Recurrence rates of diabetic foot ulcers vary widely in the published literature. The aim of this systematic review is to estimate recurrence rates of diabetic foot ulcers. We did a PubMed search and ...performed a review of reference lists for studies reporting recurrence of diabetic foot ulcers. The weighted relative risk (RR) and corresponding 95% confidence interval (CI) for recurrence was estimated. Forty‐nine studies reporting recurrence of diabetic foot ulcers were included. A pooled estimate for recurrence rate was 22.1% per person‐year (py) (95% CI, 19.0‐25.2%). Recurrence rate was 24.9% per py in Europe (95% CI, 20.0%‐29.7%), 17.8% per py in North America (95% CI, 12.7%‐22.9%), 16.9% per py in Africa (95% CI, 4.7%‐29.0%), and 17.0% per py in Asia (95% CI, 11.1%‐23.0%). Turkey had the highest recurrence rate of 44.4% per py (95% CI, 24.9%‐63.9%), and Bangladesh had the lowest of 4.3% per py (95% CI, 2.3%‐6.3%). Recurrence rates of diabetic foot ulcers before 2002, between 2002 and 2008, and after 2008 were 22.2% per py (95% CI, 17.6%‐26.8%), 21.9% per py (95% CI, 17.0%‐26.8%), and 21.8% per py (95% CI, 16.3%‐27.2%), respectively. Recurrence rates of diabetic foot ulcers are high. Recurrence rates vary widely in different regions and have decreased recently. More attention towards recurrence of diabetic foot ulcers is urgently required.
Esophageal squamous cell carcinoma (ESCC) is among the most common malignancies, but little is known about its spatial intratumoral heterogeneity (ITH) and temporal clonal evolutionary processes. To ...address this, we performed multiregion whole-exome sequencing on 51 tumor regions from 13 ESCC cases and multiregion global methylation profiling for 3 of these 13 cases. We found an average of 35.8% heterogeneous somatic mutations with strong evidence of ITH. Half of the driver mutations located on the branches of tumor phylogenetic trees targeted oncogenes, including PIK3CA, NFE2L2 and MTOR, among others. By contrast, the majority of truncal and clonal driver mutations occurred in tumor-suppressor genes, including TP53, KMT2D and ZNF750, among others. Interestingly, phyloepigenetic trees robustly recapitulated the topological structures of the phylogenetic trees, indicating a possible relationship between genetic and epigenetic alterations. Our integrated investigations of spatial ITH and clonal evolution provide an important molecular foundation for enhanced understanding of tumorigenesis and progression in ESCC.
Radiotherapy is one of the standard therapies for esophageal squamous cell carcinoma (ESCC), but the efficacy is far from desirable. Large scale genome sequencing reveals PI3Kα is frequently ...hyper-activated in ESCC. We found that ESCC cells harboring alterations in PI3K pathway were more resistant to radiation and combination of a clinical PI3Kα-selective inhibitor CYH33 and radiation synergistically inhibited cell proliferation in 14 ESCC cell lines. Radiation induced phosphorylation of FOXO1 and Akt, which sensitized ESCC cells to PI3Kα inhibitors. Both S1PR3 and DNA-PK contributed to radiation-induced Akt phosphorylation, which were revealed to be collectively dependent on PI3Kα. By contrast, constitutively active Akt abrogated the synergism between PI3Kα inhibitors and radiation. PI3Kα inhibition enhanced radiation-induced DNA damage, G2/M arrest and apoptosis. Combination of CYH33 and radiation significantly inhibited the growth of xenografts derived from ESCC patients, which was accompanied with abrogation of radiation-induced phosphorylation of Akt and filtration of M2-like macrophages. Taken together, combination of CYH33 and radiation possesses synergism in ESCC, which provides promising rationale to test this combinatorial regimen in ESCC patients.
