Predicting the effects of radiotherapy based on diffusion kurtosis imaging in a xenograft mouse model of esophageal carcinoma.

The aim of the present study was to assess the predictive value of diffusion kurtosis imaging (DKI) on the effects of radiotherapy in a xenograft model of esophageal cancer. A total of 40 tumor-bearing mice, established by injection of Eca-109 cells in nude mice, were used. The experimental group (n=24) received a single dose of 15 Gy (6 MV by X-ray), and the control group (n=16) did not receive any treatment. Tumor volume, apparent diffusion coefficient (ADC), mean kurtosis (MK) and mean diffusivity (MD) of the two groups were compared, and the expression of aquaporin (AQP) 3 and necrosis ratio at matched time points in xenografts were also observed. There was a significant difference between the two groups from the 7th day of radiotherapy onwards; the xenograft volume of the experimental group was significantly smaller compared with the control group (P<0.05). On the 3rd day, the ADC and MD of the experimental group was significantly higher compared with the control group, and MK was significantly lower compared with the control group (P<0.05). On the 3rd day, AQP3 expression in the experimental group was lower compared with the control group, and the proportion of necrotic cells was higher compared with the control group (P<0.05). Single large fraction dose radiotherapy inhibited the growth of a xenografted esophageal tumor. Changes in ADC, MK and MD were observed prior to morphological changes in the tumor. The change in AQP3 expression and necrosis ratio was in also agreement with the DKI parameters assessed. DKI may thus provide early predictive ability on the effect of radiotherapy in esophageal carcinoma.

Survival Comparision of Three-dimensional Radiotherapy Alone vs. Chemoradiotherapy for Esophageal Squamous Cell Carcinoma.

BACKGROUND AND OBJECTIVE: To compare the survival of esophageal squamous cell carcinoma (ESCC) patients who received chemoradiotherapy (CRT) or radiotherapy (RT) alone. METHODS: A total of 753 well-matched patients were enrolled. A total of 299 patients were treated with CRT, and 454 patients were treated with RT alone. Propensity score matching (PSM) was performed with the R project. The Kaplan-Meier method was used to calculate survival rates, and the log-rank test was used to assess differences in survival. RESULTS: The response rate was 99.0% with CRT and 98.3% with RT alone (p = 0.651). The 1-, 3-, 5- and 10 year overall survival (OS) rates were as follows: 72.2, 40.1, 30.7 and 13.9% with CRT, 68.1, 35.2%, 23.3 and 12.5% with RT alone (p = 0.033); 73.4, 40.1, 31.0 and 16.1% with concurrent chemoradiotherapy (CCRT); and 68.1, 35.2, 23.3 and 12.5% with RT alone (p = 0.028). There was no significant difference in OS between the CCRT group and the sequential chemoradiotherapy (SCRT) group (p = 0.527). Consolidation chemotherapy (CCT) after CCRT led to a significant increase in the OS rate compared with no CCT after CCRT (p = 0.003). Compared with the OS of patients who received 1∼2 cycles of CCT, the OS of patients who received 3∼4 cycles of CCT was significantly improved (p = 0.011). Acute toxic effects were more severe in the CRT, but no significant differences in late reactions. CRT exhibited more appetite loss and fatigue symptoms than RT alone, and dysphagia of CRT relief more obviously. The CRT group had a significantly lower rate of local control failure than the RT alone group (p = 0.019). CONCLUSIONS: For patients with ESCC, CRT led to a significantly improved OS compared to RT alone, and this trend was more obvious with CCRT. CCT after CCRT prolonged OS, especially in patients who received at least 2 cycles of CCT. CRT can reduce the deaths due to local control failure compared to RT alone.

TAp63-Regulated miRNAs Suppress Cutaneous Squamous Cell Carcinoma through Inhibition of a Network of Cell-Cycle Genes.

TAp63 is a p53 family member and potent tumor and metastasis suppressor. Here, we show that TAp63-/- mice exhibit an increased susceptibility to ultraviolet radiation-induced cutaneous squamous cell carcinoma (cuSCC). A human-to-mouse comparison of cuSCC tumors identified miR-30c-2* and miR-497 as underexpressed in TAp63-deficient cuSCC. Reintroduction of these miRNAs significantly inhibited the growth of cuSCC cell lines and tumors. Proteomic profiling of cells expressing either miRNA showed downregulation of cell-cycle progression and mitosis-associated proteins. A mouse to human and cross-platform comparison of RNA-sequencing and proteomics data identified a 7-gene signature, including AURKA, KIF18B, PKMYT1, and ORC1, which were overexpressed in cuSCC. Knockdown of these factors in cuSCC cell lines suppressed tumor cell proliferation and induced apoptosis. In addition, selective inhibition of AURKA suppressed cuSCC cell proliferation, induced apoptosis, and showed antitumor effects in vivo. Finally, treatment with miR-30c-2* or miR-497 miRNA mimics was highly effective in suppressing cuSCC growth in vivo. Our data establish TAp63 as an essential regulator of novel miRNAs that can be therapeutically targeted for potent suppression of cuSCC. SIGNIFICANCE: This study provides preclinical evidence for the use of miR-30c-2*/miR-497 delivery and AURKA inhibition in the treatment of cuSCC, which currently has no FDA-approved targeted therapies.See related commentary by Parrales and Iwakuma, p. 2439.

Mitotic deregulation by survivin in ErbB2-overexpressing breast cancer cells contributes to Taxol resistance.

PURPOSE: Taxol resistance remains a major obstacle to improve the benefit of breast cancer patients. Here, we studied whether overexpression of ErbB2 may lead to mitotic deregulation in breast cancer cells via up-regulation of survivin that confers Taxol resistance. EXPERIMENTAL DESIGN: ErbB2-overexpressing and ErbB2-low-expressing breast cancer cell lines were used to compare their mitotic exit rate, survivin expression level, and apoptosis level in response to Taxol. Survivin was then down-regulated by antisense oligonucleotides to evaluate its contribution to mitotic exit and Taxol resistance in ErbB2-overexpressing breast cancer cells. At last, specific PI3K/Akt and Src inhibitors were used to investigate the involvement of these two pathways in ErbB2-mediated survivin up-regulation and Taxol resistance. RESULTS: We found that ErbB2-overexpressing cells expressed higher levels of survivin in multiple breast cancer cell lines and patient samples. ErbB2-overexpressing cells exited M phase faster than ErbB2-low-expressing cells, which correlated with the increased resistance to Taxol-induced apoptosis. Down-regulation of survivin by antisense oligonucleotide delayed mitotic exit of ErbB2-overexpressing cells and also sensitized ErbB2-overexpressing cells to Taxol-induced apoptosis. Moreover, ErbB2 up-regulated survivin at translational level and PI3K/Akt and Src activation are involved. In addition, combination treatment of Taxol with PI3K/Akt and Src inhibitor led to increased apoptosis in ErbB2-overexpressing breast cancer cells than single treatment. CONCLUSIONS: Survivin up-regulation by ErbB2 is a critical event in ErbB2-mediated faster mitotic exit and contributes to Taxol resistance.