastic differentiation and mineralization of PDLSCs with an optimal preosteoblasts:PDLSCs ratio in the range of 2:1 to 1:1.
Objective The growth factor progranulin (PGRN) is widely expressed and plays important roles in anti-inflammatory signaling and bone regeneration. However, the anti-inflammatory and pro-osteogenic roles of PGRN in periodontitis are seldom studied. We used an in vitro model to investigate whether PGRN can promote osteogenic differentiation of periodontal ligament stem cells (PDLSCs). Methods PDLSCs were treated with PGRN (0 to 100 ng/mL) and the optimal concentrations required to induce proliferation and osteogenesis were identified. PDLSCs were cultured with 10 ng/mL tumor necrosis factor (TNF)-α, 25 ng/mL PGRN, or 10 ng/mL TNF-α + 25 ng/ml PGRN; untreated PDLSCs were used as controls. The effects of PGRN on PDLSC proliferation and osteogenic differentiation were assessed. Results PGRN (5, 25, and 50 ng/mL) promoted PDLSC proliferation and osteogenic differentiation, with the 25-ng/mL dose showing the largest effect. Furthermore, 25 ng/mL PGRN reversed inhibition of osteogenic differentiation by TNF-α. Conclusion PGRN promotes PDLSC proliferation, osteogenic differentiation, and mineralization in both inflammatory and non-inflammatory conditions. The 25-ng/mL PRGN dose was the most suitable for inducing proliferation and osteogenesis. Further studies using animal models will be required to obtain pre-clinical evidence to support using PGRN as a treatment for periodontitis.
The aim of the present study was to investigate the differential biological characteristics between cancer-associated fibroblasts (CAFs) and peri-tumor fibroblasts (PTFs) in tongue squamous cell carcinoma (TSCC). The primary CAFs and PTFs from TSCC were obtained and purified. Cell morphology was observed, and the expression of α-smooth muscle actin (α-SMA), vimentin and cytokeratin 19 (CK19) was detected by immunohistochemistry (IHC). The percentage of α-SMA positive cells in CAFs and PTFs was calculated separately, and α-SMA expression was further confirmed by western blot analysis. Cell viability and the expression of matrix metalloproteinase 2 (MMP2), stromal cell derived factor1 (SDF-1) and transforming growth factor β1 (TGFβ1) in the purified fibroblasts was detected separately. CAFs and PTFs were attained and purified. Compared with PTFs, CAFs were long-fusiform shaped cells with reduced cytoplasm and variable size. CAFs crowded together in a disorderly manner when the cell density was increased, but this phenomenon did not occur with PTFs. IHC results verified that there was no significant difference between CAFs and PTFs in the percentage of cells staining positive for CK19 and vimentin (P>0.05); the percentage of positive staining cells for α-SMA in CAFs was significantly higher compared with that in PTFs (P<0.001) Western blot analysis showed that α-SMA expression in CAFs was 4.3-fold higher compared with that in PTFs (P<0.001). A Cell Counting Kit-8 assay indicated that the viability of CAFs increased significantly compared with that in the PTFs (P<0.05). Reverse transcription-quantitative polymerase chain reaction and ELISA analysis showed that the expression of MMP2, SDF-1 and TGF β1 in CAFs was higher compared with that in PTFs (P<0.05). CAFs are distinguishable from PTFs with respect to their morphology, cellular phenotype, cell viability and pro-carcinogenic cytokine expression.
Background This study aimed to investigate the expression of neuritin in four common cancers, and to explore the association between neuritin expression and the occurrence and development of cancer. Methods We initially examined neuritin expression in human cervical, endometrial, oesophageal, and lung cancer tissues by immunohistochemistry (IHC). Based on these results, we further examined its expression in lung squamous cell carcinoma (LUSC) tissues by IHC and reverse transcription-polymerase chain reaction (RT-PCR). Results Neuritin expression levels were higher in all cancer tissues compared with normal control tissues. Neuritin protein and gene expression levels were significantly higher in LUSC tissues compared with normal lung tissues (P<0.001), according to IHC and RT-PCR, respectively. Neuritin expression levels decreased significantly with increased clinical TNM stage (I-IV) and distant metastasis (P<0.05). Conclusion Neuritin may have clinical value as a novel diagnostic and prognostic marker in patients with LUSC.
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