•ESCC cells harboring alterations in PI3K pathway were more resistant to radiation.•Combination of radiation and PI3Kα inhibitors displayed synergistic activity against ESCC cells and PDXs.•The synergism was associated with abrogation of pro-survival signals in tumor cells and tumor-associated macrophages.
Esophageal squamous cell carcinoma (ESCC) is a common cancer with poor prognosis. In order to identify useful biomarkers for accurately classifying prognostic risks for ESCC patients, we examined the ...expression of six proteins by immunohistochemistry (IHC) in 590 paraffin-embedded ESCC samples. The candidate proteins include p53, EGFR, c-KIT, TIMP1 and PI3K-p110α reported to be altered in ESCC tissues as well as another important component of PI3K, PI3K-p85α. Of the six proteins tested, p53, EGFR, c-KIT, TIMP1 and PI3K-p85α were detected with high expression in 43.0%, 36.6%, 55.9%, 70.7% and 57.1% of tumors, respectively. Significant associations were found between high expression of PI3K-p85α, EGFR and p53 and poor prognosis (P = 0.00111; 0.00001; 0.00426). Applying these three proteins as an IHC panel could divide patients into different subgroups (P<0.000001). Multivariate cox regression analysis indicated that the three-protein panel was an independent prognostic factor with very high statistical significance (HR = 2.090, 95% CI: 1.621-2.696, P = 0.00000001). The data suggest that the three-protein panel of PI3K-p85α, EGFR and p53 is an important candidate biomarker for the prognosis of patients with ESCC.
We previously revealed that the calreticulin (CRT) gene is a candidate oncogene promoting cell migration and invasion and that neuropilin-1 (NRP1) is a possible effector downstream of CRT in ...esophageal squamous carcinoma cells. This study aims to explore the mechanisms underlying the migration and invasion of esophageal cancer cells regulated by CRT through NRP1.
Quantitative reverse-transcription polymerase chain reaction, Western blot analysis, chromatin immunoprecipitation, and reporter gene assays were used to investigate the relationship between CRT and NRP1. In vitro and in vivo assays were carried out to evaluate the effects of NRP1 on malignant phenotypes of ESCC cells and tumor metastasis in NOD/SCID mice. Immunohistochemistry was performed to analyze the expression of CRT and NRP1 in esophageal squamous cell carcinomas (ESCC).
Knockdown of CRT decreased the expression of NRP1. Inhibition of NRP1 reduced ESCC cell motility in vitro and experimental metastasis in vivo. Ectopic expression of NRP1 rescued the defects of cell migration and invasion in CRT-shRNA cells. CRT depletion inhibited STAT5A phosphorylation at the Y694 site via a CaMKII-independent pathway. Moreover, STAT5A directly regulated NRP1 transcription. Knockdown of CRT or NRP1 led to a downregulation of MMP2, MMP9, and FAK. Notably, positive correlation was found between CRT and NRP1 expression in ESCC tissues (P = 5.87 × 10(-5)). CRT and NRP1 coexpression was significantly associated with lymph node metastasis (P = 0.025).
Our findings suggest that NRP1 is a critical downstream effector of CRT in promoting cell migration and invasion, which might contribute to the metastasis of ESCC.
Our aim was to identify frequent genomic aberrations in both esophageal squamous cell carcinoma (ESCC) and esophageal dysplasia and to discover important copy number-driving genes and microRNAs ...(miRNA) in ESCC.
We conducted array-based comparative genomic hybridization (array CGH) on 59 ESCC resection samples and 16 dysplasia biopsy samples. Expression of genes at 11q13.3 was analyzed by real-time PCR (RT-PCR) and immunohistochemistry (IHC). Integrated analysis was conducted to identify genes or miRNAs with copy number-expression correlations.
Array CGH identified 11 amplifications and eight homozygous deletions in ESCC. Integrated analysis of array CGH data with matched gene expression microarray data showed that 90 overexpressed genes and 24 underexpressed genes were consistent with DNA copy number changes, including 12 copy number-driving miRNAs. In esophageal dysplasia, six gains, four losses, 12 amplifications, and four homozygous deletions were detected. Amplifications of 7p11.2 and 11q13.2-11q13.3 (CCND1) and homozygous deletion at 9p21.3 (CDKN2A) were consistent genomic changes in both dysplasia and carcinoma. ANO1 at 11q13.3 was overexpressed at the mRNA and protein levels in tumors, and higher mRNA expression was correlated with the copy number increase. In particular, ANO1 expression was elevated in moderate dysplasia compared with normal esophageal epithelium. IHC revealed that ANO1 overexpression was positively correlated with lymph node metastasis and advanced clinical stage. Knockdown of ANO1 significantly inhibited the proliferation of KYSE30 and KYSE510 cells.
Copy number aberrations in both esophageal dysplasia and ESCC may be useful as potential biomarkers for early detection. In addition, ANO1 may be a candidate target gene in esophageal tumorigenesis.
Background & Aims Aberrant activation of the signal transducer and activator of transcription (Stat)3 and overexpression of polo-like kinase (PLK)1 each have been associated with cancer pathogenesis. ...The mechanisms and significance of dysregulation of Stat3 and PLK1 in carcinogenesis and cancer progression are unclear. We investigated the relationship between Stat3 and PLK1 and the effects of their dysregulation in esophageal squamous cell carcinoma (ESCC) cells. Methods We used immunoblot, quantitative reverse-transcription polymerase chain reaction, immunochemistry, chromatin immunoprecipitation, mobility shift, and reporter assays to investigate the relationship between Stat3 and PLK1. We used colony formation, fluorescence-activated cell sorting, terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling, and xenograft tumor assays to determine the effects of increased activation of Stat3 and PLK1 in proliferation and survival of ESCC cells. Results Stat3 directly activated transcription of PLK1 in esophageal cancer cells and mouse embryonic fibroblast cell NIH3T3. PLK1 then potentiated the expression of Stat3; β-catenin was involved in PLK1-dependent transcriptional activation of Stat3 . This mutual regulation between Stat3 and PLK1 was required for proliferation of esophageal cancer cells and resistance to apoptosis in culture and as tumor xenografts in mice. Furthermore, phosphorylation of Stat3 and overexpression of PLK1 were correlated in a subset of ESCC. Conclusions Stat3 and PLK1 control each other's transcription in a positive feedback loop that contributes to the development of ESCC. Increased activity of Stat3 and overexpression of PLK1 promote survival and proliferation of ESCC cells in culture and in mice.
Metastasis is the most pivotal cause of mortality in cancer patients. Immune tolerance plays a crucial role in tumor progression and metastasis.
In this study, we investigated the potential roles and ...mechanisms of TLR2 signaling on tumor metastasis in a mouse model of intravenously injected B16 melanoma cells. Multiple subtypes of TLRs were expressed on B16 cells and several human cancer cell lines; TLR2 mediated the invasive activity of these cells. High metastatic B16 cells released more heat shock protein 60 than poor metastatic B16-F1 cells. Importantly, heat shock protein 60 released by tumor cells caused a persistent activation of TLR2 and was critical in the constitutive activation of transcription factor Stat3, leading to the release of immunosuppressive cytokines and chemokines. Moreover, targeting TLR2 markedly reduced pulmonary metastases and increased the survival of B16-bearing mice by reversing B16 cells induced immunosuppressive microenvironment and restoring tumor-killing cells such as CD8(+) T cells and M1 macrophages. Combining an anti-TLR2 antibody and a cytotoxic agent, gemcitabine, provided a further improvement in the survival of tumor-bearing mice.
Our results demonstrate that TLR2 is an attractive target against metastasis and that targeting immunosuppressive microenvironment using anti-TLR2 antibody is a novel therapeutic strategy for combating a life-threatening metastasis.
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